Synthesis, Molecular Modelling and Antimicrobial Studies of New Thienopyridine-Based Compounds
摘要
Substituted thienopyridine derivatives were synthesized by reacting starting compounds 3a–b with diverse reagents. The structures of the hybrids synthesized were elucidated from their spectral data (IR, 1H-NMR, 13C-NMR, and Mass). The DFT/B3LYP methodology indicated that the thienopyridine-based compounds synthesized have a non-planar configuration. The pyrano-thienopyridine derivative 8 presented the lowest frontier molecular orbital (FMO) energy gap (ΔEH-L). The antibacterial efficacy of the synthesized thienopyridine analogs against representative pathogens was investigated using ampicillin as a reference drug. Conjugate 7 exhibited the highest activity toward Staphylococcus aureus, whereas derivative 6a was the most potent against both Streptococcus pneumoniae and Escherichia coli. Additionally, the molecular docking of such thienopyridine analogs with certain 1AJ6 amino acids, which was performed to determine their binding affinities and interactions, indicated that compound 4b was the most promising candidate, as it had a relatively high binding affinity and stable interaction profile, which included multiple hydrogen bonding and π interactions. The DNA gyrase inhibition results showed that the structure of the conjugates had a significant impact, as their IC50 values ranged from 4.61 ± 0.22 to 9.45 ± 0.27 µM for hybrids 4b and 7. Additionally, the physicochemical properties and pharmacokinetic profiles of the synthesized conjugates showed significant challenges in their application as orally accessible drugs, except for compound 8, since it did not violate Lipinski’s rule.