Part I: Mild protection of alcohols using thiotetrazole reagents Part II: Total and analogue synthesis of antimalarial peptides and chloroquine probes

Abstract

Part-I: With a view to expand the repertoire of chemoselective methods applicable to sensitive and multifunctional substrates, the p-methoxy benzylation of alcohols under essentially neutral conditions was developed. This was achieved by treating alcohols with 5-(p-methoxy benzylthio)-1-phenyl-1H-tetrazole (PMB-ST) in the presence of silver triflate (AgOTf) and 2,6-di-tert-butyl-4-methylpyridine (DTBMP). Expansion into other protecting group modalities is envisaged.

Part-II: Due to malarial parasites becoming resistant to nearly every available drug, it is important to discover new antimalarial leads against new targets. A new peptide inhibitor N1266 (IC50 of 6 µM against P. falciparum) was isolated as a promising antimalarial lead from Myxobactertium species by MerLion Pharma. After determining the absolute stereochemistry via Marfey¿s analysis, we developed the total and analogue synthesis of N1266 derivatives as well as describe their associated antimalarial activity. Coumarin-labeled probes of chloroquine analogues were also developed to track concentration-dependent drug localization and hallmark features of programmed cell death (PCD) in Plasmodium falciparum. Certain probes showed promise in distinguishing chloroquine sensitive versus resistant strains of Plasmodium falciparum.