QSAR and pharmacophore modeling of diverse aminothiazoles and aminopyridines for antimalarial potency against multidrug-resistant Plasmodium falciparum

Abstract

Artemisinin antimalarials are the frontline and effective drugs used worldwide for the treatment of deadly Plasmodium falciparum malaria. But the recent reports of artemisinin resistance have created the urgent need to discover new molecules against single and multidrug-resistant strains of P. falciparum. In this background, we have developed here 2D-quantitative structure-activity relationship (2D-QSAR) and 3D-pharmacophore models using aminothiazole and aminopyridine compounds for their activity against multidrug-resistant strain (k1) of P. falciparum. Based on the internal (Q 2), external (R pred2), overall validation (r m (O v e r a l l) 2 ¯) metrics, and number of descriptors used for model development, a QSAR equation developed from a genetic function algorithm having both linear and spline terms was found to be the best model (Q 2 = 0.675; R pred2 = 0.720; r m (O v e r a l l) 2 ¯ = 0.617). The pharmacophore models were developed in order to unveil the structural requirements for the activity, and to classify the compounds into more active and less active antimalarials against the multidrug-resistant strain (k1) of P. falciparum. The best pharmacophore model (Hypo-1) with a correlation coefficient of 0.932 showed one hydrogen bond acceptor, one hydrophobic aliphatic, and two ring aromatic features as the essential structural requirements for the antimalarial activity. The pharmacophore model (Hypo-1) also shows 86.00 % correct classification of more active compounds of the test set against the multidrug-resistant (k1) strain of P. falciparum. Both the models could be utilized further for the prediction of antimalarial potency of aminothiazole and aminopyridine compounds against multidrug-resistant P. falciparum.