One-pot synthesis and in silico ADME profiling of 1,4-dihydropyridine derivatives catalyzed by ProMSA ionic liquid under solvent-free conditions

One-pot synthesis and in silico ADME profiling of 1,4-dihydropyridine derivatives catalyzed by ProMSA ionic liquid under solvent-free conditions | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article One-pot synthesis and in silico ADME profiling of 1,4-dihydropyridine derivatives catalyzed by ProMSA ionic liquid under solvent-free conditions Nitin Rode, Kishor Kale, Santosh Terdale This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8939554/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract An efficient and convenient method has been developed for the one-pot, four-component synthesis of 1,4-dihydropyridine derivatives. The protocol involves the reaction of aromatic aldehydes, β-keto esters, and ammonium acetate catalyzed by ProMSA, a Brønsted acidic amino acid ionic liquid (AAIL), under solvent-free conditions. This methodology offers several advantages, including the use of an inexpensive, easily prepared, and recyclable catalyst; a simple experimental procedure; and a green and safer reaction profile. The desired products were obtained in excellent yields with high purity following a straightforward workup and within short reaction times. Furthermore, in silico ADME study of all synthesized compounds was conducted. The results indicate that all derivatives obey Lipinski's rule of five, as well as the Ghose filter, Egan, and Muegge rules, suggesting favorable physicochemical properties, good oral bioavailability potential, and suitability for advanced pharmacokinetic investigations. Amino acid ionic liquid dihydropyridine ADME study pharmacokinetic study Figures Figure 1 Figure 2 Introduction The six-membered heterocyclic ring system containing a nitrogen atom at the 1-position, which is saturated at the 1 and 4 positions, is known as 1,4-dihydropyridine (1,4-DHP). This scaffold was first synthesized by Arthur Hantzsch in 1881 via a pioneering multicomponent reaction (MCR) [ 1 ]. The classical Hantzsch synthesis involves the one-pot condensation of a β-keto ester (a 1,3-dicarbonyl compound), an aromatic aldehyde, and ammonia or an ammonium salt to afford 1,4-dihydropyridine derivatives, commonly referred to as Hantzsch esters [ 2 ]. The stability of these compounds is significantly enhanced when the 3 and 5 positions are substituted with electron-withdrawing groups such as cyano (CN), carbonyl (COR), or ester (COOR) functionalities [ 3 ]. Nitrogen-containing heterocycles, particularly the 1,4-DHP scaffold, are frequently found in biologically and medicinally active compounds [ 4 – 6 ]. They are widely recognized for their therapeutic applications, most notably as calcium channel blockers (e.g., nifedipine, amlodipine, felodipine, Fig. 1 ). Additionally, they exhibit a broad spectrum of pharmacological activities, including anticonvulsant, antitumor, analgesic, and anti-inflammatory effects, and are extensively used in the treatment of cardiovascular diseases [ 7 – 11 ]. To improve the productivity of 1, 4-dihydropyridines synthesis, different catalyst have been used such as HY-Zeolite [ 13 ], ceric ammonium nitrate [ 14 ], Montmorillonite K10 [ 15 ], FeF 3 [ 16 ], Triton X-100 in water [ 17 ], HPW/PEG-400 [ 18 ], N-(phenylsulfonyl)benzene sulfonamide [ 19 ], Acid catalyst such as alumina sulfuric acid (ASA) [ 11 ], organocatalyst-succinic acid [ 20 ], polyphosphoric acid (PPA)@NiO [ 21 ], borotungstic acid H 5 BW 12 O 40 [ 22 ], Polyvinylpolypyrrolidone supported chlorosulfonic acid [ 23 ], Phosphinic Acid on UiO‑66‑NH 2 [ 24 ], Ionic liquid catalyst likes tetrabutylammonium hydrogen sulfate (TBAHS) [ 25 ], Tetrabutylphosphonium Dichromate (TBPDC) (MW) [ 26 ], mild acidic ionic liquids such as N-methyl-2-pyrrolidoniumdihydrogen phosphate [NMP][H 2 PO 4 ] [ 27 ], ionic liquid sulfonic acid functionalized pyridinium chloride [ 28 ], Nanoparticle catalyst such as graphene oxide nano particles [ 29 ], nano-crystalline solid acid catalyst (nano-sulfated zirconia, nano-structured ZnO, nano-g-alumina and nano-ZSM-5 zeolites) [ 30 ], manganese ferrite nanoparticles (MnFe 2 O 4 ) [ 31 ], Cu immobilized on MgZnFe 2 O 4 nanoparticles [ 32 ], nano‑Fe 3 O 4 @dextrin/BF 3 [ 33 ], nano-sized Magnesia–Zirconia (nano-MgO–ZrO 2 ) catalyst [ 34 ], Fe 3 O 4 hybrid nanocatalyst [ 35 ], Copper(I) Iodide Nanoparticles [ 36 ], Magnetic nanoparticles likes hercynite@sulfuric acid nanomagnetic solid acid catalyst [ 37 ], {Fe 3 O4@SiO 2 @(CH2) 3 Im}C(NO 2 ) 3 magnetic nano particles [ 38 ], GO/Fe 3 O 4 /ZIF-67 magnetic nanocatalyst [ 39 ], Silica-Coated Magnetic NiFe 2 O 4 Nanoparticles [ 40 ], Magnetic MnFe 2 O 4 Nanoparticles [ 41 ], Magnetic Fe-C-O-Mo alloy nano-rods [ 42 ], MgFe 2 O 4 MNPs [ 43 ], Metal catalyst like Fe 3 O 4 @chitosan [ 44 ], AlCl 3 .6H 2 O [ 45 ], bismuth (III) chloride [ 46 ], PdRuNi@GO Catalyst [ 47 ], Aluminized polyborate‑catalysed [ 48 ], Mn(II) on Fe 3 O 4 @ Schiff base [ 49 ], MCM-41 supported cobalt (II) complex [ 50 ], TiCl 2 /Nano-γ-Al 2 O 3 [ 51 ], Mn-MOFs [ 52 ], Neat, ultrasound and microware assisted synthesis includes catalyst like visible light promoted Praseodymium Oxide (Pr 6 O 11 ) Seal Vessel [ 53 ], neat under solvent-free [ 54 ], ammonium bicarbonate (MW) [ 55 ], microwave assisted o -Iodoxybenzoic acid (IBX) [ 56 ], praseodymium oxide using visible light [ 57 ], Iodobenzene diacetate (III) by coventional heating, Ultrasound and MW [ 58 ], Ultrasound-assisted [ 59 ]. Some of the above methods for the synthesis of 1,4-dihydropyridines derivatives have one or more adverse points such as moisture sensitive, expensive reagents, tedious workup processes and harsh reaction conditions; thus, developing a proficient procedure with a potent catalyst for the synthesis of 1,4-dihydropyridine is still key importance. The physicochemical and pharmacokinetic properties of compounds were utilized to recognize the drug-likeness of compounds as a potential therapeutic drug candidate in an in silico ADME (absorption, distribution, metabolism, and excretion) study. Experimental General procedure for synthesis of 1, 4-dihydropyridine derivatives (5a-5g) A round-bottom flask was charged with aromatic aldehyde (10 mmol), ethyl or methyl acetoacetate (20 mmol), ammonium acetate (15 mmol), and the AAIL catalyst ProMSA (10 mol%). The reaction mixture was stirred at 100˚C for the appropriate time, and progress was monitored by TLC. Upon completion, the reaction mixture was cooled to room temperature, and ethanol (10 mL) was added. The mixture was stirred for 30 minutes to obtain the crude solid product. The solid was collected by filtration using Whatman filter paper, washed thoroughly with cold ethanol and hexane to remove traces of aldehyde, and recrystallized from ethanol if necessary. General procedure for synthesis of 1, 4-dihydropyridine derivatives (6a-6g) A round-bottom flask was charged with dimedone (10 mmol), aromatic aldehyde (10 mmol), ethyl or methyl acetoacetate (10 mmol), ammonium acetate (15 mmol), and the AAIL catalyst ProMSA (10 mol%). The reaction mixture was stirred at 100˚C for the appropriate time, and progress was monitored by TLC. Upon completion, the reaction mixture was cooled to room temperature, and ethanol (10 mL) was added. The mixture was stirred for 30 minutes to obtain the crude solid product. The solid was collected by filtration using Whatman filter paper, washed thoroughly with cold ethanol and hexane to remove traces of aldehyde, and recrystallized from ethanol if necessary. [5a] dimethyl 4-(4-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate [ 38 ] Colour : White, m.p. : 254–256 ˚ C % Yield : 88 1 H NMR (400 MHz, CDCl 3 ) δ 7.25–7.12 (m, 4H), 5.78 (d, J = 14.8 Hz, 1H), 5.05–4.92 (m, 1H), 3.73–3.57 (m, 6H), 2.42–2.29 (m, 6H). 13 C NMR (101 MHz, CDCl 3 ) δ 167.82, 145.97, 144.28, 131.82, 129.07, 128.13, 103.66, 51.03, 38.96, 19.59. FTIR Neat: cm − 1 : 3324, 2952, 1725, 1647, 1481, 1381, 1221, 1174, 1015, 857, 757. [5b] dimethyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate [ 54 ] Colour : White, m.p. : 124–126, % Yield : 90, 1 H NMR (400 MHz, CDCl 3 ) δ 8.28–7.86 (m, 2H), 7.76–7.50 (m, 1H), 7.50–7.21 (m, 1H), 6.04 (s, 1H), 5.30–4.96 (m, 1H), 3.84–3.45 (m, 6H), 2.61–2.16 (m, 6H). 13 C NMR (101 MHz, CDCl 3 ) δ 167.58, 149.59, 148.38, 145.09, 134.21, 128.74, 122.73, 121.42, 103.08, 51.15, 39.64, 19.57. FTIR Neat: cm − 1 : 3341, 2949, 1727, 1697, 1646, 1430, 1342, 1216, 1118, 1017, 836, 763. [5c] dimethyl 2,6-dimethyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylate [ 38 ] Colour : White, m.p. : 258–260 ˚ C % Yield : 87, 1 H NMR (400 MHz, CDCl 3 ) δ 7.44–6.95 (m, 6H), 5.83 (d, J = 46.3 Hz, 1H), 5.18–4.87 (m, 1H), 3.84–3.46 (m, 7H), 2.56–2.12 (m, 7H). 13 C NMR (101 MHz, CDCl 3 ) δ 168.11, 147.44, 144.34, 128.17, 128.04, 127.62, 126.21, 103.83, 77.38, 77.06, 76.74, 51.00, 39.29, 19.52, 17.07. FTIR Neat: cm − 1 : 3363, 2949, 1678, 1650, 1483, 1377, 1224, 1125, 1014, 841, 746. [5d] dimethyl 4-(4-methoxyphenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate [ 28 ] Colour : White, m.p. : 258–260 ˚ C % Yield : 85, 1 H NMR (400 MHz, CDCl 3 ) δ 7.25–7.14 (m, 2H), 6.87–6.65 (m, 2H), 5.95 (d, J = 13.4 Hz, 1H), 5.03–4.88 (m, 1H), 3.81–3.73 (m, 3H), 3.65 (d, J = 15.2 Hz, 6H), 2.40–2.25 (m, 6H). 13 C NMR (101 MHz, CDCl 3 ) δ 168.19, 157.96, 144.13, 140.00, 129.63, 128.60, 113.96, 113.41, 104.02, 55.34, 55.14, 50.99, 38.43, 19.50. FTIR Neat: cm − 1 : 3347, 2952, 1702, 1643, 1482, 1377, 1215, 1124, 1015, 827, 744. [5e] dimethyl 4-(4-hydroxyphenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate [ 38 ] Colour : White, m.p. : 300–302 ˚ C % Yield : 86, 1 H NMR (400 MHz, CDCl 3 ) δ 7.83 (s, 1H), 7.34–7.19 (m, 1H), 7.05 (d, J = 8.5 Hz, 2H), 6.68 (t, J = 17.0 Hz, 2H), 4.87 (s, 1H), 3.76–3.42 (m, 6H), 2.29 (s, 6H). 13 C NMR (101 MHz, CDCl 3 ) δ 168.33, 155.12, 144.45, 139.12, 128.56, 115.61, 114.91, 103.73, 50.80, 40.46, 40.26, 40.05, 39.84, 39.63, 38.25, 19.23. FTIR Neat: cm − 1 : 3353, 2954, 1730, 1683, 1646, 1482, 1378, 1213, 1097, 1023, 857, 752. [5f] diethyl 4-(4-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate [ 30 ] Colour : White, m.p. : 144–146 ˚ C % Yield : 91, 1 H NMR (400 MHz, CDCl 3 ) δ 7.39–7.00 (m, 4H), 5.86 (d, J = 91.4 Hz, 1H), 5.14–4.72 (m, 1H), 4.39–3.86 (m, 4H), 2.46–2.23 (m, 6H), 1.43–1.04 (m, 6H). 13 C NMR (101 MHz, CDCl 3 ) δ 167.54, 146.38, 144.20, 131.70, 129.41, 127.95, 103.77, 59.84, 39.26, 19.50, 14.27. FTIR Neat: cm − 1 : 3347, 2982, 1726, 1678, 1512, 1486, 1367, 1270, 1208, 1118, 1026, 858, 751, 692. [5g] diethyl 4-(4-hydroxy-3-methoxyphenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Colour : White, m.p. :188–190, % Yield : 88, 1 H NMR (400 MHz, CDCl 3 ) δ 6.98–6.67 (m, 6H), 5.82–5.33 (m, 4H), 5.09–4.83 (m, 2H), 4.29–3.93 (m, 8H), 3.96–3.71 (m, 6H), 2.48–2.19 (m, 11H), 1.34–1.14 (m, 11H). 3 C NMR (101 MHz, CDCl 3 ) δ 167.79, 145.75, 143.82, 143.57, 140.02, 120.49, 113.79, 110.83, 104.33, 59.72, 55.66, 39.15, 19.51, 14.51. FTIR Neat: cm − 1 : 3354, 2987, 1693, 1647, 1483, 1370, 1296, 1209, 1115, 1014, 826, 743, 694. [6a] methyl 4-(4-chlorophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate [ 16 ] Colour : White, m.p. : 218–220 ˚ C % Yield : 89, 1 H NMR (400 MHz, DMSO) δ 9.16 (s, 1H), 7.33–7.06 (m, 4H), 4.85 (s, 1H), 3.52 (s, 3H), 2.47–2.37 (m, 1H), 2.30 (s, 3H), 2.30–2.10 (m, 2H), 1.98 (d, J = 16.0 Hz, 1H), 1.00 (s, 3H), 0.82 (s, 3H). 13 C NMR (101 MHz, DMSO) δ 194.78, 167.62, 150.11, 146.88, 146.19, 130.71, 129.62, 128.27, 110.16, 103.24, 51.19, 50.63, 39.79, 35.85, 32.61, 29.55, 26.87, 18.79. FTIR Neat: cm − 1 : 3195, 2955, 1741, 1679, 1486, 1381, 1223, 1111, 1004, 885, 775. [6b] methyl 4-(4-hydroxy-3-methoxyphenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate Colour : White, m.p. : 274–276, % Yield : 88, 1 H NMR (400 MHz, DMSO) δ 8.81 (d, J = 171.0 Hz, 2H), 6.84–6.24 (m, 3H), 4.78 (s, 1H), 3.62 (d, J = 45.3 Hz, 6H), 2.42 (d, J = 17.0 Hz, 1H), 2.29 (d, J = 12.1 Hz, 4H), 2.18 (d, J = 16.1 Hz, 1H), 2.00 (d, J = 16.1 Hz, 1H), 0.95 (d, J = 52.7 Hz, 6H). 13 C NMR (101 MHz, DMSO) δ 194.84, 167.99, 149.72, 147.37, 145.13, 145.10, 139.35, 119.86, 115.49, 112.45, 112.32, 110.73, 104.21, 56.03, 55.95, 51.02, 50.83, 39.87, 35.33, 32.58, 29.69, 26.90, 18.70. FTIR Neat: cm − 1 : 3187, 2945, 1741, 1695, 1484, 1378, 1215, 1104, 1028, 857, 165. [6c] methyl 2,7,7-trimethyl-5-oxo-4-phenyl-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate [ 17 ] Colour : White, m.p. : 210–212 ˚ C % Yield : 87, 1 H NMR (400 MHz, DMSO) δ 9.07 (d, J = 19.9 Hz, 1H), 7.24–6.99 (m, 5H), 4.88 (s, 1H), 3.53 (s, 3H), 2.42 (d, J = 17.1 Hz, 1H), 2.35–2.24 (m, 4H), 2.16 (t, J = 13.2 Hz, 1H), 1.99 (d, J = 16.0 Hz, 1H), 1.05–0.96 (m, 3H), 0.84 (s, 3H). 13 C NMR (101 MHz, DMSO) δ 194.88, 167.85, 150.07, 147.94, 145.76, 128.30, 127.73, 126.19, 110.48, 103.76, 51.12, 50.71, 39.72, 36.11, 32.59, 29.59, 26.88, 18.74. FTIR Neat: cm − 1 : 3200, 3076, 2944, 1738, 1705, 1604, 1483, 1377, 1211, 1106, 1023, 885, 761. [6d] methyl 2,7,7-trimethyl-4-(3-nitrophenyl)-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate [ 49 ] Colour : White, m.p. : 218–220, % Yield : 90, 1 H NMR (400 MHz, DMSO) δ 9.29 (s, 1H), 8.07–7.81 (m, 2H), 7.56 (dt, J = 28.3, 7.8 Hz, 2H), 4.99 (s, 1H), 3.53 (s, 3H), 2.46 (d, J = 17.1 Hz, 1H), 2.37–2.27 (m, 4H), 2.19 (t, J = 12.0 Hz, 1H), 1.99 (d, J = 16.2 Hz, 1H), 1.07–0.96 (m, 3H), 0.80 (d, J = 19.5 Hz, 3H). 13 C NMR (101 MHz, DMSO) δ 194.88, 167.43, 150.66, 149.98, 148.01, 146.81, 134.61, 129.93, 122.18, 121.43, 109.70, 102.81, 51.30, 50.49, 39.75, 36.63, 32.65, 29.52, 26.74, 18.85. FTIR Neat: cm − 1 : 3210, 3079, 2942,1739, 1697, 1617, 1480, 1378, 1285, 1104, 1006, 824, 776. [6e] ethyl 4-(4-fluorophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate [ 56 ] Colour : White, m.p. : 180–182 ˚ C % Yield : 90, 1 H NMR (400 MHz, DMSO) δ 9.12 (s, 1H), 7.16 (dd, J = 8.7, 5.7 Hz, 2H), 6.99 (t, J = 8.9 Hz, 2H), 4.84 (s, 1H), 4.05–3.90 (m, 2H), 2.41 (d, J = 17.0 Hz, 1H), 2.29 (d, J = 9.4 Hz, 4H), 2.17 (d, J = 16.2 Hz, 1H), 1.97 (d, J = 16.1 Hz, 1H), 1.11 (t, J = 7.1 Hz, 3H), 1.00 (s, 3H), 0.82 (s, 3H). 13 C NMR (101 MHz, DMSO) δ 195.06, 167.29, 162.09, 159.69, 150.21, 145.64, 144.29, 144.26, 129.64, 129.56, 114.91, 114.70, 110.35, 104.02, 59.62, 50.61, 39.78, 35.76, 32.56, 29.51, 26.84, 18.68, 14.55. FTIR Neat: cm − 1 : 3284, 3081, 2957, 1797, 1695, 1480, 1379, 1276, 1104, 1027, 877, 758. [6f] ethyl 2,7,7-trimethyl-5-oxo-4-(p-tolyl)-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate [ 44 ] Colour : White, m.p. : 256–258 ˚ C % Yield : 89, 1 H NMR (400 MHz, DMSO) δ 9.02 (s, 1H), 7.03 (d, J = 8.1 Hz, 2H), 6.98 (d, J = 8.0 Hz, 2H), 4.81 (s, 1H), 3.97 (q, J = 7.1 Hz, 2H), 2.41 (d, J = 17.0 Hz, 1H), 2.32–2.25 (m, 4H), 2.22–2.12 (m, 4H), 1.97 (d, J = 16.0 Hz, 1H), 1.14 (t, J = 7.1 Hz, 3H), 1.01 (s, 3H), 0.85 (s, 3H). 13 C NMR (101 MHz, DMSO) δ 194.77, 167.38, 149.89, 145.23, 145.16, 135.01, 128.75, 127.81, 110.55, 104.30, 59.48, 50.74, 39.75, 35.86, 32.58, 29.61, 26.94, 21.02. FTIR Neat: cm − 1 : 3190, 3078, 2956, 1803, 1697, 1488, 1384, 1279, 1105, 1028, 848, 737. [6g] ethyl 4-(4-methoxyphenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate [ 57 ] Colour : White, m.p. : 258–260 ˚ C % Yield : 86, 1 H NMR (400 MHz, DMSO) δ 9.00 (s, 1H), 7.06 (d, J = 8.7 Hz, 2H), 6.74 (d, J = 11.6 Hz, 2H), 4.80 (s, 1H), 3.98 (q, J = 7.1 Hz, 2H), 3.67 (s, 3H), 2.41 (d, J = 17.0 Hz, 1H), 2.34–2.25 (m, 4H), 2.16 (d, J = 16.1 Hz, 1H), 1.98 (d, J = 16.0 Hz, 1H), 1.14 (t, J = 7.1 Hz, 3H), 1.01 (s, 3H), 0.86 (s, 3H). 13 C NMR (101 MHz, DMSO) δ 194.74, 167.41, 157.76, 149.70, 145.07, 140.49, 128.86, 113.56, 110.68, 104.41, 59.45, 55.33, 50.77, 39.81, 35.39, 32.59, 29.61, 26.99, 18.72, 14.64. FTIR Neat: cm − 1 : 3199, 3074, 2956, 1802, 1698, 1491, 1379, 1276, 1105, 1031, 847, 765. Result and discussion A Brønsted amino acid ionic liquid (AAIL), proline methane sulphonate (ProMSA) [ 60 ], was employed as a catalyst for the synthesis of a series of dihydropyridine derivatives ( 5a-5g and 6a-6g ). The reaction conditions were systematically optimized by evaluating key parameters, including temperature, solvent effects, and catalyst loading. To establish the optimal conditions, the synthesis of dimethyl 4-(4-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate ( 5a ) was selected as a model reaction. This compound was prepared via a multicomponent reaction of 4-chlorobenzaldehyde ( 1 ), methyl acetoacetate ( 2 ), and ammonium acetate ( 3 ) (Scheme 1 ). The reaction was investigated using various catalyst concentrations and at different temperatures; the results of this optimization study are summarized in Table 1 . In preliminary experiments, the model reaction was heated at 60°C for 3 hours in the absence of a catalyst; no product formation was observed by TLC (Table 1 , entry 1 ). Subsequently, the reaction was investigated using 5 mol% catalysts at 80˚C. As the reaction time was extended from one to three hours, the product yield increased marginally from 30% to 46% (Table 1 , entries 2–4 ). Increasing the catalyst loading to 10 mol% and raising the temperature to 100˚C further improved the yield from 36% to 55% (Table 1 , entries 5 and 6 ). The optimal result was achieved under solvent-free conditions using 10 mol% catalyst at 100˚C for one hour, affording the desired product in 91% yield (Table 1 , entry 7 ). It is noteworthy that no significant increase in yield was observed when the temperature was raised above 100˚C or when the catalyst loading was increased from 10 to 20 mol% (Table 1 , entries 8–10 ). Additionally, the reaction was performed in various solvents, including ethanol, water, and a water-ethanol mixture. The results indicate that solvent choice significantly influences reaction efficiency, with all tested solvents affording relatively low yields compared to solvent-free conditions (Table 1 , entries 11–13 ). Table 1 Optimization of reaction conditions for the synthesis of 5a Entry ProMSA (mol %) Solvent Temperature ( 0 C) Time (h) % Yield b 1 - - 60 3 - 2 5 - 80 1 30 3 5 - 80 2 39 4 5 - 80 3 46 5 10 - 80 1 36 6 10 - 80 3 55 7 10 - 100 1 91 8 10 - 100 2 90 9 20 - 100 1 89 10 10 - 120 1 87 11 10 Ethanol Reflux 2 71 12 10 Water Reflux 2 - 13 10 Water-Ethanol Reflux 2 42 a Reaction condition: 4-chlorobenzaldehyde ( 10 mmol ), methyl acetoacetate ( 20 mmol ), ammonium acetate ( 20 mmol ) and catalyst ProMSA , b Isolated yield, c Optimized condition shown in bold A series of dihydropyridine derivatives were synthesized via a multicomponent condensation reaction catalyzed by ProMSA under solvent-free conditions (Scheme 2 ). The reaction afforded the desired products in excellent yields, ranging from 86% to 91%, as summarized in Table 2 . Due to the good solubility of the ProMSA catalyst in ethanol, it could be readily separated from the reaction mixture. To explore the substrate scope, a variety of aromatic aldehydes bearing both electron-donating groups (e.g., -CH₃, -OH, -OCH₃) and electron-withdrawing groups (e.g., halides, -NO₂) were employed. Aldehydes containing electron-withdrawing substituents reacted more rapidly and afforded slightly higher product yields compared to those with electron-donating groups. A total of fourteen dihydropyridine derivatives ( 5a-5g and 6a-6g , Table 2 ) were successfully synthesized in moderate to excellent yields. All synthesized compounds were characterized by their physical properties, such as melting point, and spectroscopic techniques, including FTIR, ¹H NMR, and ¹³C NMR spectroscopy. The synthesis of 1,4-dihydropyridine derivatives was investigated via a three-component reaction involving aromatic aldehydes, β-keto esters, and ammonium acetate, catalyzed by ProMSA , a Brønsted amino acid ionic liquid (AAIL). Under optimized conditions, all substrates reacted smoothly with 10 mol% of the AAIL under solvent-free conditions, affording the desired 1,4-dihydropyridine derivatives ( 5a-5g and 6a-6g , Table 2 ) in moderate to excellent yields. Both electron-rich and electron-deficient aldehydes performed well, giving comparable product yields. Table 2 One-pot synthesis of 1, 4-dihyropyridine derivatives ( 5a-5g and 6a-6g ) Entry R 1 β-keto esters % Yield c Melting Point 0 C Observed d Reported 5a 4-Cl MAA/MAA 91 254–256 257–258 5b 3-NO 2 MAA/MAA 90 124–126 125–127 5c H MAA/MAA 87 258–260 259–261 5d 4-OCH 3 MAA/MAA 85 258–260 257–259 5e 4-OH MAA/MAA 86 300–302 297–298 5f 4-Cl EAA/EAA 91 144–146 145–146 5g 3-OCH 3 ,4-OH EAA/EAA 88 188–190 - 6a 4-Cl MAA/DM 89 218–220 221–223 6b 3-OCH 3 ,4-OH MAA/DM 88 236–238 - 6c H MAA/DM 87 210–212 212–214 6d 3-NO 2 MAA/DM 90 218–220 221–223 6e 4-F EAA/DM 90 180–182 180–182 6f 4-CH 3 EAA/DM 89 256–258 258–260 6g 4-OCH 3 EAA/DM 86 258–260 258–259 a All aldehydes available commercially and were used as received. MAA: methyl acetoacetate, EAA; Ethyl acetoacetate, DM: Dimedone, b The progress of reaction was followed by TLC, c Refers to yield of isolated products. d All the products have been reported previously and characterized by comparison of their points with the literature values. As a representative example, the structure of dimethyl 4-(4-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate ( 5a ) was unequivocally established by spectroscopic analysis. The ¹H NMR spectrum of 5a exhibited a multiplet at δ 7.25–7.12 integrating for four protons, corresponding to the aromatic protons (C-18, C-19, C-21, and C-22). A doublet at δ 5.78 integrating for one proton was assigned to the amine proton (N-3). A multiplet at δ 5.05–4.92 integrating for one proton was attributed to the methylene proton at C-6. Multiplets at δ 3.73–3.57 integrating for six protons corresponded to the methoxy groups of the esters (C-12 and C-17). Another multiplet at δ 2.40–2.29 integrating for six protons was assigned to the methyl groups at C-7 and C-8. The ¹³C NMR spectrum displayed three aliphatic carbon signals: a methylene at δ 19.59 (C-6), methyl carbons at δ 38.96 (C-7 and C-8), and methoxy carbons at δ 51.03 (C-17 and C-18). The eight aromatic carbons resonated in the region δ 103.66–145.97 (C-1, C-2, C-4, C-5, C-13, and C-18 to C-22), while the ester carbonyl carbon appeared at δ 167.82, confirming the structure of compound 5a . The FTIR spectrum further supported the structure, showing characteristic absorption bands at 3324 cm⁻¹ (N–H stretching), 2952 cm⁻¹ (C–H stretching), and 1725 cm⁻¹ (ester carbonyl stretching). The catalytic activity of ProMSA was compared with previously reported catalysts for the synthesis of dihydropyridine derivatives, considering key parameters such as reaction time, temperature, solvent, and isolated product yield. ProMSA demonstrated superior performance, affording moderate to excellent yields under solvent-free conditions with a short reaction time of just 60 minutes (Table 2 , entry 12 ). In contrast, several literature catalysts required organic solvents and longer reaction times ranging from 8 to 300 minutes to achieve comparable yields, often at different temperatures. Table 3 Comparison of the activity of different catalysts with ProMSA Entry Name of the catalyst Time (min) T (˚C) % Yield 1 Alumina sulphuric acid (ASA) 120–300 70 82–95 [ 11 ] 2 Polyphosphoric acid (PPA)@NiO 40 40 94–97 [ 21 ] 3 Tetrabutylammonium hydrogen sulfate 55–90 70 65–80 [ 25 ] 4 Sulfonic acid functionalized pyridinium chloride 8–12 50 76–96 [ 28 ] 5 Manganese ferrite nanoparticles (MnFe 2 O 4 ) 14–90 RT 80–94 [ 31 ] 6 Nano-MgO–ZrO 2 metal oxide 15 RT 95 [ 34 ] 7 Hercynite@sulfuric acid 15–115 100 80–97 [ 37 ] 8 Silica-Coated NiFe 2 O 4 nanoparticles 10–60 120 65–94 [ 40 ] 9 Bismuth (III) chloride 15–20 70 83–96[ 46 ] 10 Aluminized polyborate 10–30 100 85 [ 48 ] 11 MCM-41 supported cobalt (II) complex 10 130 90 [ 50 ] 12 ProMSA 60 100 86–91 Present Work Mechanism of reaction: A plausible mechanism for the formation of 1,4-dihydropyridine derivatives catalyzed by ProMSA is proposed in Scheme 3 . Initially, the Brønsted acidic ionic liquid ProMSA facilitates the conversion of the β-keto ester to its enol form, which subsequently reacts with the activated aldehyde to generate intermediate A . Concurrently; ammonium acetate generates ammonia, which reacts with another molecule of activated β-keto ester to form enamine B . The nucleophilic addition of enamine B to intermediate A affords intermediate C , which undergoes tautomerization to yield intermediate D . This intermediate then undergoes intramolecular nucleophilic attack by the NH₂ group on the activated carbonyl group, accompanied by the loss of a water molecule, to form intermediate E . Finally, tautomerization of E furnishes the desired 1,4-dihydropyridine derivative. Throughout the catalytic cycle, ProMSA plays a crucial role in activating the carbonyl groups via proton donation, with the proton being subsequently transferred back to the catalyst to regenerate it for subsequent cycles. This proposed mechanism is consistent with previously reported literature [ 28 ]. In-silico ADME analysis: The ADME (Absorption, Distribution, Metabolism, and Excretion) profiles of potential drug candidates can be reliably predicted using computational tools, thereby increasing confidence in their suitability for further drug development. In this study, the SwissADME online server ( http://swissadme.ch/ ) [ 61 ] was employed to evaluate the pharmacokinetic properties and drug-likeness of the synthesized compounds. This program reduces the time and cost associated with early-stage research by rapidly assessing oral bioavailability and drug-relevant features based on established filters, including Lipinski's rule of five. Table 4 ADME study of docked dihydropyridine derivatives Entry MW H-bond acceptors H-bond donors iLOGP Rotatable bonds TPSA WLOGP MR Heavy atoms 1 335.78 4 1 3.24 5 64.63 2.54 90.71 23 2 346.33 6 1 2.68 6 110.5 1.79 94.52 25 3 346.33 6 1 2.68 6 110.5 1.79 94.52 25 4 331.36 5 1 3.29 6 73.86 1.9 92.19 24 5 317.34 5 2 2.68 5 84.86 1.59 87.73 23 6 359.85 3 1 3.39 3 55.4 3.74 101.67 25 7 371.43 5 2 3.23 4 84.86 2.8 105.18 27 8 325.4 3 1 3.1 3 55.4 3.08 96.66 24 9 370.4 5 1 2.9 4 101.2 2.99 105.49 27 10 363.84 4 1 3.59 7 64.63 3.32 100.33 25 11 375.42 6 2 3.37 8 94.09 2.38 103.83 27 12 357.42 4 1 3.48 4 55.4 4.03 101.43 26 13 353.45 3 1 3.57 4 55.4 3.78 106.44 26 14 369.45 4 1 3.49 5 64.63 3.48 107.96 27 The ADME prediction tool evaluates a range of key physicochemical and pharmacokinetic parameters, such as molecular weight (MW), gastrointestinal absorption (HIA), blood-brain barrier permeability (BBB), P-glycoprotein substrate status (Pgp), number of hydrogen bond donors (nHBD) and acceptors (nHBA), bioavailability score (BS), topological polar surface area (TPSA), lipophilicity (WLOGP), drug-likeness (DL), and drug score (DS). The predicted ADME data for all synthesized compounds are presented in Table 4 . The boiled-Egg model provides a predictive assessment of passive gastrointestinal absorption (HIA) and blood-brain barrier (BBB) penetration [ 62 ]. As illustrated in Fig. 2 , the results indicate that compounds 2, 3, 4, 5, 7, 9, and 11 are located in the white region (outside the yolk), predicting high gastrointestinal absorption but no BBB permeation. In contrast, derivatives 1, 6, 8, 10, 12, 13, and 14 were positioned in the yolk (BBB-permeable region), suggesting they can passively cross the blood-brain barrier and are not effluxed by P-glycoprotein, thereby enabling these molecules to reach therapeutically relevant concentrations within the brain. The physicochemical parameters related to drug-likeness, based on Lipinski's rule of five, are summarized in Table 4 and illustrated graphically in Fig. 2 . Lipophilicity [ 63 ] was evaluated using multiple computational models, including iLOGP, XLOGP3, WLOGP, MLOGP, and Silicos-IT, with consensus LOGP values ranging from approximately 1.59 to 4.03. This range reflects moderate lipophilicity, which is generally favorable for oral drug candidates. The predicted aqueous solubility (ESOL Log S) values ranged from approximately − 3.1 to − 4.5, indicating a moderate to low solubility characteristic that falls within an acceptable range for oral bioavailability. Compounds with higher Log P values exhibited lower solubility, which is associated with enhanced membrane permeability and an increased likelihood of crossing the blood-brain barrier. In contrast, less lipophilic analogues are predicted to favor peripheral distribution. Overall, the in silico ADME results confirm that all synthesized compounds satisfy the established drug-likeness criteria. Lipinski’s rule such as (MW: ≤ 500; logP: ≤ 4–15; H-bond acceptor ≤ 10; H-bond donor ≤ 5; Molar refractivity ( MR ) is in between 40–130), Veber rule (TPSA ≤ 140 A˚; rotatable bonds ≤ 10 ), Ghose filter (MW: ≤ 500; logP: ≤ 4–15; MR: 40–130), Egan rule (logP: ≤ 4–15; TPSA ≤ 140 A˚), and Muegge (MW: ≤ 500; logP: ≤ 4–15; H-bond acceptor ≤ 10; H-bond donor ≤ 5;) not violate the guidelines indicating favorable physicochemical properties, good oral absorption potential, and suitability for further pharmacokinetic evaluation. In the present series, compounds exhibiting low topological polar surface area (TPSA) combined with moderate to high lipophilicity (LOGP) were consistently predicted to be blood-brain barrier (BBB) permeable. The most favorable predictions for central nervous system (CNS) indications were observed for entries 1, 6, 8, 10, 12, 13, and 14 , which collectively demonstrate an optimal balance of negligible P-glycoprotein substrate liability, BBB permeability, and high gastrointestinal absorption. Among these, compounds 6, 12, and 13 possess the lowest TPSA values, a characteristic that enhances CNS exposure but is also associated with reduced aqueous solubility and a potentially higher risk of metabolic interactions. Notably, the absence of CYP2D6 inhibition across the entire series significantly reduces the likelihood of serious CNS-related drug-drug interactions. Overall, compounds 6, 8, 12, and 13 emerge as the most promising CNS-focused leads, achieving a favorable balance between BBB penetration, oral absorption, and manageable metabolic risk. Conclusion In conclusion, we have developed an efficient protocol for the one-pot, multicomponent synthesis of 1,4-dihydropyridine derivatives. The reaction employs aromatic aldehydes, β-keto esters, and ammonium acetate in the presence of a catalytic amount of a Brønsted acidic amino acid ionic liquid ( ProMSA ) under solvent-free conditions. The advantages of this methodology include the use of a readily available and inexpensive catalyst, mild reaction conditions, a simple work-up procedure, and the attainment of moderate to excellent product yields without the need for special precautions. This developed protocol represents a simple, environmentally benign, and safer synthetic approach. Furthermore, all synthesized compounds satisfied the Lipinski, Veber, Ghose, Egan, and Muegge drug-likeness criteria, indicating favorable physicochemical properties, good oral absorption potential, and suitability for further pharmacokinetic evaluation. Declarations Conflict of Interest Authors declares no conflict of interest. Author Contribution Author Nitin Rode developed the methodolgy for the synthesis of dihydropyridines and wrote the result and discussion section of the manuscript.Author Kishor Kale wrote the introduction and ADME profoling of the synthesised compunds.Author Santosh Terdale and other authors reviewed the manuscript. Supplementary Information The online version contains supplementary material available at http://doi.org/10.1007/s11164-026-xxxxx-x. References A. Hantzsch Justus L. Ann. Cheime. 215 , 1 (1882). S. S. Makone, S. N. Niwadange, Der Chemica Sinica, 3(5) , 1293 (2012). M. F. Litvic, M. Litvic , I. Cepanec, V. Vinkovic. Molecule, 12 , 2546 ( 2007). M. M. Heravi, V. Zadsirjan, RSC Adv., 10 44247 (2020). E. Frank, G. Szollosi, Molecule, 26 , 4617 (2021). M. C. Sanu, J. Joseph, D. Chacko, Int. J. Pharm. Sci. Rev. Res., 69(2) , 64 (2021). S. Bijani, D. Iqbal, S. Mirza, V. Jain, S. Jahan, M. Alsaweed, Y. Madkhali, S. A. Alsagaby, S. Banawas, A. Algarni, F. Alrumaihi, R. M. Rawal, W. 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V Shelar, K. Pai, R. H. Patil, S. S. Terdale, Res. Chem. Intermed. 4 , (2023). A. Daina, O. Michielin, V. Zoete, Sci. Rep. 7 , 42717 (2017). A. Daina, V. Zoete, ChemMedChem , 11 , 1117 (2016). A. Daina, O. Michielin, V. Zoete, J. Chem. Inf. Model, 51(12) , 3284 (2014). Additional Declarations No competing interests reported. Supplementary Files SupplementaryMaterial.docx schem1.jpg Scheme 1: Model reaction for optimization of reaction conditions schem2.jpg Scheme 2: Synthesis of dihydropyridine derivatives schem3.jpg Scheme 3: Plausible mechanism for synthesis of dihydropyridine derivatives Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8939554","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":602755705,"identity":"eb6521f6-8d6c-4e75-a6ff-bba2e161f6ce","order_by":0,"name":"Nitin 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09:42:17","extension":"jpg","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":41284,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eScheme 1: \u003c/strong\u003eModel\u003cstrong\u003e \u003c/strong\u003ereaction for optimization of reaction conditions\u003c/p\u003e","description":"","filename":"schem1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8939554/v1/f9238a76c3c944b7abe972de.jpg"},{"id":104305165,"identity":"b7566b87-7b5b-46b3-a186-5bec76bf1b40","added_by":"auto","created_at":"2026-03-10 09:42:06","extension":"jpg","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":84876,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eScheme 2: \u003c/strong\u003eSynthesis of dihydropyridine derivatives\u003c/p\u003e","description":"","filename":"schem2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8939554/v1/66a8dd4c7cb5d706cbaf5d12.jpg"},{"id":104305208,"identity":"a3ca3cdc-6c43-4144-ab52-7947c29ac25f","added_by":"auto","created_at":"2026-03-10 09:42:17","extension":"jpg","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":104103,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eScheme 3: \u003c/strong\u003ePlausible mechanism for synthesis of dihydropyridine derivatives\u003c/p\u003e","description":"","filename":"schem3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8939554/v1/d59b3d6eddf8cdabb1ba6940.jpg"}],"financialInterests":"No competing interests reported.","formattedTitle":"One-pot synthesis and in silico ADME profiling of 1,4-dihydropyridine derivatives catalyzed by ProMSA ionic liquid under solvent-free conditions","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe six-membered heterocyclic ring system containing a nitrogen atom at the 1-position, which is saturated at the 1 and 4 positions, is known as 1,4-dihydropyridine (1,4-DHP). This scaffold was first synthesized by Arthur Hantzsch in 1881 via a pioneering multicomponent reaction (MCR) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The classical Hantzsch synthesis involves the one-pot condensation of a β-keto ester (a 1,3-dicarbonyl compound), an aromatic aldehyde, and ammonia or an ammonium salt to afford 1,4-dihydropyridine derivatives, commonly referred to as Hantzsch esters [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The stability of these compounds is significantly enhanced when the 3 and 5 positions are substituted with electron-withdrawing groups such as cyano (CN), carbonyl (COR), or ester (COOR) functionalities [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Nitrogen-containing heterocycles, particularly the 1,4-DHP scaffold, are frequently found in biologically and medicinally active compounds [\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. They are widely recognized for their therapeutic applications, most notably as calcium channel blockers (e.g., nifedipine, amlodipine, felodipine, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Additionally, they exhibit a broad spectrum of pharmacological activities, including anticonvulsant, antitumor, analgesic, and anti-inflammatory effects, and are extensively used in the treatment of cardiovascular diseases [\u003cspan additionalcitationids=\"CR8 CR9 CR10\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eTo improve the productivity of 1, 4-dihydropyridines synthesis, different catalyst have been used such as HY-Zeolite [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], ceric ammonium nitrate [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], Montmorillonite K10 [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], FeF\u003csub\u003e3\u003c/sub\u003e [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], Triton X-100 in water [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], HPW/PEG-400 [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], N-(phenylsulfonyl)benzene sulfonamide [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], Acid catalyst such as alumina sulfuric acid (ASA) [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], organocatalyst-succinic acid [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], polyphosphoric acid (PPA)@NiO [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], borotungstic acid H\u003csub\u003e5\u003c/sub\u003eBW\u003csub\u003e12\u003c/sub\u003eO\u003csub\u003e40\u003c/sub\u003e [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], Polyvinylpolypyrrolidone supported chlorosulfonic acid [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], Phosphinic Acid on UiO‑66‑NH\u003csub\u003e2\u003c/sub\u003e [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e], Ionic liquid catalyst likes tetrabutylammonium hydrogen sulfate (TBAHS) [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e], Tetrabutylphosphonium Dichromate (TBPDC) (MW) [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e], mild acidic ionic liquids such as N-methyl-2-pyrrolidoniumdihydrogen phosphate [NMP][H\u003csub\u003e2\u003c/sub\u003ePO\u003csub\u003e4\u003c/sub\u003e] [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e], ionic liquid sulfonic acid functionalized pyridinium chloride [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e], Nanoparticle catalyst such as graphene oxide nano particles [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e], nano-crystalline solid acid catalyst (nano-sulfated zirconia, nano-structured ZnO, nano-g-alumina and nano-ZSM-5 zeolites) [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e], manganese ferrite nanoparticles (MnFe\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e) [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e], Cu immobilized on MgZnFe\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e nanoparticles [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e], nano‑Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@dextrin/BF\u003csub\u003e3\u003c/sub\u003e [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e], nano-sized Magnesia\u0026ndash;Zirconia (nano-MgO\u0026ndash;ZrO\u003csub\u003e2\u003c/sub\u003e) catalyst [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e], Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e hybrid nanocatalyst [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e], Copper(I) Iodide Nanoparticles [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e], Magnetic nanoparticles likes hercynite@sulfuric acid nanomagnetic solid acid catalyst [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e], {Fe\u003csub\u003e3\u003c/sub\u003eO4@SiO\u003csub\u003e2\u003c/sub\u003e@(CH2)\u003csub\u003e3\u003c/sub\u003eIm}C(NO\u003csub\u003e2\u003c/sub\u003e)\u003csub\u003e3\u003c/sub\u003e magnetic nano particles [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e], GO/Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e/ZIF-67 magnetic nanocatalyst [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e], Silica-Coated Magnetic NiFe\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e Nanoparticles [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e], Magnetic MnFe\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e Nanoparticles [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e], Magnetic Fe-C-O-Mo alloy nano-rods [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e], MgFe\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e MNPs [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e], Metal catalyst like Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@chitosan [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e], AlCl\u003csub\u003e3\u003c/sub\u003e.6H\u003csub\u003e2\u003c/sub\u003eO [\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e], bismuth (III) chloride [\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e], PdRuNi@GO Catalyst [\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e], Aluminized polyborate‑catalysed [\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e], Mn(II) on Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@ Schiff base [\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e], MCM-41 supported cobalt (II) complex [\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e], TiCl\u003csub\u003e2\u003c/sub\u003e/Nano-γ-Al\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e3\u003c/sub\u003e [\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e], Mn-MOFs [\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e], Neat, ultrasound and microware assisted synthesis includes catalyst like visible light promoted Praseodymium Oxide (Pr\u003csub\u003e6\u003c/sub\u003eO\u003csub\u003e11\u003c/sub\u003e) Seal Vessel [\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e], neat under solvent-free [\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e], ammonium bicarbonate (MW) [\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e], microwave assisted \u003cem\u003eo\u003c/em\u003e-Iodoxybenzoic acid (IBX) [\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e], praseodymium oxide using visible light [\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e], Iodobenzene diacetate (III) by coventional heating, Ultrasound and MW [\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e], Ultrasound-assisted [\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e]. Some of the above methods for the synthesis of 1,4-dihydropyridines derivatives have one or more adverse points such as moisture sensitive, expensive reagents, tedious workup processes and harsh reaction conditions; thus, developing a proficient procedure with a potent catalyst for the synthesis of 1,4-dihydropyridine is still key importance. The physicochemical and pharmacokinetic properties of compounds were utilized to recognize the drug-likeness of compounds as a potential therapeutic drug candidate in an \u003cem\u003ein silico\u003c/em\u003e ADME (absorption, distribution, metabolism, and excretion) study.\u003c/p\u003e"},{"header":"Experimental","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eGeneral procedure for synthesis of 1, 4-dihydropyridine derivatives (5a-5g)\u003c/h2\u003e \u003cp\u003eA round-bottom flask was charged with aromatic aldehyde (10 mmol), ethyl or methyl acetoacetate (20 mmol), ammonium acetate (15 mmol), and the AAIL catalyst ProMSA (10 mol%). The reaction mixture was stirred at 100˚C for the appropriate time, and progress was monitored by TLC. Upon completion, the reaction mixture was cooled to room temperature, and ethanol (10 mL) was added. The mixture was stirred for 30 minutes to obtain the crude solid product. The solid was collected by filtration using Whatman filter paper, washed thoroughly with cold ethanol and hexane to remove traces of aldehyde, and recrystallized from ethanol if necessary.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eGeneral procedure for synthesis of 1, 4-dihydropyridine derivatives (6a-6g)\u003c/h3\u003e\n\u003cp\u003eA round-bottom flask was charged with dimedone (10 mmol), aromatic aldehyde (10 mmol), ethyl or methyl acetoacetate (10 mmol), ammonium acetate (15 mmol), and the AAIL catalyst ProMSA (10 mol%). The reaction mixture was stirred at 100˚C for the appropriate time, and progress was monitored by TLC. Upon completion, the reaction mixture was cooled to room temperature, and ethanol (10 mL) was added. The mixture was stirred for 30 minutes to obtain the crude solid product. The solid was collected by filtration using Whatman filter paper, washed thoroughly with cold ethanol and hexane to remove traces of aldehyde, and recrystallized from ethanol if necessary.\u003c/p\u003e \u003cp\u003e \u003cb\u003e[5a] dimethyl 4-(4-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate\u003c/b\u003e [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]\u003c/p\u003e \u003cp\u003e \u003cb\u003eColour\u003c/b\u003e: White, \u003cb\u003em.p.\u003c/b\u003e: 254\u0026ndash;256\u003cb\u003e˚\u003c/b\u003eC \u003cb\u003e% Yield\u003c/b\u003e: 88 \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 7.25\u0026ndash;7.12 (m, 4H), 5.78 (d, J\u0026thinsp;=\u0026thinsp;14.8 Hz, 1H), 5.05\u0026ndash;4.92 (m, 1H), 3.73\u0026ndash;3.57 (m, 6H), 2.42\u0026ndash;2.29 (m, 6H).\u003csup\u003e13\u003c/sup\u003eC NMR (101 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 167.82, 145.97, 144.28, 131.82, 129.07, 128.13, 103.66, 51.03, 38.96, 19.59. FTIR Neat: cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e: 3324, 2952, 1725, 1647, 1481, 1381, 1221, 1174, 1015, 857, 757.\u003c/p\u003e \u003cp\u003e \u003cb\u003e[5b] dimethyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate\u003c/b\u003e [\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e]\u003c/p\u003e \u003cp\u003e \u003cb\u003eColour\u003c/b\u003e: White, \u003cb\u003em.p.\u003c/b\u003e: 124\u0026ndash;126, \u003cb\u003e% Yield\u003c/b\u003e: 90, \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 8.28\u0026ndash;7.86 (m, 2H), 7.76\u0026ndash;7.50 (m, 1H), 7.50\u0026ndash;7.21 (m, 1H), 6.04 (s, 1H), 5.30\u0026ndash;4.96 (m, 1H), 3.84\u0026ndash;3.45 (m, 6H), 2.61\u0026ndash;2.16 (m, 6H). \u003csup\u003e13\u003c/sup\u003eC NMR (101 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 167.58, 149.59, 148.38, 145.09, 134.21, 128.74, 122.73, 121.42, 103.08, 51.15, 39.64, 19.57. FTIR Neat: cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e: 3341, 2949, 1727, 1697, 1646, 1430, 1342, 1216, 1118, 1017, 836, 763.\u003c/p\u003e \u003cp\u003e \u003cb\u003e[5c] dimethyl 2,6-dimethyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylate\u003c/b\u003e [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]\u003c/p\u003e \u003cp\u003e \u003cb\u003eColour\u003c/b\u003e: White, \u003cb\u003em.p.\u003c/b\u003e: 258\u0026ndash;260\u003cb\u003e˚\u003c/b\u003eC \u003cb\u003e% Yield\u003c/b\u003e: 87, \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 7.44\u0026ndash;6.95 (m, 6H), 5.83 (d, J\u0026thinsp;=\u0026thinsp;46.3 Hz, 1H), 5.18\u0026ndash;4.87 (m, 1H), 3.84\u0026ndash;3.46 (m, 7H), 2.56\u0026ndash;2.12 (m, 7H).\u003csup\u003e13\u003c/sup\u003eC NMR (101 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 168.11, 147.44, 144.34, 128.17, 128.04, 127.62, 126.21, 103.83, 77.38, 77.06, 76.74, 51.00, 39.29, 19.52, 17.07. FTIR Neat: cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e: 3363, 2949, 1678, 1650, 1483, 1377, 1224, 1125, 1014, 841, 746.\u003c/p\u003e \u003cp\u003e \u003cb\u003e[5d] dimethyl 4-(4-methoxyphenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate\u003c/b\u003e[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/p\u003e \u003cp\u003e \u003cb\u003eColour\u003c/b\u003e: White, \u003cb\u003em.p.\u003c/b\u003e: 258\u0026ndash;260\u003cb\u003e˚\u003c/b\u003eC \u003cb\u003e% Yield\u003c/b\u003e: 85, \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 7.25\u0026ndash;7.14 (m, 2H), 6.87\u0026ndash;6.65 (m, 2H), 5.95 (d, J\u0026thinsp;=\u0026thinsp;13.4 Hz, 1H), 5.03\u0026ndash;4.88 (m, 1H), 3.81\u0026ndash;3.73 (m, 3H), 3.65 (d, J\u0026thinsp;=\u0026thinsp;15.2 Hz, 6H), 2.40\u0026ndash;2.25 (m, 6H). \u003csup\u003e13\u003c/sup\u003eC NMR (101 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 168.19, 157.96, 144.13, 140.00, 129.63, 128.60, 113.96, 113.41, 104.02, 55.34, 55.14, 50.99, 38.43, 19.50. FTIR Neat: cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e: 3347, 2952, 1702, 1643, 1482, 1377, 1215, 1124, 1015, 827, 744.\u003c/p\u003e \u003cp\u003e \u003cb\u003e[5e] dimethyl 4-(4-hydroxyphenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate\u003c/b\u003e[\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]\u003c/p\u003e \u003cp\u003e \u003cb\u003eColour\u003c/b\u003e: White, \u003cb\u003em.p.\u003c/b\u003e: 300\u0026ndash;302\u003cb\u003e˚\u003c/b\u003eC \u003cb\u003e% Yield\u003c/b\u003e: 86, \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 7.83 (s, 1H), 7.34\u0026ndash;7.19 (m, 1H), 7.05 (d, J\u0026thinsp;=\u0026thinsp;8.5 Hz, 2H), 6.68 (t, J\u0026thinsp;=\u0026thinsp;17.0 Hz, 2H), 4.87 (s, 1H), 3.76\u0026ndash;3.42 (m, 6H), 2.29 (s, 6H). \u003csup\u003e13\u003c/sup\u003eC NMR (101 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 168.33, 155.12, 144.45, 139.12, 128.56, 115.61, 114.91, 103.73, 50.80, 40.46, 40.26, 40.05, 39.84, 39.63, 38.25, 19.23. FTIR Neat: cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e: 3353, 2954, 1730, 1683, 1646, 1482, 1378, 1213, 1097, 1023, 857, 752.\u003c/p\u003e \u003cp\u003e \u003cb\u003e[5f] diethyl 4-(4-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate\u003c/b\u003e [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]\u003c/p\u003e \u003cp\u003e \u003cb\u003eColour\u003c/b\u003e: White, \u003cb\u003em.p.\u003c/b\u003e: 144\u0026ndash;146\u003cb\u003e˚\u003c/b\u003eC \u003cb\u003e% Yield\u003c/b\u003e: 91, \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 7.39\u0026ndash;7.00 (m, 4H), 5.86 (d, J\u0026thinsp;=\u0026thinsp;91.4 Hz, 1H), 5.14\u0026ndash;4.72 (m, 1H), 4.39\u0026ndash;3.86 (m, 4H), 2.46\u0026ndash;2.23 (m, 6H), 1.43\u0026ndash;1.04 (m, 6H). \u003csup\u003e13\u003c/sup\u003eC NMR (101 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 167.54, 146.38, 144.20, 131.70, 129.41, 127.95, 103.77, 59.84, 39.26, 19.50, 14.27. FTIR Neat: cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e: 3347, 2982, 1726, 1678, 1512, 1486, 1367, 1270, 1208, 1118, 1026, 858, 751, 692.\u003c/p\u003e\n\u003ch3\u003e[5g] diethyl 4-(4-hydroxy-3-methoxyphenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate\u003c/h3\u003e\n\u003cp\u003e \u003cb\u003eColour\u003c/b\u003e: White, \u003cb\u003em.p.\u003c/b\u003e:188\u0026ndash;190, \u003cb\u003e% Yield\u003c/b\u003e: 88, \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 6.98\u0026ndash;6.67 (m, 6H), 5.82\u0026ndash;5.33 (m, 4H), 5.09\u0026ndash;4.83 (m, 2H), 4.29\u0026ndash;3.93 (m, 8H), 3.96\u0026ndash;3.71 (m, 6H), 2.48\u0026ndash;2.19 (m, 11H), 1.34\u0026ndash;1.14 (m, 11H). \u003csup\u003e3\u003c/sup\u003eC NMR (101 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 167.79, 145.75, 143.82, 143.57, 140.02, 120.49, 113.79, 110.83, 104.33, 59.72, 55.66, 39.15, 19.51, 14.51. FTIR Neat: cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e: 3354, 2987, 1693, 1647, 1483, 1370, 1296, 1209, 1115, 1014, 826, 743, 694.\u003c/p\u003e \u003cp\u003e \u003cb\u003e[6a] methyl 4-(4-chlorophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate\u003c/b\u003e [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/p\u003e \u003cp\u003e \u003cb\u003eColour\u003c/b\u003e: White, \u003cb\u003em.p.\u003c/b\u003e: 218\u0026ndash;220\u003cb\u003e˚\u003c/b\u003eC \u003cb\u003e% Yield\u003c/b\u003e: 89, \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, DMSO) δ 9.16 (s, 1H), 7.33\u0026ndash;7.06 (m, 4H), 4.85 (s, 1H), 3.52 (s, 3H), 2.47\u0026ndash;2.37 (m, 1H), 2.30 (s, 3H), 2.30\u0026ndash;2.10 (m, 2H), 1.98 (d, J\u0026thinsp;=\u0026thinsp;16.0 Hz, 1H), 1.00 (s, 3H), 0.82 (s, 3H). \u003csup\u003e13\u003c/sup\u003eC NMR (101 MHz, DMSO) δ 194.78, 167.62, 150.11, 146.88, 146.19, 130.71, 129.62, 128.27, 110.16, 103.24, 51.19, 50.63, 39.79, 35.85, 32.61, 29.55, 26.87, 18.79. FTIR Neat: cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e: 3195, 2955, 1741, 1679, 1486, 1381, 1223, 1111, 1004, 885, 775.\u003c/p\u003e\n\u003ch3\u003e[6b] methyl 4-(4-hydroxy-3-methoxyphenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate\u003c/h3\u003e\n\u003cp\u003e \u003cb\u003eColour\u003c/b\u003e: White, \u003cb\u003em.p.\u003c/b\u003e: 274\u0026ndash;276, \u003cb\u003e% Yield\u003c/b\u003e: 88, \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, DMSO) δ 8.81 (d, J\u0026thinsp;=\u0026thinsp;171.0 Hz, 2H), 6.84\u0026ndash;6.24 (m, 3H), 4.78 (s, 1H), 3.62 (d, J\u0026thinsp;=\u0026thinsp;45.3 Hz, 6H), 2.42 (d, J\u0026thinsp;=\u0026thinsp;17.0 Hz, 1H), 2.29 (d, J\u0026thinsp;=\u0026thinsp;12.1 Hz, 4H), 2.18 (d, J\u0026thinsp;=\u0026thinsp;16.1 Hz, 1H), 2.00 (d, J\u0026thinsp;=\u0026thinsp;16.1 Hz, 1H), 0.95 (d, J\u0026thinsp;=\u0026thinsp;52.7 Hz, 6H). \u003csup\u003e13\u003c/sup\u003eC NMR (101 MHz, DMSO) δ 194.84, 167.99, 149.72, 147.37, 145.13, 145.10, 139.35, 119.86, 115.49, 112.45, 112.32, 110.73, 104.21, 56.03, 55.95, 51.02, 50.83, 39.87, 35.33, 32.58, 29.69, 26.90, 18.70. FTIR Neat: cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e: 3187, 2945, 1741, 1695, 1484, 1378, 1215, 1104, 1028, 857, 165.\u003c/p\u003e \u003cp\u003e \u003cb\u003e[6c] methyl 2,7,7-trimethyl-5-oxo-4-phenyl-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate\u003c/b\u003e [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/p\u003e \u003cp\u003e \u003cb\u003eColour\u003c/b\u003e: White, \u003cb\u003em.p.\u003c/b\u003e: 210\u0026ndash;212\u003cb\u003e˚\u003c/b\u003eC \u003cb\u003e% Yield\u003c/b\u003e: 87, \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, DMSO) δ 9.07 (d, J\u0026thinsp;=\u0026thinsp;19.9 Hz, 1H), 7.24\u0026ndash;6.99 (m, 5H), 4.88 (s, 1H), 3.53 (s, 3H), 2.42 (d, J\u0026thinsp;=\u0026thinsp;17.1 Hz, 1H), 2.35\u0026ndash;2.24 (m, 4H), 2.16 (t, J\u0026thinsp;=\u0026thinsp;13.2 Hz, 1H), 1.99 (d, J\u0026thinsp;=\u0026thinsp;16.0 Hz, 1H), 1.05\u0026ndash;0.96 (m, 3H), 0.84 (s, 3H). \u003csup\u003e13\u003c/sup\u003eC NMR (101 MHz, DMSO) δ 194.88, 167.85, 150.07, 147.94, 145.76, 128.30, 127.73, 126.19, 110.48, 103.76, 51.12, 50.71, 39.72, 36.11, 32.59, 29.59, 26.88, 18.74. FTIR Neat: cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e: 3200, 3076, 2944, 1738, 1705, 1604, 1483, 1377, 1211, 1106, 1023, 885, 761.\u003c/p\u003e \u003cp\u003e \u003cb\u003e[6d] methyl 2,7,7-trimethyl-4-(3-nitrophenyl)-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate\u003c/b\u003e [\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e]\u003c/p\u003e \u003cp\u003e \u003cb\u003eColour\u003c/b\u003e: White, \u003cb\u003em.p.\u003c/b\u003e: 218\u0026ndash;220, \u003cb\u003e% Yield\u003c/b\u003e: 90, \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, DMSO) δ 9.29 (s, 1H), 8.07\u0026ndash;7.81 (m, 2H), 7.56 (dt, J\u0026thinsp;=\u0026thinsp;28.3, 7.8 Hz, 2H), 4.99 (s, 1H), 3.53 (s, 3H), 2.46 (d, J\u0026thinsp;=\u0026thinsp;17.1 Hz, 1H), 2.37\u0026ndash;2.27 (m, 4H), 2.19 (t, J\u0026thinsp;=\u0026thinsp;12.0 Hz, 1H), 1.99 (d, J\u0026thinsp;=\u0026thinsp;16.2 Hz, 1H), 1.07\u0026ndash;0.96 (m, 3H), 0.80 (d, J\u0026thinsp;=\u0026thinsp;19.5 Hz, 3H). \u003csup\u003e13\u003c/sup\u003eC NMR (101 MHz, DMSO) δ 194.88, 167.43, 150.66, 149.98, 148.01, 146.81, 134.61, 129.93, 122.18, 121.43, 109.70, 102.81, 51.30, 50.49, 39.75, 36.63, 32.65, 29.52, 26.74, 18.85. FTIR Neat: cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e: 3210, 3079, 2942,1739, 1697, 1617, 1480, 1378, 1285, 1104, 1006, 824, 776.\u003c/p\u003e \u003cp\u003e \u003cb\u003e[6e] ethyl 4-(4-fluorophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate\u003c/b\u003e [\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e]\u003c/p\u003e \u003cp\u003e \u003cb\u003eColour\u003c/b\u003e: White, \u003cb\u003em.p.\u003c/b\u003e: 180\u0026ndash;182\u003cb\u003e˚\u003c/b\u003eC \u003cb\u003e% Yield\u003c/b\u003e: 90, \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, DMSO) δ 9.12 (s, 1H), 7.16 (dd, J\u0026thinsp;=\u0026thinsp;8.7, 5.7 Hz, 2H), 6.99 (t, J\u0026thinsp;=\u0026thinsp;8.9 Hz, 2H), 4.84 (s, 1H), 4.05\u0026ndash;3.90 (m, 2H), 2.41 (d, J\u0026thinsp;=\u0026thinsp;17.0 Hz, 1H), 2.29 (d, J\u0026thinsp;=\u0026thinsp;9.4 Hz, 4H), 2.17 (d, J\u0026thinsp;=\u0026thinsp;16.2 Hz, 1H), 1.97 (d, J\u0026thinsp;=\u0026thinsp;16.1 Hz, 1H), 1.11 (t, J\u0026thinsp;=\u0026thinsp;7.1 Hz, 3H), 1.00 (s, 3H), 0.82 (s, 3H). \u003csup\u003e13\u003c/sup\u003eC NMR (101 MHz, DMSO) δ 195.06, 167.29, 162.09, 159.69, 150.21, 145.64, 144.29, 144.26, 129.64, 129.56, 114.91, 114.70, 110.35, 104.02, 59.62, 50.61, 39.78, 35.76, 32.56, 29.51, 26.84, 18.68, 14.55. FTIR Neat: cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e: 3284, 3081, 2957, 1797, 1695, 1480, 1379, 1276, 1104, 1027, 877, 758.\u003c/p\u003e \u003cp\u003e \u003cb\u003e[6f] ethyl 2,7,7-trimethyl-5-oxo-4-(p-tolyl)-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate\u003c/b\u003e [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]\u003c/p\u003e \u003cp\u003e \u003cb\u003eColour\u003c/b\u003e: White, \u003cb\u003em.p.\u003c/b\u003e: 256\u0026ndash;258\u003cb\u003e˚\u003c/b\u003eC \u003cb\u003e% Yield\u003c/b\u003e: 89, \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, DMSO) δ 9.02 (s, 1H), 7.03 (d, J\u0026thinsp;=\u0026thinsp;8.1 Hz, 2H), 6.98 (d, J\u0026thinsp;=\u0026thinsp;8.0 Hz, 2H), 4.81 (s, 1H), 3.97 (q, J\u0026thinsp;=\u0026thinsp;7.1 Hz, 2H), 2.41 (d, J\u0026thinsp;=\u0026thinsp;17.0 Hz, 1H), 2.32\u0026ndash;2.25 (m, 4H), 2.22\u0026ndash;2.12 (m, 4H), 1.97 (d, J\u0026thinsp;=\u0026thinsp;16.0 Hz, 1H), 1.14 (t, J\u0026thinsp;=\u0026thinsp;7.1 Hz, 3H), 1.01 (s, 3H), 0.85 (s, 3H). \u003csup\u003e13\u003c/sup\u003eC NMR (101 MHz, DMSO) δ 194.77, 167.38, 149.89, 145.23, 145.16, 135.01, 128.75, 127.81, 110.55, 104.30, 59.48, 50.74, 39.75, 35.86, 32.58, 29.61, 26.94, 21.02. FTIR Neat: cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e: 3190, 3078, 2956, 1803, 1697, 1488, 1384, 1279, 1105, 1028, 848, 737.\u003c/p\u003e \u003cp\u003e \u003cb\u003e[6g] ethyl 4-(4-methoxyphenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate\u003c/b\u003e [\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e]\u003c/p\u003e \u003cp\u003e \u003cb\u003eColour\u003c/b\u003e: White, \u003cb\u003em.p.\u003c/b\u003e: 258\u0026ndash;260\u003cb\u003e˚\u003c/b\u003eC \u003cb\u003e% Yield\u003c/b\u003e: 86, \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, DMSO) δ 9.00 (s, 1H), 7.06 (d, J\u0026thinsp;=\u0026thinsp;8.7 Hz, 2H), 6.74 (d, J\u0026thinsp;=\u0026thinsp;11.6 Hz, 2H), 4.80 (s, 1H), 3.98 (q, J\u0026thinsp;=\u0026thinsp;7.1 Hz, 2H), 3.67 (s, 3H), 2.41 (d, J\u0026thinsp;=\u0026thinsp;17.0 Hz, 1H), 2.34\u0026ndash;2.25 (m, 4H), 2.16 (d, J\u0026thinsp;=\u0026thinsp;16.1 Hz, 1H), 1.98 (d, J\u0026thinsp;=\u0026thinsp;16.0 Hz, 1H), 1.14 (t, J\u0026thinsp;=\u0026thinsp;7.1 Hz, 3H), 1.01 (s, 3H), 0.86 (s, 3H). \u003csup\u003e13\u003c/sup\u003eC NMR (101 MHz, DMSO) δ 194.74, 167.41, 157.76, 149.70, 145.07, 140.49, 128.86, 113.56, 110.68, 104.41, 59.45, 55.33, 50.77, 39.81, 35.39, 32.59, 29.61, 26.99, 18.72, 14.64. FTIR Neat: cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e: 3199, 3074, 2956, 1802, 1698, 1491, 1379, 1276, 1105, 1031, 847, 765.\u003c/p\u003e"},{"header":"Result and discussion","content":"\u003cp\u003eA Br\u0026oslash;nsted amino acid ionic liquid (AAIL), proline methane sulphonate (ProMSA) [\u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e], was employed as a catalyst for the synthesis of a series of dihydropyridine derivatives (\u003cb\u003e5a-5g and 6a-6g\u003c/b\u003e). The reaction conditions were systematically optimized by evaluating key parameters, including temperature, solvent effects, and catalyst loading. To establish the optimal conditions, the synthesis of dimethyl 4-(4-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (\u003cb\u003e5a\u003c/b\u003e) was selected as a model reaction. This compound was prepared via a multicomponent reaction of 4-chlorobenzaldehyde (\u003cb\u003e1\u003c/b\u003e), methyl acetoacetate (\u003cb\u003e2\u003c/b\u003e), and ammonium acetate (\u003cb\u003e3\u003c/b\u003e) (Scheme \u003cspan refid=\"Sch1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The reaction was investigated using various catalyst concentrations and at different temperatures; the results of this optimization study are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. In preliminary experiments, the model reaction was heated at 60\u0026deg;C for 3 hours in the absence of a catalyst; no product formation was observed by TLC (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, \u003cb\u003eentry 1\u003c/b\u003e). Subsequently, the reaction was investigated using 5 mol% catalysts at 80˚C. As the reaction time was extended from one to three hours, the product yield increased marginally from 30% to 46% (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, \u003cb\u003eentries 2\u0026ndash;4\u003c/b\u003e). Increasing the catalyst loading to 10 mol% and raising the temperature to 100˚C further improved the yield from 36% to 55% (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, \u003cb\u003eentries 5 and 6\u003c/b\u003e). The optimal result was achieved under solvent-free conditions using 10 mol% catalyst at 100˚C for one hour, affording the desired product in 91% yield (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, \u003cb\u003eentry 7\u003c/b\u003e). It is noteworthy that no significant increase in yield was observed when the temperature was raised above 100˚C or when the catalyst loading was increased from 10 to 20 mol% (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, \u003cb\u003eentries 8\u0026ndash;10\u003c/b\u003e). Additionally, the reaction was performed in various solvents, including ethanol, water, and a water-ethanol mixture. The results indicate that solvent choice significantly influences reaction efficiency, with all tested solvents affording relatively low yields compared to solvent-free conditions (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, \u003cb\u003eentries 11\u0026ndash;13\u003c/b\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eOptimization of reaction conditions for the synthesis of \u003cb\u003e5a\u003c/b\u003e\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEntry\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eProMSA\u003c/p\u003e \u003cp\u003e(mol %)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSolvent\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTemperature\u003c/p\u003e \u003cp\u003e(\u003csup\u003e0\u003c/sup\u003eC)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTime\u003c/p\u003e \u003cp\u003e(h)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e% Yield \u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e-\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e-\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e60\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e3\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e-\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e39\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e46\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e36\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e55\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e7\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e10\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e-\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e100\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e1\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e91\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e90\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e89\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e120\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e87\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEthanol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eReflux\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e71\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eWater\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eReflux\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eWater-Ethanol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eReflux\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003csup\u003e\u003cb\u003ea\u003c/b\u003e\u003c/sup\u003e Reaction condition: 4-chlorobenzaldehyde (\u003cb\u003e10 mmol\u003c/b\u003e), methyl acetoacetate (\u003cb\u003e20 mmol\u003c/b\u003e ), ammonium acetate (\u003cb\u003e20 mmol\u003c/b\u003e ) and catalyst ProMSA\u003csub\u003e,\u003c/sub\u003e \u003csup\u003e\u003cb\u003eb\u003c/b\u003e\u003c/sup\u003e Isolated yield, \u003csup\u003ec\u003c/sup\u003e Optimized condition shown in bold\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eA series of dihydropyridine derivatives were synthesized via a multicomponent condensation reaction catalyzed by \u003cb\u003eProMSA\u003c/b\u003e under solvent-free conditions (Scheme \u003cspan refid=\"Sch3\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The reaction afforded the desired products in excellent yields, ranging from 86% to 91%, as summarized in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Due to the good solubility of the \u003cb\u003eProMSA\u003c/b\u003e catalyst in ethanol, it could be readily separated from the reaction mixture. To explore the substrate scope, a variety of aromatic aldehydes bearing both electron-donating groups (e.g., -CH₃, -OH, -OCH₃) and electron-withdrawing groups (e.g., halides, -NO₂) were employed. Aldehydes containing electron-withdrawing substituents reacted more rapidly and afforded slightly higher product yields compared to those with electron-donating groups. A total of fourteen dihydropyridine derivatives (\u003cb\u003e5a-5g and 6a-6g\u003c/b\u003e, Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) were successfully synthesized in moderate to excellent yields. All synthesized compounds were characterized by their physical properties, such as melting point, and spectroscopic techniques, including FTIR, \u0026sup1;H NMR, and \u0026sup1;\u0026sup3;C NMR spectroscopy. The synthesis of 1,4-dihydropyridine derivatives was investigated via a three-component reaction involving aromatic aldehydes, β-keto esters, and ammonium acetate, catalyzed by \u003cb\u003eProMSA\u003c/b\u003e, a Br\u0026oslash;nsted amino acid ionic liquid (AAIL). Under optimized conditions, all substrates reacted smoothly with 10 mol% of the AAIL under solvent-free conditions, affording the desired 1,4-dihydropyridine derivatives (\u003cb\u003e5a-5g and 6a-6g\u003c/b\u003e, Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) in moderate to excellent yields. Both electron-rich and electron-deficient aldehydes performed well, giving comparable product yields.\u003c/p\u003e\u003cp\u003eTable 2 One-pot synthesis of 1, 4-dihyropyridine derivatives (\u003cb\u003e5a-5g\u003c/b\u003e and \u003cb\u003e6a-6g\u003c/b\u003e)\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Taba\" border=\"1\"\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEntry\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eR\u003csub\u003e1\u003c/sub\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eβ-keto esters\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e% Yield\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eMelting Point \u003csup\u003e0\u003c/sup\u003eC\u003c/p\u003e \u003cp\u003eObserved\u003csup\u003ed\u003c/sup\u003e Reported\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4-Cl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMAA/MAA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e254\u0026ndash;256\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e257\u0026ndash;258\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5b\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3-NO\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMAA/MAA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e124\u0026ndash;126\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e125\u0026ndash;127\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5c\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMAA/MAA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e258\u0026ndash;260\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e259\u0026ndash;261\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5d\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4-OCH\u003csub\u003e3\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMAA/MAA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e258\u0026ndash;260\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e257\u0026ndash;259\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4-OH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMAA/MAA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e300\u0026ndash;302\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e297\u0026ndash;298\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5f\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4-Cl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEAA/EAA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e144\u0026ndash;146\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e145\u0026ndash;146\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5g\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3-OCH\u003csub\u003e3\u003c/sub\u003e,4-OH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEAA/EAA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e188\u0026ndash;190\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4-Cl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMAA/DM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e218\u0026ndash;220\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e221\u0026ndash;223\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6b\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3-OCH\u003csub\u003e3\u003c/sub\u003e,4-OH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMAA/DM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e236\u0026ndash;238\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6c\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMAA/DM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e210\u0026ndash;212\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e212\u0026ndash;214\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6d\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3-NO\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMAA/DM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e218\u0026ndash;220\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e221\u0026ndash;223\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4-F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEAA/DM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e180\u0026ndash;182\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e180\u0026ndash;182\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6f\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4-CH\u003csub\u003e3\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEAA/DM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e256\u0026ndash;258\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e258\u0026ndash;260\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6g\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4-OCH\u003csub\u003e3\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEAA/DM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e258\u0026ndash;260\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e258\u0026ndash;259\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003csup\u003e\u003cem\u003ea\u003c/em\u003e\u003c/sup\u003eAll aldehydes available commercially and were used as received. MAA: methyl acetoacetate, EAA; Ethyl acetoacetate, DM: Dimedone, \u003csup\u003e\u003cem\u003eb\u003c/em\u003e\u003c/sup\u003eThe progress of reaction was followed by TLC, \u003csup\u003e\u003cem\u003ec\u003c/em\u003e\u003c/sup\u003eRefers to yield of isolated products. \u003csup\u003e\u003cem\u003ed\u003c/em\u003e\u003c/sup\u003eAll the products have been reported previously and characterized by comparison of their points with the literature values.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAs a representative example, the structure of dimethyl 4-(4-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (\u003cb\u003e5a\u003c/b\u003e) was unequivocally established by spectroscopic analysis. The \u0026sup1;H NMR spectrum of \u003cb\u003e5a\u003c/b\u003e exhibited a multiplet at δ 7.25\u0026ndash;7.12 integrating for four protons, corresponding to the aromatic protons (C-18, C-19, C-21, and C-22). A doublet at δ 5.78 integrating for one proton was assigned to the amine proton (N-3). A multiplet at δ 5.05\u0026ndash;4.92 integrating for one proton was attributed to the methylene proton at C-6. Multiplets at δ 3.73\u0026ndash;3.57 integrating for six protons corresponded to the methoxy groups of the esters (C-12 and C-17). Another multiplet at δ 2.40\u0026ndash;2.29 integrating for six protons was assigned to the methyl groups at C-7 and C-8. The \u0026sup1;\u0026sup3;C NMR spectrum displayed three aliphatic carbon signals: a methylene at δ 19.59 (C-6), methyl carbons at δ 38.96 (C-7 and C-8), and methoxy carbons at δ 51.03 (C-17 and C-18). The eight aromatic carbons resonated in the region δ 103.66\u0026ndash;145.97 (C-1, C-2, C-4, C-5, C-13, and C-18 to C-22), while the ester carbonyl carbon appeared at δ 167.82, confirming the structure of compound \u003cb\u003e5a\u003c/b\u003e. The FTIR spectrum further supported the structure, showing characteristic absorption bands at 3324 cm⁻\u0026sup1; (N\u0026ndash;H stretching), 2952 cm⁻\u0026sup1; (C\u0026ndash;H stretching), and 1725 cm⁻\u0026sup1; (ester carbonyl stretching).\u003c/p\u003e \u003cp\u003eThe catalytic activity of \u003cb\u003eProMSA\u003c/b\u003e was compared with previously reported catalysts for the synthesis of dihydropyridine derivatives, considering key parameters such as reaction time, temperature, solvent, and isolated product yield. \u003cb\u003eProMSA\u003c/b\u003e demonstrated superior performance, affording moderate to excellent yields under solvent-free conditions with a short reaction time of just 60 minutes (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, \u003cb\u003eentry 12\u003c/b\u003e). In contrast, several literature catalysts required organic solvents and longer reaction times ranging from 8 to 300 minutes to achieve comparable yields, often at different temperatures.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of the activity of different catalysts with \u003cb\u003eProMSA\u003c/b\u003e\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEntry\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eName of the catalyst\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTime (min)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eT\u003c/p\u003e \u003cp\u003e(˚C)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e%\u003c/p\u003e \u003cp\u003eYield\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAlumina sulphuric acid (ASA)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e120\u0026ndash;300\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e82\u0026ndash;95 [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePolyphosphoric acid (PPA)@NiO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e94\u0026ndash;97 [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTetrabutylammonium hydrogen sulfate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e55\u0026ndash;90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e65\u0026ndash;80 [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSulfonic acid functionalized pyridinium chloride\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8\u0026ndash;12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e76\u0026ndash;96 [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eManganese ferrite nanoparticles (MnFe\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14\u0026ndash;90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e80\u0026ndash;94 [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNano-MgO\u0026ndash;ZrO\u003csub\u003e2\u003c/sub\u003e metal oxide\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e95 [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHercynite@sulfuric acid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15\u0026ndash;115\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e80\u0026ndash;97 [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSilica-Coated NiFe\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e nanoparticles\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10\u0026ndash;60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e120\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e65\u0026ndash;94 [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBismuth (III) chloride\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15\u0026ndash;20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e83\u0026ndash;96[\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAluminized polyborate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10\u0026ndash;30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e85 [\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMCM-41 supported cobalt (II) complex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e130\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e90 [\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e12\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eProMSA\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e60\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e100\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e86\u0026ndash;91\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003ePresent Work\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eMechanism of reaction:\u003c/h2\u003e \u003cp\u003eA plausible mechanism for the formation of 1,4-dihydropyridine derivatives catalyzed by \u003cb\u003eProMSA\u003c/b\u003e is proposed in \u003cb\u003eScheme 3\u003c/b\u003e. Initially, the Br\u0026oslash;nsted acidic ionic liquid \u003cb\u003eProMSA\u003c/b\u003e facilitates the conversion of the β-keto ester to its enol form, which subsequently reacts with the activated aldehyde to generate intermediate \u003cb\u003eA\u003c/b\u003e. Concurrently; ammonium acetate generates ammonia, which reacts with another molecule of activated β-keto ester to form enamine \u003cb\u003eB\u003c/b\u003e. The nucleophilic addition of enamine \u003cb\u003eB\u003c/b\u003e to intermediate \u003cb\u003eA\u003c/b\u003e affords intermediate \u003cb\u003eC\u003c/b\u003e, which undergoes tautomerization to yield intermediate \u003cb\u003eD\u003c/b\u003e. This intermediate then undergoes intramolecular nucleophilic attack by the NH₂ group on the activated carbonyl group, accompanied by the loss of a water molecule, to form intermediate \u003cb\u003eE\u003c/b\u003e. Finally, tautomerization of \u003cb\u003eE\u003c/b\u003e furnishes the desired 1,4-dihydropyridine derivative. Throughout the catalytic cycle, \u003cb\u003eProMSA\u003c/b\u003e plays a crucial role in activating the carbonyl groups via proton donation, with the proton being subsequently transferred back to the catalyst to regenerate it for subsequent cycles. This proposed mechanism is consistent with previously reported literature [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eIn-silico ADME analysis:\u003c/h3\u003e\n\u003cp\u003eThe ADME (Absorption, Distribution, Metabolism, and Excretion) profiles of potential drug candidates can be reliably predicted using computational tools, thereby increasing confidence in their suitability for further drug development. In this study, the SwissADME online server (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://swissadme.ch/\u003c/span\u003e\u003cspan address=\"http://swissadme.ch/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) [\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e] was employed to evaluate the pharmacokinetic properties and drug-likeness of the synthesized compounds. This program reduces the time and cost associated with early-stage research by rapidly assessing oral bioavailability and drug-relevant features based on established filters, including Lipinski's rule of five.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eADME study of docked dihydropyridine derivatives\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"10\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEntry\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMW\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eH-bond acceptors\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eH-bond donors\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eiLOGP\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRotatable bonds\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eTPSA\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eWLOGP\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eMR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eHeavy atoms\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e335.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e64.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e2.54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e90.71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e346.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2.68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e110.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e1.79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e94.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e346.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2.68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e110.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e1.79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e94.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e331.36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e73.86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e1.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e92.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e317.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2.68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e84.86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e1.59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e87.73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e359.85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e55.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e3.74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e101.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e371.43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e84.86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e2.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e105.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e325.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e55.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e3.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e96.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e370.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e101.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e2.99\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e105.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e363.84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e64.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e3.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e100.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e375.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e94.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e2.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e103.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e357.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e55.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e4.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e101.43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e353.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e55.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e3.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e106.44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e369.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e64.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e3.48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e107.96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe ADME prediction tool evaluates a range of key physicochemical and pharmacokinetic parameters, such as molecular weight (MW), gastrointestinal absorption (HIA), blood-brain barrier permeability (BBB), P-glycoprotein substrate status (Pgp), number of hydrogen bond donors (nHBD) and acceptors (nHBA), bioavailability score (BS), topological polar surface area (TPSA), lipophilicity (WLOGP), drug-likeness (DL), and drug score (DS). The predicted ADME data for all synthesized compounds are presented in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e. The boiled-Egg model provides a predictive assessment of passive gastrointestinal absorption (HIA) and blood-brain barrier (BBB) penetration [\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e]. As illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, the results indicate that compounds \u003cb\u003e2, 3, 4, 5, 7, 9, and 11\u003c/b\u003e are located in the white region (outside the yolk), predicting high gastrointestinal absorption but no BBB permeation.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIn contrast, derivatives \u003cb\u003e1, 6, 8, 10, 12, 13, and 14\u003c/b\u003e were positioned in the yolk (BBB-permeable region), suggesting they can passively cross the blood-brain barrier and are not effluxed by P-glycoprotein, thereby enabling these molecules to reach therapeutically relevant concentrations within the brain. The physicochemical parameters related to drug-likeness, based on Lipinski's rule of five, are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e and illustrated graphically in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Lipophilicity [\u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e] was evaluated using multiple computational models, including iLOGP, XLOGP3, WLOGP, MLOGP, and Silicos-IT, with consensus LOGP values ranging from approximately 1.59 to 4.03. This range reflects moderate lipophilicity, which is generally favorable for oral drug candidates. The predicted aqueous solubility (ESOL Log S) values ranged from approximately\u0026thinsp;\u0026minus;\u0026thinsp;3.1 to \u0026minus;\u0026thinsp;4.5, indicating a moderate to low solubility characteristic that falls within an acceptable range for oral bioavailability. Compounds with higher Log P values exhibited lower solubility, which is associated with enhanced membrane permeability and an increased likelihood of crossing the blood-brain barrier. In contrast, less lipophilic analogues are predicted to favor peripheral distribution. Overall, the \u003cem\u003ein silico\u003c/em\u003e ADME results confirm that all synthesized compounds satisfy the established drug-likeness criteria. Lipinski\u0026rsquo;s rule such as (MW: \u0026le; 500; logP: \u0026le; 4\u0026ndash;15; H-bond acceptor\u0026thinsp;\u0026le;\u0026thinsp;10; H-bond donor\u0026thinsp;\u0026le;\u0026thinsp;5; Molar refractivity (\u003cem\u003eMR\u003c/em\u003e) is in between 40\u0026ndash;130), Veber rule (TPSA\u0026thinsp;\u0026le;\u0026thinsp;140 A˚; rotatable bonds\u0026thinsp;\u0026le;\u0026thinsp;10 ), Ghose filter (MW: \u0026le; 500; logP: \u0026le; 4\u0026ndash;15; MR: 40\u0026ndash;130), Egan rule (logP: \u0026le; 4\u0026ndash;15; TPSA\u0026thinsp;\u0026le;\u0026thinsp;140 A˚), and Muegge (MW: \u0026le; 500; logP: \u0026le; 4\u0026ndash;15; H-bond acceptor\u0026thinsp;\u0026le;\u0026thinsp;10; H-bond donor\u0026thinsp;\u0026le;\u0026thinsp;5;) not violate the guidelines indicating favorable physicochemical properties, good oral absorption potential, and suitability for further pharmacokinetic evaluation. In the present series, compounds exhibiting low topological polar surface area (TPSA) combined with moderate to high lipophilicity (LOGP) were consistently predicted to be blood-brain barrier (BBB) permeable. The most favorable predictions for central nervous system (CNS) indications were observed for entries \u003cb\u003e1, 6, 8, 10, 12, 13, and 14\u003c/b\u003e, which collectively demonstrate an optimal balance of negligible P-glycoprotein substrate liability, BBB permeability, and high gastrointestinal absorption. Among these, compounds \u003cb\u003e6, 12, and 13\u003c/b\u003e possess the lowest TPSA values, a characteristic that enhances CNS exposure but is also associated with reduced aqueous solubility and a potentially higher risk of metabolic interactions. Notably, the absence of CYP2D6 inhibition across the entire series significantly reduces the likelihood of serious CNS-related drug-drug interactions. Overall, compounds \u003cb\u003e6, 8, 12, and 13\u003c/b\u003e emerge as the most promising CNS-focused leads, achieving a favorable balance between BBB penetration, oral absorption, and manageable metabolic risk.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, we have developed an efficient protocol for the one-pot, multicomponent synthesis of 1,4-dihydropyridine derivatives. The reaction employs aromatic aldehydes, β-keto esters, and ammonium acetate in the presence of a catalytic amount of a Br\u0026oslash;nsted acidic amino acid ionic liquid (\u003cb\u003eProMSA\u003c/b\u003e) under solvent-free conditions. The advantages of this methodology include the use of a readily available and inexpensive catalyst, mild reaction conditions, a simple work-up procedure, and the attainment of moderate to excellent product yields without the need for special precautions. This developed protocol represents a simple, environmentally benign, and safer synthetic approach. Furthermore, all synthesized compounds satisfied the Lipinski, Veber, Ghose, Egan, and Muegge drug-likeness criteria, indicating favorable physicochemical properties, good oral absorption potential, and suitability for further pharmacokinetic evaluation.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eConflict of Interest\u003c/h2\u003e \u003cp\u003eAuthors declares no conflict of interest.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eAuthor Nitin Rode developed the methodolgy for the synthesis of dihydropyridines and wrote the result and discussion section of the manuscript.Author Kishor Kale wrote the introduction and ADME profoling of the synthesised compunds.Author Santosh Terdale and other authors reviewed the manuscript.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eSupplementary Information\u003c/strong\u003e The online version contains supplementary material available at http://doi.org/10.1007/s11164-026-xxxxx-x.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eA. 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Model, \u003cstrong\u003e51(12)\u003c/strong\u003e, 3284 (2014).\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Amino acid ionic liquid, dihydropyridine, ADME study, pharmacokinetic study","lastPublishedDoi":"10.21203/rs.3.rs-8939554/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8939554/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eAn efficient and convenient method has been developed for the one-pot, four-component synthesis of 1,4-dihydropyridine derivatives. The protocol involves the reaction of aromatic aldehydes, β-keto esters, and ammonium acetate catalyzed by ProMSA, a Br\u0026oslash;nsted acidic amino acid ionic liquid (AAIL), under solvent-free conditions. This methodology offers several advantages, including the use of an inexpensive, easily prepared, and recyclable catalyst; a simple experimental procedure; and a green and safer reaction profile. The desired products were obtained in excellent yields with high purity following a straightforward workup and within short reaction times. Furthermore, \u003cem\u003ein silico\u003c/em\u003e ADME study of all synthesized compounds was conducted. The results indicate that all derivatives obey Lipinski's rule of five, as well as the Ghose filter, Egan, and Muegge rules, suggesting favorable physicochemical properties, good oral bioavailability potential, and suitability for advanced pharmacokinetic investigations.\u003c/p\u003e","manuscriptTitle":"One-pot synthesis and in silico ADME profiling of 1,4-dihydropyridine derivatives catalyzed by ProMSA ionic liquid under solvent-free conditions","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-10 09:40:16","doi":"10.21203/rs.3.rs-8939554/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"3d7e86e1-2fe1-4c40-b71e-1e3a0c254126","owner":[],"postedDate":"March 10th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-03-18T02:55:33+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-10 09:40:16","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8939554","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8939554","identity":"rs-8939554","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}