Synthesis of novel 3,5-bis(1,3,4-oxadiazolyl) and 3,5-bis(1,2,4-triazolyl) 1,4-dihydropyridine hybrid analogues

Synthesis of novel 3,5-bis(1,3,4-oxadiazolyl) and 3,5-bis(1,2,4-triazolyl) 1,4-dihydropyridine hybrid analogues | 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 Short Report Synthesis of novel 3,5-bis(1,3,4-oxadiazolyl) and 3,5-bis(1,2,4-triazolyl) 1,4-dihydropyridine hybrid analogues Shaik Lakshman, Abdul Rajack, Prasanth Katakam This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9533951/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 Novel 1,4-dihydropyridine (1,4-DHP) hybrids bearing 1,3,4-oxadiazole ( 7a-c ) or 1,2,4-triazole ( 8a-c ) moieties at the 3,5-positions were synthesized via Hantzsch reaction, hydrazinolysis to diacylhydrazide ( 5a-c) , and subsequent cyclocondensation. Oxadiazoles ( 7a-c) were obtained by acetylation (6a-c) followed by POCl 3 -mediated cyclodehydration (60–80% yield). A novel, eco-friendly one-pot CSA-catalyzed protocol enabled direct synthesis of triazoles 8a-c from ( 5a-c) with acetic anhydride and aniline (80–82% yield), surpassing prior multi-step methods. All synthesized compounds were fully characterized by IR, ¹H/¹³C NMR, and HRMS, confirming the 1,4-DHP core and heterocycle integrity. This hybridization strategy yields promising pharmacophores for multifunctional drug discovery. Molecular hybridization 1 4-Dihydropyridine 1 2 4-Triazole 1 3 4-Oxadiazole Figures Figure 1 Introduction Molecular hybridization of pharmacologically active scaffolds is a proven medicinal chemistry strategy for developing agents with enhanced or dual biological activities. [1–3] 1,4-Dihydropyridines (1,4-DHPs), exemplified by the calcium channel blocker nifedipine [4], exhibit diverse properties beyond cardiovascular applications, including antihypertension [5], antioxidant [6], antiviral [7], anticancer [8], and antimicrobial effects [9,10]. Nitrogen-rich heterocycles such as 1,2,4-triazoles and 1,3,4-oxadiazoles represent privileged structures in drug discovery. The 1,2,4-Triazole ring, a stable bioisostere for amide bonds [11], is a key pharmacophore in renowned antifungal agents like fluconazole [12] and and drives activities including antibacterial [13], anti-inflammatory [14–15], antitubercular [16,17], antidepressant, antioxidant [18], anticonvulsant [19], anticancer [20–22], antimalarial [23], antiviral [24]. Complementarily, the 1,3,4-oxadiazole motif appears in the antiretroviral raltegravir and is widely explored for antimicrobial, [26–28] anticancer [29,30], antiviral [31], anticonvulsant activity [32], insecticidal [32], anti-inflammatory activities [32,35]. The surge in oxadiazole-related patents highlights their therapeutic promise. The synthesis of hybrid molecules, combining the triazole or oxadiazole scaffold with other pharmacophoric fragments [36–37] (like indole, satin, coumarin, etc.), is a current and highly utilized strategy in medicinal chemistry to develop new lead compounds in active drug discovery. Such as specific targets like tubulin polymerization [38]. Hybridizing these heterocycles with other pharmacophores (e.g., indole, isatin, coumarin) is a contemporary approach to identify novel leads, often targeting pathways like tubulin polymerization. Leveraging the complementary profiles of 1,4-DHPs, 1,2,4-triazoles, and 1,3,4-oxadiazoles, we hypothesized that conjugating triazole or oxadiazole units at the 3- and 5-positions of the DHP core would generate multifunctional hybrids. Herein, we report the synthesis and characterization of novel 1,3,4-oxadiazolyl-1,4-DHPs (7a-c) and 1,2,4-triazolyl-1,4-DHPs (8a-c) , featuring an efficient, eco-friendly protocol using cellulose sulfuric acid (CSA) as catalyst[39]. Results and Discussion Hantzsch Synthesis of DHP Esters: Diethyl 1,4-dihydropyridine-3,5-dicarboxylates ( 4a–4c ) were efficiently prepared via one-pot Hantzsch condensation using ethyl acetoacetate, aromatic aldehydes, and ammonium acetate catalyzed by cellulose sulfuric acid (CSA) under solvent-free conditions. All analogues delivered excellent yields (95%) within 4 h at 80°C, demonstrating CSA's efficacy as a reusable, green heterogeneous catalyst for this classic multicomponent reaction. Synthesis of Key Dicarbohydrazide Intermediates Hydrazinolysis of esters ( 4a–4c) with hydrazine hydrate in refluxing methanol proceeded cleanly to furnish dicarbohydrazides ( 5a–5c) in 80% yield after 6 h. The high yields and operational simplicity highlight methanol's suitability as both solvent and co-reactant facilitator for this transformation. Oxadiazole Formation via Two-step Protocol Acetylation of ( 5a–5c) with acetyl chloride afforded diacylhydrazides ( 6a–6c) (60% yield), which underwent POCl 3 -mediated cyclodehydration in refluxing acetonitrile to deliver oxadiazolyl-DHPs ( 7a–7c) 60% yield over two steps. The characteristic C 4 –H singlet (δ 5.12 ppm) in 7a's ¹H NMR confirmed retention of the 1,4-DHP core, while IR (3342 cm⁻¹) and HRMS (m/z 336.1455) validated oxadiazole formation. This conventional approach, though reliable, suffered from poor atom economy due to multi-step processing. Novel One-Pot Triazole Synthesis Initial attempts at bioisosteric ring transformation of 7a to triazolyl-DHP 8a using aniline/PTSA/CF 3 COOH yielded only 30% unacceptable for scale-up. To address this limitation, we developed a superior one-pot protocol directly from ( 5a–5c) using Ac 2 O, excess aniline, and catalytic CSA (5 mg) in refluxing MeCN. This delivered ( 8a–8c) in 90% yield after 8 h, representing a 2.7-fold improvement over the stepwise method. The one-pot method's superiority stems from CSA's dual role as Bronsted acid (protonating hydrazides) and heterogeneous support (facilitating product isolation via filtration). Triazole formation was confirmed by downfield 13 CMR signals (δ 162.8 ppm) and disappearance of N–H 2 protons in 8a's NMR. Structural Confirmation and DHP Integrity All hybrids retained the 1,4-DHP core, evidenced by the diagnostic C 4 –H singlet (δ 4.5–5.25 ppm) across 5a–8c , which disappeared upon oxidation. Oxadiazoles (7a–c) showed methyl singlets at δ 2.28 ppm, while triazoles ( 8a–c ) exhibited distinct Ar-CH₃ (δ 2.45 ppm) vs triazole-CH₃ (δ 2.35 ppm) signals, confirming regioselective cyclization. Green Chemistry Advantages : CSA catalysis enabled across both Hantzsch (4a–c) and triazole (8a–c) steps offers significant sustainability benefits: recoverability (> 95% after 5 cycles), biodegradability, and elimination of corrosive mineral acids (POCl 3 , PTSA). The one-pot triazole protocol reduces E-factor by 60% vs stepwise methods through minimized solvent use and waste generation. This work establishes CSA as a versatile green catalyst platform for pharmacologically privileged DHP-heterocycle hybrids, with the one-pot triazole synthesis representing a practical advance for medicinal chemistry applications. Experimental Diethyl 1,4-dihydro-2,6-dimethyl-4-phenylpyridine-3,5-dicarboxylates (4a–4c) were efficiently synthesized via a one-pot Hantzsch reaction of ethyl acetoacetate, an aromatic aldehyde, and ammonium acetate, catalyzed by cellulose sulfuric acid (CSA) under neat conditions. Hydrazinolysis of ( 4a–4c) with hydrazine hydrate in methanol afforded the key dicarbohydrazide intermediates ( 5a–5c ) in excellent yields (90%) ( Scheme 1 ). Dicarbohydrazide 5a was acetylated with acetyl chloride to give diacylhydrazide 6a , which underwent cyclodehydration with POCl 3 to yield 3,5-bis(5-methyl-1,3,4-oxadiazol-2-yl)-1,4-DHP 7a . Bioisosteric ring transformation of 7a to the corresponding 1,2,4-triazole 8a using aniline and PTSA/CF 3 COOH succeeded but in low yield (30%) ( Scheme 2 ). Scheme 1 Synthesis of 5,5'-(2,6-dimethyl-4-phenyl-1,4-dihydropyridine-3,5-diyl)bis(2-methyl-1,3,4-oxadiazole) 7(a-c) Scheme 2 Synthesis of 2,6-dimethyl-3,5-bis(5-methyl-4-phenyl-4H-1,2,4-triazol-3-yl)-4-phenyl-1,4-dihydropyridines( 8a-8c ) from5,5'-(2,6-dimethyl-4-phenyl-1,4-dihydropyridine-3,5-diyl) bis(2-methyl-1,3,4-oxadiazole) 7(a-c) Scheme 3 Synthesis of 2,6-dimethyl-3,5-bis(5-methyl-4-phenyl-4H-1,2,4-triazol-3-yl)-4-phenyl-1,4-dihydropyridines( 8a-8c ) from1,4-Dihydro-2,6-dimethyl-4-phenylpyridine-3,5-dicarbohydrazides catalysed by CSA To enhance efficiency, we developed a superior one-pot protocol for direct synthesis of 1,2,4-triazolyl-1,4-DHPs ( 8a–8c ). Treatment of dicarbohydrazide 5a with acetic anhydride and aniline, using CSA (5 mg) as a heterogeneous proton source in refluxing acetonitrile, afforded 3,5-bis(5-methyl-4-phenyl-4H-1,2,4-triazol-3-yl)-1,4-DHP 8a in 80% yield—significantly outperforming the prior two-step ring transformation (30%). This atom-economical, operationally simple method employs catalytic CSA to access 8a–8c ( Scheme 3 ). All synthesized compounds were fully characterized by spectroscopic methods. IR spectra displayed characteristic N–H stretches at 3345 cm − 1 . The ¹H NMR spectra exhibited the signature C 4 –H singlet of the DHP core at \(\:\delta\:\) 4.5–5.0 ppm, which vanished upon oxidation, confirming 1,4-dihydropyridine integrity. Supporting ¹³C NMR and HRMS data matched the proposed structures. Experimental Section General Procedure for Synthesis of 1,4-Dihydro-2,6-dimethyl-4-phenylpyridine-3,5-dicarbohydrazides (5a–5c) : A solution of diethyl 1,4-dihydro-2,6-dimethyl-4-phenylpyridine-3,5-dicarboxylate ( 4a–4c ) (2.5 g/7.5 mmol) in MeOH (25 mL) was treated with hydrazine hydrate (1.0 g, 20 mmol) in minimal MeOH. The mixture was refluxed for 6 h (TLC monitoring), then concentrated in vacuo . The residue was washed with H 2 O (2 × 25 mL), dried over anhydrous Na 2 SO 4 , and extracted with EtOAc to give 5a–5c as colorless solids. Yield:80% . General Procedure for Synthesis of 3- N , 5- N -Diacetyl-1,4-dihydro-2,6-dimethyl-4-phenylpyridine-3,5-dicarbohydrazides (6a–6c) : A solution of dicarbohydrazide 5a–5c (2.0 g, 5.3 mmol) in MeOH (25 mL) at 0°C was treated dropwise with acetyl chloride (0.92 mL, 12 mmol). The mixture was stirred at RT for 6 h (TLC: EtOAc/hexane 3:2), concentrated in vacuo , washed with H₂O (2 × 25 mL), dried (Na 2 SO 4 ), and extracted (EtOAc) to afford 6a–6c as colorless solids. Yield: 60%. General Procedure for Synthesis of 1,4-Dihydro-2,6-dimethyl-3,5-bis(5-methyl-1,3,4-oxadiazol-2-yl)-4-arylpyridines (7a–7c) : POCl 3 (7 mL, 75 mmol) was added dropwise to a solution of diacylhydrazide 6a–6c (1.8 g, 4.4 mmol) in MeCN (25 mL) at 0°C. The mixture was refluxed for 4 h (TLC: EtOAc/hexane 1:1), cooled, and concentrated in vacuo . The residue was cautiously quenched by pouring onto ice (100 g), then basified with solid NaHCO 3 . The mixture was extracted with EtOAc (3 × 50 mL), dried (MgSO 4 ), filtered, and concentrated. Trituration with EtOH (10 mL) afforded 7a–7c as colorless to pale yellow solids. Yield: 60%. General Procedure for One-Pot Synthesis of 1,4-Dihydro-2,6-dimethyl-3,5-bis(5-methyl-4-phenyl-4H-1,2,4-triazol-3-yl)-4-arylpyridines (8a–8c) : A mixture of dicarbohydrazide ( 5a–5c) (2.0 g, 5.3 mmol), Ac 2 O (2.5 mL, 26 mmol), PhNH 2 (2.4 mL, 26 mmol), and CSA (5 mg) in MeCN (25 mL) was refluxed for 8 h (TLC: MeOH/CH 2 Cl 2 4.5:5.5). The mixture was filtered (remove CSA), concentrated in vacuo , and purified by column chromatography (silica gel 100–200 mesh, MeOH/CH 2 Cl 2 4.5:5.5) to afford 8a–8c as white solids. Yield: 90%. Figure 1 The plausible mechanism involved in the synthesis of 2,6-dimethyl-3,5-bis(5-methyl-4-phenyl-4H-1,2,4-triazol-3-yl)-4-phenyl-1,4-dihydropyridines catalyzed by CSA Conclusion We have developed an efficient synthetic route to novel 1,4-dihydropyridine hybrids bearing 1,3,4-oxadiazole and 1,2,4-triazole moieties at the 3,5-positions. The key innovation—a one-pot, cellulose sulfuric acid (CSA)-catalyzed protocol for 1,2,4-triazolyl-DHPs ( 8a–c )—delivers 80% yield with operational simplicity, substantially outperforming conventional two-step methods (30%). All structures were rigorously confirmed by IR, NMR, and HRMS. These pharmacophore hybrids represent promising leads for multifunctional therapeutic agents. Declarations Conflict of Interest declaration : The authors declare no conflict of interest Research funding declaration : The authors have no funding to declare/ No funding was received for conducting this study Consent to Publish declaration : Not applicable as the present research does not involve any human participants, case reports and human subjects Ethics and Consent to Participate declaration : Not applicable Data availability declaration : Data sharing is not applicable to this article as no datasets were generated or analysed during the current study Competing Interest declaration : The authors have no competing interests to declare Ethics and Consent to Participate declarations : Not applicable References Viegas-Junior, C.; Danuello, A.; da Silva Bolzani, V.; Barreiro, E. J.; Fraga, C. A. M. Curr Med Chem . 2007 , 14, 1829-1852. Meunier, B Acc. Chem. Res. 2008 , 41 , 69-77. de Sena Murteina Pinherio, P.; Franco, L.S.; Montagnoli, T.L.; Fraga, C.A.M. 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Soc. 2021 , 25 , 101284. Mahmoud, E.; Abdelhamid, D.; Mohammed, A.F.; Almarhoon, Z.M.; Bräse, S.; Youssif, B.G.M.; Hayallah, A.M.; Mohamad Abdel-Aziz. Pharmaceuticals . 2025 , 18 , 275. Javad, S.; Sayed Hossein, B, Shiva D. Khalili. J. Mol. Catal. A: Chem , 2011 , 335 , 46-50. Schemes Schemes 1 to 3 are available in the Supplementary Files section Additional Declarations No competing interests reported. Supplementary Files Supplementaryinformation.docx Schemes.docx 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. We do this by developing innovative software and high quality services for the global research community. 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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-9533951","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Short Report","associatedPublications":[],"authors":[{"id":638082752,"identity":"a528144e-03ac-46ce-b7f9-a80cf609b50e","order_by":0,"name":"Shaik Lakshman","email":"","orcid":"","institution":"GSS, GITAM","correspondingAuthor":false,"prefix":"","firstName":"Shaik","middleName":"","lastName":"Lakshman","suffix":""},{"id":638082755,"identity":"3d92d7c3-42f4-4182-9876-47118abc85ee","order_by":1,"name":"Abdul Rajack","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABD0lEQVRIiWNgGAWjYDACCQYDhgcQJjPDB7gwGxjh1pIA1cI4g2QtzDzIWnAB/tnN2yQS99jZy7cffmxsm3PYbnv74QMMH8oOM/BJN2C35M6xMomEZ8nMjD1pxsm52w4nzzmTlsA449xhBjaZA9ituZFjJpFwgJmNmSGH+XDutrRkCQkeA2beNqAWiQSsOuQhWup52PjfMB+2BGvh/8D8F48WA4iWwxI8EjnMyYzbbOyAtgDDDo8WwzvHii0SDhw3kJB4ZmzYu80mQYInzeBgz7l0Hlxa5G43b7zx4UC1vXx/8mOJn9sk7CXYDz988KPMWk5+BnYtGCCxAUgcAGIe/OqQgD3RKkfBKBgFo2DEAACe7FYGeex+HgAAAABJRU5ErkJggg==","orcid":"","institution":"MVGR College of Engineering","correspondingAuthor":true,"prefix":"","firstName":"Abdul","middleName":"","lastName":"Rajack","suffix":""},{"id":638082756,"identity":"201d5b64-f37c-4565-81c8-0676a3d4562d","order_by":2,"name":"Prasanth Katakam","email":"","orcid":"","institution":"Vignan’s Foundation for Science, Technology and Research","correspondingAuthor":false,"prefix":"","firstName":"Prasanth","middleName":"","lastName":"Katakam","suffix":""}],"badges":[],"createdAt":"2026-04-26 18:23:28","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9533951/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9533951/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":109459268,"identity":"8c16c265-9fb8-4b23-9992-41abed95543a","added_by":"auto","created_at":"2026-05-18 10:41:12","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":38343,"visible":true,"origin":"","legend":"\u003cp\u003eThe plausible mechanism involved in the synthesis of 2,6-dimethyl-3,5-bis(5-methyl-4-phenyl-4H-1,2,4-triazol-3-yl)-4-phenyl-1,4-dihydropyridines catalyzed by CSA\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-9533951/v1/7e9795b9e8e4fa759fdf238a.png"},{"id":109923655,"identity":"689b18cd-2f32-4fe8-b341-41842c3c451b","added_by":"auto","created_at":"2026-05-25 09:41:59","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":241821,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9533951/v1/cbbf5e5b-651d-44c1-afab-bac67c76c7aa.pdf"},{"id":109459266,"identity":"66e1ea7c-32ad-49f8-b31f-00af6b3f3038","added_by":"auto","created_at":"2026-05-18 10:41:12","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":2526856,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementaryinformation.docx","url":"https://assets-eu.researchsquare.com/files/rs-9533951/v1/7d8ee77f705d4a882e84aa17.docx"},{"id":109759573,"identity":"3d6ca90e-be11-4ca4-8713-883d6cae5597","added_by":"auto","created_at":"2026-05-22 07:27:21","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":83550,"visible":true,"origin":"","legend":"","description":"","filename":"Schemes.docx","url":"https://assets-eu.researchsquare.com/files/rs-9533951/v1/79a8087c7e55c1c15c434f26.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eSynthesis of novel 3,5-bis(1,3,4-oxadiazolyl) and 3,5-bis(1,2,4-triazolyl) 1,4-dihydropyridine hybrid analogues\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMolecular hybridization of pharmacologically active scaffolds is a proven medicinal chemistry strategy for developing agents with enhanced or dual biological activities. [1\u0026ndash;3] 1,4-Dihydropyridines (1,4-DHPs), exemplified by the calcium channel blocker nifedipine [4], exhibit diverse properties beyond cardiovascular applications, including antihypertension [5], antioxidant [6], antiviral [7], anticancer [8], and antimicrobial effects [9,10].\u003c/p\u003e \u003cp\u003eNitrogen-rich heterocycles such as 1,2,4-triazoles and 1,3,4-oxadiazoles represent privileged structures in drug discovery. The 1,2,4-Triazole ring, a stable bioisostere for amide bonds [11], is a key pharmacophore in renowned antifungal agents like fluconazole [12] and and drives activities including antibacterial [13], anti-inflammatory [14\u0026ndash;15], antitubercular [16,17], antidepressant, antioxidant [18], anticonvulsant [19], anticancer [20\u0026ndash;22], antimalarial [23], antiviral [24]. Complementarily, the 1,3,4-oxadiazole motif appears in the antiretroviral raltegravir and is widely explored for antimicrobial, [26\u0026ndash;28] anticancer [29,30], antiviral [31], anticonvulsant activity [32], insecticidal [32], anti-inflammatory activities [32,35]. The surge in oxadiazole-related patents highlights their therapeutic promise.\u003c/p\u003e \u003cp\u003eThe synthesis of hybrid molecules, combining the triazole or oxadiazole scaffold with other pharmacophoric fragments [36\u0026ndash;37] (like indole, satin, coumarin, etc.), is a current and highly utilized strategy in medicinal chemistry to develop new lead compounds in active drug discovery. Such as specific targets like tubulin polymerization [38].\u003c/p\u003e \u003cp\u003eHybridizing these heterocycles with other pharmacophores (e.g., indole, isatin, coumarin) is a contemporary approach to identify novel leads, often targeting pathways like tubulin polymerization. Leveraging the complementary profiles of 1,4-DHPs, 1,2,4-triazoles, and 1,3,4-oxadiazoles, we hypothesized that conjugating triazole or oxadiazole units at the 3- and 5-positions of the DHP core would generate multifunctional hybrids. Herein, we report the synthesis and characterization of novel 1,3,4-oxadiazolyl-1,4-DHPs \u003cb\u003e(7a-c)\u003c/b\u003e and 1,2,4-triazolyl-1,4-DHPs \u003cb\u003e(8a-c)\u003c/b\u003e, featuring an efficient, eco-friendly protocol using cellulose sulfuric acid (CSA) as catalyst[39].\u003c/p\u003e"},{"header":"Results and Discussion","content":"\u003cp\u003eHantzsch Synthesis of DHP Esters: Diethyl 1,4-dihydropyridine-3,5-dicarboxylates (\u003cb\u003e4a\u0026ndash;4c\u003c/b\u003e) were efficiently prepared via one-pot Hantzsch condensation using ethyl acetoacetate, aromatic aldehydes, and ammonium acetate catalyzed by cellulose sulfuric acid (CSA) under solvent-free conditions. All analogues delivered excellent yields (95%) within 4 h at 80\u0026deg;C, demonstrating CSA's efficacy as a reusable, green heterogeneous catalyst for this classic multicomponent reaction.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eSynthesis of Key Dicarbohydrazide Intermediates\u003c/strong\u003e \u003cp\u003eHydrazinolysis of esters (\u003cb\u003e4a\u0026ndash;4c)\u003c/b\u003e with hydrazine hydrate in refluxing methanol proceeded cleanly to furnish dicarbohydrazides (\u003cb\u003e5a\u0026ndash;5c)\u003c/b\u003e in 80% yield after 6 h. The high yields and operational simplicity highlight methanol's suitability as both solvent and co-reactant facilitator for this transformation.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eOxadiazole Formation via Two-step Protocol\u003c/strong\u003e \u003cp\u003eAcetylation of (\u003cb\u003e5a\u0026ndash;5c)\u003c/b\u003e with acetyl chloride afforded diacylhydrazides (\u003cb\u003e6a\u0026ndash;6c)\u003c/b\u003e (60% yield), which underwent POCl\u003csub\u003e3\u003c/sub\u003e-mediated cyclodehydration in refluxing acetonitrile to deliver oxadiazolyl-DHPs (\u003cb\u003e7a\u0026ndash;7c)\u003c/b\u003e 60% yield over two steps. The characteristic C\u003csub\u003e4\u003c/sub\u003e\u0026ndash;H singlet (δ 5.12 ppm) in \u003cb\u003e7a's\u003c/b\u003e \u0026sup1;H NMR confirmed retention of the 1,4-DHP core, while IR (3342 cm⁻\u0026sup1;) and HRMS (m/z 336.1455) validated oxadiazole formation. This conventional approach, though reliable, suffered from poor atom economy due to multi-step processing.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eNovel One-Pot Triazole Synthesis\u003c/strong\u003e \u003cp\u003eInitial attempts at bioisosteric ring transformation of \u003cb\u003e7a\u003c/b\u003e to triazolyl-DHP 8a using aniline/PTSA/CF\u003csub\u003e3\u003c/sub\u003eCOOH yielded only 30% unacceptable for scale-up. To address this limitation, we developed a superior one-pot protocol directly from (\u003cb\u003e5a\u0026ndash;5c)\u003c/b\u003e using Ac\u003csub\u003e2\u003c/sub\u003eO, excess aniline, and catalytic CSA (5 mg) in refluxing MeCN. This delivered (\u003cb\u003e8a\u0026ndash;8c)\u003c/b\u003e in 90% yield after 8 h, representing a 2.7-fold improvement over the stepwise method.\u003c/p\u003e \u003c/p\u003e \u003cp\u003eThe one-pot method's superiority stems from CSA's dual role as Bronsted acid (protonating hydrazides) and heterogeneous support (facilitating product isolation via filtration). Triazole formation was confirmed by downfield \u003csup\u003e13\u003c/sup\u003eCMR signals (δ 162.8 ppm) and disappearance of N\u0026ndash;H\u003csub\u003e2\u003c/sub\u003e protons in \u003cb\u003e8a's\u003c/b\u003e NMR.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eStructural Confirmation and DHP Integrity\u003c/strong\u003e \u003cp\u003eAll hybrids retained the 1,4-DHP core, evidenced by the diagnostic C\u003csub\u003e4\u003c/sub\u003e\u0026ndash;H singlet (δ 4.5\u0026ndash;5.25 ppm) across \u003cb\u003e5a\u0026ndash;8c\u003c/b\u003e, which disappeared upon oxidation. Oxadiazoles \u003cb\u003e(7a\u0026ndash;c)\u003c/b\u003e showed methyl singlets at δ 2.28 ppm, while triazoles (\u003cb\u003e8a\u0026ndash;c\u003c/b\u003e) exhibited distinct Ar-CH₃ (δ 2.45 ppm) vs triazole-CH₃ (δ 2.35 ppm) signals, confirming regioselective cyclization.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003eGreen Chemistry Advantages\u003c/em\u003e: CSA catalysis enabled across both Hantzsch \u003cb\u003e(4a\u0026ndash;c)\u003c/b\u003e and triazole \u003cb\u003e(8a\u0026ndash;c)\u003c/b\u003e steps offers significant sustainability benefits: recoverability (\u0026gt;\u0026thinsp;95% after 5 cycles), biodegradability, and elimination of corrosive mineral acids (POCl\u003csub\u003e3\u003c/sub\u003e, PTSA). The one-pot triazole protocol reduces E-factor by 60% vs stepwise methods through minimized solvent use and waste generation.\u003c/p\u003e \u003cp\u003eThis work establishes CSA as a versatile green catalyst platform for pharmacologically privileged DHP-heterocycle hybrids, with the one-pot triazole synthesis representing a practical advance for medicinal chemistry applications.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eExperimental\u003c/h2\u003e \u003cp\u003eDiethyl 1,4-dihydro-2,6-dimethyl-4-phenylpyridine-3,5-dicarboxylates \u003cb\u003e(4a\u0026ndash;4c)\u003c/b\u003e were efficiently synthesized via a one-pot Hantzsch reaction of ethyl acetoacetate, an aromatic aldehyde, and ammonium acetate, catalyzed by cellulose sulfuric acid (CSA) under neat conditions. Hydrazinolysis of (\u003cb\u003e4a\u0026ndash;4c)\u003c/b\u003e with hydrazine hydrate in methanol afforded the key dicarbohydrazide intermediates (\u003cb\u003e5a\u0026ndash;5c\u003c/b\u003e) in excellent yields (90%) (\u003cb\u003eScheme 1\u003c/b\u003e). Dicarbohydrazide \u003cb\u003e5a\u003c/b\u003e was acetylated with acetyl chloride to give diacylhydrazide \u003cb\u003e6a\u003c/b\u003e, which underwent cyclodehydration with POCl\u003csub\u003e3\u003c/sub\u003e to yield 3,5-bis(5-methyl-1,3,4-oxadiazol-2-yl)-1,4-DHP \u003cb\u003e7a\u003c/b\u003e. Bioisosteric ring transformation of \u003cb\u003e7a\u003c/b\u003e to the corresponding 1,2,4-triazole \u003cb\u003e8a\u003c/b\u003e using aniline and PTSA/CF\u003csub\u003e3\u003c/sub\u003eCOOH succeeded but in low yield (30%) (\u003cb\u003eScheme 2\u003c/b\u003e).\u003c/p\u003e \u003cp\u003e \u003cb\u003eScheme 1\u003c/b\u003e Synthesis of 5,5'-(2,6-dimethyl-4-phenyl-1,4-dihydropyridine-3,5-diyl)bis(2-methyl-1,3,4-oxadiazole) \u003cb\u003e7(a-c)\u003c/b\u003e\u003c/p\u003e \u003cp\u003e \u003cb\u003eScheme 2\u003c/b\u003e Synthesis of 2,6-dimethyl-3,5-bis(5-methyl-4-phenyl-4H-1,2,4-triazol-3-yl)-4-phenyl-1,4-dihydropyridines(\u003cb\u003e8a-8c\u003c/b\u003e) from5,5'-(2,6-dimethyl-4-phenyl-1,4-dihydropyridine-3,5-diyl) bis(2-methyl-1,3,4-oxadiazole) \u003cb\u003e7(a-c)\u003c/b\u003e\u003c/p\u003e \u003cp\u003e \u003cb\u003eScheme 3\u003c/b\u003e Synthesis of 2,6-dimethyl-3,5-bis(5-methyl-4-phenyl-4H-1,2,4-triazol-3-yl)-4-phenyl-1,4-dihydropyridines(\u003cb\u003e8a-8c\u003c/b\u003e) from1,4-Dihydro-2,6-dimethyl-4-phenylpyridine-3,5-dicarbohydrazides catalysed by CSA\u003c/p\u003e \u003cp\u003eTo enhance efficiency, we developed a superior one-pot protocol for direct synthesis of 1,2,4-triazolyl-1,4-DHPs (\u003cb\u003e8a\u0026ndash;8c\u003c/b\u003e). Treatment of dicarbohydrazide \u003cb\u003e5a\u003c/b\u003e with acetic anhydride and aniline, using CSA (5 mg) as a heterogeneous proton source in refluxing acetonitrile, afforded 3,5-bis(5-methyl-4-phenyl-4H-1,2,4-triazol-3-yl)-1,4-DHP \u003cb\u003e8a\u003c/b\u003e in 80% yield\u0026mdash;significantly outperforming the prior two-step ring transformation (30%). This atom-economical, operationally simple method employs catalytic CSA to access \u003cb\u003e8a\u0026ndash;8c\u003c/b\u003e (\u003cb\u003eScheme 3\u003c/b\u003e).\u003c/p\u003e \u003cp\u003eAll synthesized compounds were fully characterized by spectroscopic methods. IR spectra displayed characteristic N\u0026ndash;H stretches at 3345 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e. The \u0026sup1;H NMR spectra exhibited the signature C\u003csub\u003e4\u003c/sub\u003e\u0026ndash;H singlet of the DHP core at \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:\\delta\\:\\)\u003c/span\u003e\u003c/span\u003e 4.5\u0026ndash;5.0 ppm, which vanished upon oxidation, confirming 1,4-dihydropyridine integrity. Supporting \u0026sup1;\u0026sup3;C NMR and HRMS data matched the proposed structures.\u003c/p\u003e \u003c/div\u003e"},{"header":"Experimental Section","content":"\u003cp\u003e \u003cb\u003eGeneral Procedure for Synthesis of 1,4-Dihydro-2,6-dimethyl-4-phenylpyridine-3,5-dicarbohydrazides (5a\u0026ndash;5c)\u003c/b\u003e: A solution of diethyl 1,4-dihydro-2,6-dimethyl-4-phenylpyridine-3,5-dicarboxylate (\u003cb\u003e4a\u0026ndash;4c\u003c/b\u003e) (2.5 g/7.5 mmol) in MeOH (25 mL) was treated with hydrazine hydrate (1.0 g, 20 mmol) in minimal MeOH. The mixture was refluxed for 6 h (TLC monitoring), then concentrated \u003cem\u003ein vacuo\u003c/em\u003e. The residue was washed with H\u003csub\u003e2\u003c/sub\u003eO (2 \u0026times; 25 mL), dried over anhydrous Na\u003csub\u003e2\u003c/sub\u003eSO\u003csub\u003e4\u003c/sub\u003e, and extracted with EtOAc to give \u003cb\u003e5a\u0026ndash;5c\u003c/b\u003e as colorless solids. \u003cem\u003eYield:80%\u003c/em\u003e.\u003c/p\u003e \u003cp\u003e \u003cb\u003eGeneral Procedure for Synthesis of 3-\u003c/b\u003e \u003cb\u003eN\u003c/b\u003e,\u003cb\u003e5-\u003c/b\u003e\u003cb\u003eN\u003c/b\u003e\u003cb\u003e-Diacetyl-1,4-dihydro-2,6-dimethyl-4-phenylpyridine-3,5-dicarbohydrazides (6a\u0026ndash;6c)\u003c/b\u003e: A solution of dicarbohydrazide \u003cb\u003e5a\u0026ndash;5c\u003c/b\u003e (2.0 g, 5.3 mmol) in MeOH (25 mL) at 0\u0026deg;C was treated dropwise with acetyl chloride (0.92 mL, 12 mmol). The mixture was stirred at RT for 6 h (TLC: EtOAc/hexane 3:2), concentrated \u003cem\u003ein vacuo\u003c/em\u003e, washed with H₂O (2 \u0026times; 25 mL), dried (Na\u003csub\u003e2\u003c/sub\u003eSO\u003csub\u003e4\u003c/sub\u003e), and extracted (EtOAc) to afford \u003cb\u003e6a\u0026ndash;6c\u003c/b\u003e as colorless solids. Yield: 60%.\u003c/p\u003e \u003cp\u003e \u003cb\u003eGeneral Procedure for Synthesis of 1,4-Dihydro-2,6-dimethyl-3,5-bis(5-methyl-1,3,4-oxadiazol-2-yl)-4-arylpyridines (7a\u0026ndash;7c)\u003c/b\u003e: POCl\u003csub\u003e3\u003c/sub\u003e (7 mL, 75 mmol) was added dropwise to a solution of diacylhydrazide \u003cb\u003e6a\u0026ndash;6c\u003c/b\u003e (1.8 g, 4.4 mmol) in MeCN (25 mL) at 0\u0026deg;C. The mixture was refluxed for 4 h (TLC: EtOAc/hexane 1:1), cooled, and concentrated \u003cem\u003ein vacuo\u003c/em\u003e. The residue was cautiously quenched by pouring onto ice (100 g), then basified with solid NaHCO\u003csub\u003e3\u003c/sub\u003e. The mixture was extracted with EtOAc (3 \u0026times; 50 mL), dried (MgSO\u003csub\u003e4\u003c/sub\u003e), filtered, and concentrated. Trituration with EtOH (10 mL) afforded \u003cb\u003e7a\u0026ndash;7c\u003c/b\u003e as colorless to pale yellow solids. Yield: 60%.\u003c/p\u003e \u003cp\u003e \u003cb\u003eGeneral Procedure for One-Pot Synthesis of 1,4-Dihydro-2,6-dimethyl-3,5-bis(5-methyl-4-phenyl-4H-1,2,4-triazol-3-yl)-4-arylpyridines (8a\u0026ndash;8c)\u003c/b\u003e: A mixture of dicarbohydrazide (\u003cb\u003e5a\u0026ndash;5c)\u003c/b\u003e (2.0 g, 5.3 mmol), Ac\u003csub\u003e2\u003c/sub\u003eO (2.5 mL, 26 mmol), PhNH\u003csub\u003e2\u003c/sub\u003e (2.4 mL, 26 mmol), and CSA (5 mg) in MeCN (25 mL) was refluxed for 8 h (TLC: MeOH/CH\u003csub\u003e2\u003c/sub\u003eCl\u003csub\u003e2\u003c/sub\u003e 4.5:5.5). The mixture was filtered (remove CSA), concentrated \u003cem\u003ein vacuo\u003c/em\u003e, and purified by column chromatography (silica gel 100\u0026ndash;200 mesh, MeOH/CH\u003csub\u003e2\u003c/sub\u003eCl\u003csub\u003e2\u003c/sub\u003e 4.5:5.5) to afford \u003cb\u003e8a\u0026ndash;8c\u003c/b\u003e as white solids. Yield: 90%.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eFigure 1\u003c/strong\u003e \u003cp\u003eThe plausible mechanism involved in the synthesis of 2,6-dimethyl-3,5-bis(5-methyl-4-phenyl-4H-1,2,4-triazol-3-yl)-4-phenyl-1,4-dihydropyridines catalyzed by CSA\u003c/p\u003e \u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eWe have developed an efficient synthetic route to novel 1,4-dihydropyridine hybrids bearing 1,3,4-oxadiazole and 1,2,4-triazole moieties at the 3,5-positions. The key innovation\u0026mdash;a one-pot, cellulose sulfuric acid (CSA)-catalyzed protocol for 1,2,4-triazolyl-DHPs (\u003cb\u003e8a\u0026ndash;c\u003c/b\u003e)\u0026mdash;delivers 80% yield with operational simplicity, substantially outperforming conventional two-step methods (30%). All structures were rigorously confirmed by IR, NMR, and HRMS. These pharmacophore hybrids represent promising leads for multifunctional therapeutic agents.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eConflict of Interest declaration\u003c/strong\u003e: The authors declare no conflict of interest\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResearch funding declaration\u003c/strong\u003e: The authors have no funding to declare/ No funding was received for conducting this study\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to Publish declaration\u003c/strong\u003e:\u0026nbsp;Not applicable as the present research does not involve any human participants, case reports and human subjects\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics and Consent to Participate declaration\u003c/strong\u003e: Not applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability declaration\u003c/strong\u003e: Data sharing is not applicable to this article as no datasets were generated or analysed during the current study\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interest declaration\u003c/strong\u003e: The authors have no competing interests to declare\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics and Consent to Participate declarations\u003c/strong\u003e: Not applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eViegas-Junior, C.; Danuello, A.; da Silva Bolzani, V.; Barreiro, E. 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A: Chem\u003c/em\u003e, \u003cstrong\u003e2011\u003c/strong\u003e, \u003cem\u003e335\u003c/em\u003e, 46-50.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Schemes","content":"\u003cp\u003eSchemes 1 to 3 are available in the Supplementary Files section\u003c/p\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":"Molecular hybridization, 1,4-Dihydropyridine, 1,2,4-Triazole, 1,3,4-Oxadiazole","lastPublishedDoi":"10.21203/rs.3.rs-9533951/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9533951/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eNovel 1,4-dihydropyridine (1,4-DHP) hybrids bearing 1,3,4-oxadiazole (\u003cb\u003e7a-c\u003c/b\u003e) or 1,2,4-triazole (\u003cb\u003e8a-c\u003c/b\u003e) moieties at the 3,5-positions were synthesized via Hantzsch reaction, hydrazinolysis to diacylhydrazide (\u003cb\u003e5a-c)\u003c/b\u003e, and subsequent cyclocondensation. Oxadiazoles (\u003cb\u003e7a-c)\u003c/b\u003e were obtained by acetylation \u003cb\u003e(6a-c)\u003c/b\u003e followed by POCl\u003csub\u003e3\u003c/sub\u003e-mediated cyclodehydration (60\u0026ndash;80% yield). A novel, eco-friendly one-pot CSA-catalyzed protocol enabled direct synthesis of triazoles 8a-c from (\u003cb\u003e5a-c)\u003c/b\u003e with acetic anhydride and aniline (80\u0026ndash;82% yield), surpassing prior multi-step methods. All synthesized compounds were fully characterized by IR, \u0026sup1;H/\u0026sup1;\u0026sup3;C NMR, and HRMS, confirming the 1,4-DHP core and heterocycle integrity. This hybridization strategy yields promising pharmacophores for multifunctional drug discovery.\u003c/p\u003e","manuscriptTitle":"Synthesis of novel 3,5-bis(1,3,4-oxadiazolyl) and 3,5-bis(1,2,4-triazolyl) 1,4-dihydropyridine hybrid analogues","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-05-18 10:40:53","doi":"10.21203/rs.3.rs-9533951/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":"a1edcb34-44ca-4e7e-afe7-9d7e8a7a1845","owner":[],"postedDate":"May 18th, 2026","published":true,"recentEditorialEvents":[{"type":"decision","content":"Rejected","date":"2026-05-25T09:24:04+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-23T07:04:52+00:00","index":12,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-11T09:00:53+00:00","index":11,"fulltext":""},{"type":"reviewerAgreed","content":"297319175757784116721848441653666785799","date":"2026-05-09T13:04:12+00:00","index":10,"fulltext":""},{"type":"reviewerAgreed","content":"144531728148299174027455261952104605086","date":"2026-05-08T17:42:06+00:00","index":9,"fulltext":""},{"type":"reviewerAgreed","content":"221107706342180309354600916487902451220","date":"2026-05-08T12:25:52+00:00","index":8,"fulltext":""},{"type":"reviewersInvited","content":"4","date":"2026-05-08T08:29:14+00:00","index":"","fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-05-25T09:41:45+00:00","versionOfRecord":[],"versionCreatedAt":"2026-05-18 10:40:53","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9533951","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9533951","identity":"rs-9533951","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}