2,4-disubstituted 6-fluoroquinolines as potent antiplasmodial agents: QSAR, homology modeling, molecular docking and ADMET studies

Abstract

Objective: This work was designed to study 2,4- disubstituted 6-fluoroquinolines as antiplasmodial agents by using in silico techniques, to aid in the design of novel analogs with high potency against malaria and high inhibition of Plasmodium falciparum translation elongation factor 2 (PfeEF2), a novel drug target. Methods: Quantitative structure-activity relationships (QSAR) of 2,4-disubstituted 6-fluoroquinolines were studied with the genetic function approximation technique in Material Studio software. The 3D structure of PfeEF2 was modeled in the SWISS-MODEL workspace through homology modeling. A molecular docking study of the modeled PfeEF2 and 2,4-disubstituted 6- fluoroquinolines was conducted with Autodock Vina in Pyrx software. Furthermore, the in silico pharmacokinetic properties of selected compounds were investigated. Results: A robust, reliable and predictive QSAR model was developed that related the chemical structures of 2,4- disubstituted 6-fluoroquinolines to their antiplasmodium activities. The model had an internal squared correlation coefficient R2 of 0.921, adjusted squared correlation coefficient R2 adj of 0.878, leave-one-out cross-validation coefficient Q2 cv of 0.801 and predictive squared correlation coefficient R2 pred of 0.901. The antiplasmodium activity of 6-fluoroquinolines was found to depend on the n5Ring, GGI9, TDB7u, TDB8u and RDF75i physicochemical properties: n5Ring, TDB8u and RDF75i were positively associated, whereas GGI9 and TDB7u were negatively associated, with the antiplasmodium activity of the compounds. Stable complexes formed between the compounds and modeled PfeEF2, with binding affinity ranging from 8.200 to 10.700 kcal/mol. Compounds 5, 11, 16, 22 and 24 had better binding affinities than quinoline-4-carboxamide (DDD107498), as well as good pharmacokinetic properties, and therefore may be better inhibitors of this novel target. Conclusion: QSAR and docking studies provided insight into designing novel 2,4-disubstituted 6-fluoroquinolines with high antiplasmodial activity and good structural properties for inhibiting a novel antimalarial drug target.