Synthesis, Characterization and Evaluation of Some Novel 2-Mercaptobenzothiazole Derivatives: In Silico and Experimental Approach

Abstract

Recently, QSAR technique and molecular docking have become widespread in designing new series of compounds, depending upon the different models developed, before actually synthesizing and testing them. Due to the diverse activity profile of substituted Benzothiazole, it has become a pharmacophore of interest. The main motive of the study was to design some novel 2- Mercaptobenzothiazole molecules with potential anti-inflammatory effect. Thus, in order to get a better insight into the structural features of 2- Mercaptobenzothiazole, a series of analogues were taken from the literature and 2D, 3D QSAR models were developed and molecular docking and ADME studies were also performed. For 2D QSAR study, stepwise forwarding variable selection method, coupled with Partial Least Square (SWF-PLS) regression-based method, was used to generate the best 2D model giving r2= 0.9425, q2=0.9018, F-value=90.0118, pred_r2=0.8976. In contrast, the forward stepwise variable selection k-nearest neighbour molecular field analysis approach was used to generate best 3D QSAR model (q2=0.8171 and pred_r2=0.7006). Docking studies were performed on 29 derivatives of 2-Mercaptobenzothiazoles. The ligands were prepared and docked against protein S. aureus TYrRS with a resolution of 3.2Å. The three derivatives K6, K18 and K20 were found to have the best docking scores (-48.44, -47.46, -48.52). Further, synthesis of these three derivatives was carried out. Spectral characterization was carried out by IR, 1H NMR and 13C NMR and all the structures were found to be in agreement with the data obtained. In vitro anti-inflammatory evaluation of these compounds was carried out by following the protein denaturation method and HRBC membrane stabilization method. Compound K20 displayed potential anti-inflammatory activity, which may be attributed to the electronegative group on the phenyl ring substituted on the pyrazole part of the pharmacophore.