3D-QSAR studies of 4-aminoquinoline-pyrimidine hybrids as antimalarial inhibitors targeting wild-type P. falciparum dihydrofolate reductase

Three-dimensional quantitative structure–activity relationship (3D-QSAR) was determined on a set of 4-aminoquinoline-pyrimidine hybrids to elucidate the 3D structural features affecting the antimalaria activity against wild-type Plasmodium falciparum dihydrofolate reductase (PfDHFR). Several combined analyses of comparative molecular field (CoMFA), comparative molecular similarity indices (CoMSIA) and noncovalent interaction (NCI) were carried out. The 3D descriptors capturing steric, electrostatic and hydrophobic features of molecules and their correlation with experimental activity were established (CoMFA; q²= 0.506, r²= 0.875, SEE = 0.227 and CoMSIA; q²= 0.614, r²= 0.871, SEE = 0.230). Key structural features are drawn from the models: The R¹substituent prefers small, less steric groups, while the R²substituent favors larger, more sterically bulky hydrophobic groups. Introducing hydrogen bond acceptor and donor groups at R²and the N-substituted linkage enhances activity. The docking and NCI results revealed extensive hydrophobic interactions and its stabilization to the binding process of PfDHFR.