QSAR studies on imidazopyridazine derivatives as PfPK7 inhibitors

Abstract

Quantitative structure–activity relationship (QSAR) studies were carried out on a series of 35 recently synthesised imidazopyridazine derivatives to investigate the structural requirements of their inhibitory activity against malarial kinase, Plasmodium falciparum protein kinase 7 (PfPK7). Partial least square (PLS) methodology coupled with various feature selection methods, viz. stepwise (SW), genetic algorithm (GA) and simulated annealing, was applied to derive QSAR models which were further validated for statistical significance and predictive ability by internal and external validation. The statistically significant best 2D-QSAR model having correlation coefficient r 2 = 0.9190 and cross-validated squared correlation coefficient q 2 = 0.8575 with external predictive ability of pred_r 2 = 0.7212 was developed by SW-PLS with the descriptors like StNE-index, T_N_O_2, T_N_O_7, YcompDipole and SaasCE-index. Molecular field analysis was used to construct the best 3D-QSAR model using GA-PLS method, showing good correlative and predictive capabilities in terms of q 2 = 0.7494 and pred_r 2 = 0.8841. The information rendered by 2D- and 3D-QSAR models may lead to a better understanding of structural requirements of PfPK7 inhibitors and also aid in designing novel potent antimalarial molecules.