Topomer-CoMFA-based predictive modelling on 2,3-diaryl-substituted-1,3-thiazolidin-4-ones as non-nucleoside reverse transcriptase inhibitors

Abstract

The reverse transcriptase enzyme has been identified as an attractive target to inhibit the HIV-1 proliferations. Studies about the structure activity relationship on a dataset of thiazolidin-4-ones were performed using the topomer-CoMFA. The obtained topomer-CoMFA model with steric and electrostatic field parameters based on two (labelled R1 and R2) fragments gave a statistically robust model (R2 = 0.938; Q2 = 0.719). The predictability of the developed model was assessed on a test set data with rpred2 = 0.798. The results of topomer-CoMFA suggested that at R1 position, the large bulky groups at C-2 position with less electronegativity and small bulky groups with large electronegativity at C-6 position are favourable for bioactivity. The topomer-CoMFA results for electrostatic contour maps at R2 position, electron releasing groups at C-4, C-5 and C-6 position along with electronegative atoms at N1 and N3 of pyrimidine, N1 of pyridine or O1 of furan moiety, whereas steric contour maps favour the substitution of small bulky groups at the same position. Finally, the applicability domain of the model was defined on external dataset of thiazolidin-4-ones and the results further supported the reliability and robustness of topomer-CoMFA model, which could be further used for prediction of potential new thiazolidin-4-one analogues.