New Glycine derived peptides bearing benzenesulphonamide as antiplasmodial agent

Abstract Background : In the tropics, malaria is among the most serious infections disease in developing countries. The discovery of artemesinin antimalarial drug not too long ago was a major breakthrough in effort to combat malaria disease. However, recent reports of resistance even to combination therapy involving artemisinin are very worrisome and have led to search for new chemical agents to sustain the fight against malaria. Carboxamide functionality has been shown as an important pharmacophore in over 25 % of commercial chemotherapeutic agents. Method : Three benzensulphonamides ( 3a-c ) were prepared from the reaction of appropriate benzensulphonyl chloride ( 1a-c ) and alanine ( 2 ) in aqueous basic medium. Eight tert-butylamino-oxo-ethylcarbamates ( 5a-h ) were also prepared from reacting commercially available boc-glycine( 4 ) and different amines using peptide coupling reagents such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC), 1-hydroxybenzotriazole (HOBt), with triethyl amine and dichloromethane (DCM) as solvents. The target compounds were prepared by reacting compounds ( 3a-c ) with compounds ( 5a-h ) in the presence of coupling reagents. The compounds were characterized and evaluated for their antiplasmodial activity Results : Computed molecular descriptors and assessed biochemical parameters showed that the compounds were drug-like and safe. All the compounds had favourable binding interaction with residues at PABA binding site of homology modeled P. falciparum dihydropteroate synthase and henceforward in vitro and in vivo antiplasmodial activities were evaluated. Compounds 7a-7x showed activity against the P. falciparum (W2 strain) at MIC values ranging from 3.52 to 0.09 µM. Moreover, seven of the compounds ( 7c , 7d , 7i , 7j , 7p , 7r and 7s ) showed better activity than quinine (MIC = 0.72 µM). In addition, 16 of the 24 compounds were found to clear more than 50 percent of P. berghei (NK-65 strain) from the blood of infected mice at 12 post-infection day. The percentages of parasites cleared by 20 mg/kg of the three most effective compounds ( 7g , 7n and 7r ) were 74.98, 74.98 and 74.07 respectively Conclusion : In coclusion, this class of glycine derived sulfonamides, especially 7r (MIC 0.71 µM), ability to clear 74.07 % of P. berghei from blood of infected mice at 20 mg/kg and interesting pharmacokinetic profile (MW = 430.31 Da, HBA = 7, HBD = 3, log P = 2.56, NRB = 9 and TPSA = 104.37 Å 2 ), could serve as leads in developing new antiplasmodial agent.