A combined 2-D and 3-D QSAR modeling, molecular docking study, design, and pharmacokinetic profiling of some arylimidamide-azole hybrids as superior L. donovani inhibitors

Abstract

Abstract Background Leishmaniasis is one of the neglected tropical diseases which is prevalent in the tropical regions of the world most especially in Africa. It is caused by the Leishmania species and transmitted to humans majorly through the bite of the female sandfly. This study was carried out in support of the continuous search for new drug molecules effective enough for the treatment of leishmaniasis, and which have very limited side effects. This study was focused on a combined 2-D and 3-D QSAR modeling of thirty-six arylimidamide-azole hybrids, molecular docking study, design, and pharmacokinetic analysis of some selected and newly designed arylimidamide-azole analogs. The density functional theory (DFT) with B3LYP and 6-31G** basis set was employed for the geometry optimization of the various compounds. Genetic function approximation (GFA) and multi-linear regression (MLR) approaches were used for the 2-D QSAR model building, while the fractional factorial design (FFD) and uninformative variable elimination-partial least square (UVEPLS) were employed for building the 3-D QSAR model. Pyridoxal kinase (PdxK) receptor (PDB: 6K91) was the target protein of interest in this study. Results The built 2-D and 3-D QSAR models were found to satisfy the requirement of both internal and external validation tests as follows: 2-D QSAR; R2 = 0.9614, R2adj = 0.9513, Q2cv = 0.9350, R2test = 0.6766 and cRp2 = 0.8779, and for 3-D QSAR (UVEPLS at PC = 5); R2 = 0.9839, Q2LOO = 0.7539 and Q2LTO = 0.7367. The CoMFA steric and electrostatic field contributions were 68.96% and 31.04%, respectively. All the designed analogs showed higher predicted activities than that of the template (36). Also, the new compounds showed higher binding affinities (MolDock scores) than that of the reference drug pentamidine (− 141.793 kcal/mol), with 36e showing the highest negative MolDock score of − 208.595 kcal/mol. Additionally, these newly designed compounds were said to be orally bioavailable (excluding 36f and 36g that violated 2 of the Lipinski’s provisions), with perfect intestinal absorption, less difficult to synthesize, AMES toxicity free, and showed strong interactions with the target. Conclusions The newly designed compounds especially 36e have shown a marked pharmacological improvement over the template molecule and are therefore recommended for further practical evaluation as superior pyridoxal kinase inhibitors.