Design, synthesis, biological evaluation and molecular docking studies of thiophene derivatives

A series of 1-(2-amino-2,4,5,6,7,7a-hexahydrobenzo[b]-3-yl)-3-substitued-phenylpropane-1,3-dionederivatives were synthesized using the Gewald synthesis in first step which is followed by Baker−Venkataraman rearrangement to yield title compounds. The FTIR, MS and 1H NMR results of the produced derivatives were validated. The biological potential such as antimicrobial, antioxidant and antimycobacterial activity against a particularly virulent strain of MTB (MTB H37Ra) of the synthesized compounds were examined. Antimicrobial screening outcomes showed that compound S₁₇ turned to be the most effective antibacterial agent against Gram positive bacteria such as Staphylococcus aureus (MIC = 16.87 µM) and Bacillus subtilis (MIC = 9.45 µM) and Gram negative bacteria such as Escherichia coli (MIC = 16.87 µM) and compound S₇ against Salmonella typhi (MIC = 9.74 µM) and compound S₁₆ displayed remarkable antifungal activity toward each Candida albicans and Aspergillus niger (MIC = 15.23 µM). The standard drugs, cefadroxil (antibacterial), have MIC value against S. aureus, B. subtilis, E. coli and S. Typhi are 16.40 µM, 32.80 µM, 16.40 µM and 16.40 µM, respectively, and fluconazole (antifungal) has MIC value 20.40 µM against both the C. albicans and A.niger strain. In comparison with ascorbic acid, a standard drug (IC₅₀ 44.91 µg/mL), compound S₁₀ demonstrated good antioxidant activity, with an IC₅₀ value of 45.29 µg/mL, according to the results of the antioxidant screening. The results of the in vitro antituberculosis screening showed that compound S₂₃ was found to be effective with an MIC value of 78.125 µg/mL. Molecular docking study of an enzymatic active site of “DprE1-decaprenylphosphoryl-β-D-ribose-2′-epimerase” shows a comparable binding mode to the native ligand with better docking score which contributes in understanding and development of models for ligand–protein interactions. Compound S₂₃ showed better docking score of − 8.516 as compared to the Isoniazid with the docking score of − 6.315 which in future will create the fundamental structural framework for MTB inhibition.

Graphic abstract