In-silico combinatorial design and pharmacophore modeling of potent antimalarial 4-anilinoquinolines utilizing QSAR and computed descriptors

Abstract

There are very few studies for combinatorial library design and high throughput screening of 4-anilinoquinoline antimalarial compounds having activities against parasitic strain of P. falciparum. Therefore, an attempt has been made in the present paper to design potent lead compounds in this congener utilizing quantitative structure activity relationship utilizing theoretical molecular descriptors. QSAR models for a series of 4-anilinoquinolines considering various theoretical molecular descriptors including topological, constitutional, geometrical, functional group and atom-centered fragments has been carried out by stepwise forward–backward variable selections assimilating multiple linear regression (MLR) methods showing the topological indices contribute maximum impact on parasitic P. falciparum strain. A combinatorial library of 2160 compounds has been generated and finally, 16 compounds were screened through high throughput screening as promising 4-anilinoquinoline antimalarial hits based on their predicted activities utilizing topological descriptor based validated QSAR model. Highly predicted active compounds were then undergone for pharmacophore modeling to predict mode of binding and to optimize leads having greater affinity towards malarial P. falciparum parasitic strain.