Discovery of new hit-molecules targeting Plasmodium falciparum through a global SAR study of the 4-substituted-2-trichloromethylquinazoline antiplasmodial scaffold

Abstract

From 4 antiplasmodial hit-molecules identified in 2-trichloromethylquinazoline series, we conducted a global Structure-Activity relationship (SAR) study involving 26 compounds and covering 5 molecular regions (I - V), aiming at defining the corresponding pharmacophore and identifying new bioactive derivatives. Thus, after studying the aniline moiety in detail, thienopyrimidine, quinoline and quinoxaline bio-isosters were synthesized and tested on the K1 multi-resistant P. falciparum strain, along with a cytotoxicity evaluation on the human HepG2 cell line, to define selectivity indecies. SARs first showed that thienopyrimidines and quinolines were globally more cytotoxic, while quinoxaline analogs appeared as active as- and less cytotoxic than their quinazoline counterparts. Such pharmacomodulation in quinoxaline series not only provided a new antiplasmodial reference hit-molecule (IC₅₀ = 0.4 μM, selectivity index = 100), but also highlighted an active (IC₅₀ = 0.4 μM) and quite selective (SI = 265) synthesis intermediate.

Keywords: In vitro HepG2 cytotoxicity; In vitro antiplasmodial activity; Plasmodium falciparum; Quinazoline; Quinoline; Quinoxaline; Structure-activity relationships; Thienopyrimidine; Trichloromethyl goup.