Structure-activity relationship and molecular modelling studies of quinazolinedione derivatives MMV665916 as...

A series of new quinazolinedione derivatives have been readily synthesized and evaluated for their in vitro antiplasmodial growth inhibition activity. Most of the compounds inhibited P. falciparum FcB1 strain in the low to medium micromolar concentration. The 2-ethoxy 8ag', 2-trifluoromethoxy 8ai' and 4-fluoro-2-methoxy 8ak' showed the best inhibitory activity with EC₅₀ values around 5 µM and were non-toxic to the primary human fibroblast cell line AB943. However, these compounds were less potent than the original hit MMV665916, which showed remarkable growth inhibition with EC₅₀ value of 0.4 µM and presented the highest selectivity index (SI > 250). In addition, a novel approach for determining the docking poses of these quinazolinedione derivatives with their potential protein target, the P. falciparum farnesyltransferase PfFT, was investigated.