Design, Synthesis, and Antimalarial Evaluation of Novel Quinazolin-4(3H)‑one Derivatives with Molecular Modeling Insights into Target Selectivity.

Malaria is a tropical disease caused by protozoa of the genus Plasmodium and is responsible for several deaths worldwide. Current therapies are limited by the high incidence of adverse effects and the rising prevalence of parasite drug resistance, underscoring the need for research into new chemical scaffolds that can overcome these limitations and for the identification of novel drug targets to advance antimalarial development. In this context, quinazolines show promising potential as new antimalarials. Therefore, in this study, a new series of quinazolin-4-(3H)-one analogs was synthesized and evaluated for antiplasmodial activity. As a result, 36 compounds were synthesized and characterized, of which 3d, 3e, 4a, and 4e showed promising activity in assays against P. falciparum-3D7HT-GFP (IC50 = 4.36, 2.26, 1.70, and 4.10 μM) with no cytotoxicity (CC50 = 44.56, 22.91, 26.42, and 48.15 μM) and acceptable selectivity indexes (10.22, 10.14, 15.55, and 11.75). The compounds were evaluated against Leishmania donovani and Trypanosoma congolense but did not inhibit these parasites, suggesting that this chemical scaffold is selective for plasmodial targets. Accordingly, molecular modeling proposed N-myristoyltransferase (NMT) as a potential target and identified the specific binding mode of compound 4a for P. falciparum NMT (PfNMT) relative to L. donovani NMT (LdNMT), T. congolense NMT (TcNMT), and Homo sapiens NMT (HsNMT). It was found that the presence of Leu411, Leu369, Ser337, and Phe336 in PfNMT, substituted by Met412, Val370, Val338, and Tyr337 in LdNMT, and Met445, Tyr370, Ile371, and Tyr370 in TcNMT, may be related to the predicted target selectivity and the greater affinity of 4a for PfNMT. Finally, molecular dynamics simulations suggest that 4a is most stable against PfNMT, and MM-PBSA calculations indicate a binding energy for this target (ΔGbinding = -130.873 kJ/mol). These findings corroborate the promising potential of 4a and support its proposed selectivity against PfNMT, yielding a scaffold that can be explored in subsequent optimization studies.