Insilco Study, Synthesis Of Thiazole Molecules As Possible Dihydrofolate Reductase Inhibitors Against Malaria

Abstract

Heterocyclic compounds are the main class of medicinally important compounds. Many heterocyclic compounds bearing a five-membered ring in their structure have a good spectrum of biological activities. In medicinal chemistry, thiazole and its analogues are promising scaffolds. Many of them have been reported to exhibit a variety of biological responses, including anti-hyperlipidemic, anti-HIV, anticancer, anti-Alzheimer, antihypertensive, anti-inflammatory, antimicrobial, anticonvulsant, antiviral, antimalarial, and antidiabetic activities. In this study a modern approach has been undertaken to identify new hits of thiazole derivatives as antimalarials targeting against Pf-DHFR. It has been conceived, synthesised, and tested for potential anti-malarial action to create a number of new thiazole derivatives. The antimalarial activity of the synthesized thiazole derivatives was assessed against human pathogenic malarial strain viz. Plasmodium falciparum while quinine was taken as the standard drug. compound 1a-1e was found to be most promising which exhibited strongest inhibitory activity against Pf-DHFR which was higher than the reference drug quinine. The aim of this research is to identify and try making a SAR (Structure Activity Relationship) of substituted thiazole nucleus as possible new antimalarials as shown in compound 1a-1e. The result of molecular docking studies showed that compounds 1a, 1b, 1c, 1d and 1e showed good docking scores with protein (protein ID-7CTZ). The compounds with the greatest docking scores were 1a and 1b (-9.9 and -9.8). Contrarily, compounds 1a, 1b, 1c, 1d, and 1e displayed favorable docking results and important interactions with amino acid residues such Gly150, leu146, Phe197, Val198, Asp145, Asp148, Thr152, Thr149, Glu144, and Ala178. The results of biological activity and docking studies showed that an electron-withdrawing group at the fourth position of the attached phenyl ring of thiazole derivatives is essential for better anti-malarial activity and a favorable drug-like profile that can lead to the emergence of a potential drug molecule in further development.