Trisubstituted Methanes (TRSMs): Synthesis and Bioevaluation as Anti-malarials

Abstract

Focused libraries of Trisubstituted methanes (TRSMs) have been synthesized through Grignard reaction of aryl magnesium bromide with various carbaldehydes followed by Friedel-Crafts alkylation of diaryl carbinols with electron rich aryl and heteroaryl thiols. These compounds were investigated to inhibit parasite growth and development and displayed strong anti-malarial activity in vitro against human malaria parasite Plasmodium falciparum. The synthesized TRSMs interact well with free heme and form stable TRSM-heme complexes. Furthermore, they also inhibit β-hematin formation (hemozoin formation) in a concentration dependent manner. Measurement of heme binding affinity and hemozoin inhibition for TRSMs revealed strong correlation with anti-malarial potency. Structure activity relationship revealed that TRSMs containing pyridyl and quinoline ring were more efficient to offer anti-malarial activity.