Novel benzothiophene-tethered - tethered 1,3,4-oxadiazoles - oxadiazoles as potent antimicrobial targets: Design, synthesis, biological evaluation, DFT exploration and in silico docking study

Based on previous developments of oxadiazole research programs in trying to find novel compounds with multiple biological targets, such as antibacterial and antitubercular medications. In the context, a new series of 1,3,4-oxadiazole derivatives based on benzo[b]thiophene b ]thiophene moiety 6a-d, - d, 7a - d , and 8a-d - d was synthesized from 5-(3-methylbenzo[b]thiophen-2-yl)-1,3,4-oxadiazole-2-thiol. b ]thiophen-2-yl)-1,3,4-oxadiazole-2-thiol. The structures of 1,3,4-oxadiazole derivatives were elucidated via NMR (1H 1 H and 13 C), IR, and HRMS spectrum data as well as physical data. Subsequently, the derivatives were evaluated for their inhibitory activity against different bacterial microorganisms, and the MICs were determined in vitro tubercular activity against the sensitive M. tuberculosis H37Rv 37 Rv strain. Remarkably, hybrids 6c and 7a exhibited excellent antibacterial activity against S. aureus with ZI values of 31 +/- 0.99, and 30 +/- 0.32 mm, and it has been noticed that 8b demonstrated the most prominent antibacterial efficiency with MICs = 3.1, 3.6, 5.6, and 5.1 mu g/mL against S. pneumoniae, S. pyrogenes, E. coli, , and K. pneumoniae. . Among them, compound 8b , featuring a benzo[b]thiophene b ]thiophene moiety linked to oxadiazole, exhibited a significant tubercular inhibitory effect with an MIC value of 2.2.5 mu M. Additionally, the docked compound 7a showed the strongest key active key amino acids Arg44(A), 44 (A), Arg45(A), 45 (A), Ala126(A), 126 (A), Gly18(A), 18 (A), Ser49(A), 49 (A), Asp48(A) 48 (A) in the antitubercular active site of 1DG5 protein. The study of computer aided ADMET was also carried out, using SwissADME and ADMETlab2.0 to investigate the pharmacokinetic properties of the tested triazole compounds. To support the experimental data, molecular docking and density functional theory (DFT) studies help in understanding the interactions better.