Synthesis and Molecular Modeling Studies of New Thiadiazole-Thiophene Compounds as Potent Antimicrobial Agents

Eight thiadiazole-thiophene hybrids 4, 5, 6, and 7 were prepared by incorporating a thiophene ring system into the precursor 2-(cyanomethyl)-1,3,4-thiadiazole compounds 3a and 3b, through different strategic methods. The structures of these hybrids were elucidated using spectral techniques (IR, NMR, and Mass spectrometry). The DFT (B3LYP) modeling of the built hybrids revealed comparable non-planar configurations and HOMO-LUMO composition, covering the full skeleton (π- and π*-orbitals, respectively). The antimicrobial efficacies of the produced analogues were appraised against both Gram (+ve) and (-ve) bacterial pathogens. Analogues 5a, 5b, 6a, and 7b revealed potent activity (MIC 3.125-6.25 μg/mL). Meanwhile, these analogues established moderate to good inhibitory efficiency of DNA gyrase (IC₅₀ = 4.46 ± 0.09-8.38 ± 0.33 μM), where the analogue 5a exhibited the highest activity, very close to the novobiocin (reference drug; IC₅₀ = 4.01 ± 0.03 μM). Moreover, the molecular docking with a target protein PDB: 6FQM has been performed to discover the interaction patterns of synthesized hybrids. Hybrids 5a, 5b, and 4b showed significant binding energies and stable interaction profiles. Furthermore, the investigated hybrids were evaluated for their pharmacokinetic and drug-likeness properties using SwissADME predictions, where compounds 3a and 3b are the most promising drug-like leads among the thiadiazole hybrids.