Design and synthesis of small molecule inhibitors as antimalarial agents

Abstract

Malaria has been a global issue for the last two decades and resulted in 409,000 deaths and 229 million cases in 2019 by Plasmodium falciparum (Pf) species alone. Dihydropteroate synthetase (DHPS) and Dihydrofolate reductase (DHFR) acts as promising targets for antimalarial drug candidates. We have designed different heterocyclic cores as small molecule inhibitors for PfDHFR and PfDHPS proteins. Initially, single-target therapy was used for the treatment of malaria but as resistant strains emerged, it was replaced by combination therapy using multiple drugs to overcome the resistance and these combination drugs show high synergistic effect. By using protein crystal data and molecular docking studies we determined the optimal interactions of inhibitors to explore the binding modes and binding affinities to the active site. In this project we try to design and synthesize compounds, having better activity towards resistant strains and exhibit low cytotoxicity, which can be further developed as promising antimalarial drugs. In this work, we have reported two step syntheses that can be used for the gram scale synthesis of sulfonamides. We started our synthesis using naturally occurring L-amino acids as the chiral source and successfully synthesized intermediates which can be used for furnishing the final sulfonamide products. All the intermediates are well characterized using various spectroscopic techniques.