Thieno-quinoline Derivatives as Promising Antimicrobial Agents: In Vitro and In Silico Insights

Introduction: The global rise in antimicrobial resistance demands innovative therapeutic approaches. This study investigates novel 2-Aryl-9-chloro-5,6,7,8-tetrahydrothieno[3,2-b]quinoline derivatives (2a-e) as potential dual-action agents, targeting both pathogenic microorganisms and the phospholipase C-γ (PLC-γ) signaling pathway implicated in inflammatory responses. Method: Five derivatives were synthesized through a single-step POCl3-catalyzed cyclocondensation of thiophene carboxylic acids with cyclohexanone, yielding 55-71% of purified products. Antimicrobial efficacy was evaluated against Gram-positive (Staphylococcus aureus ATCC 25923, Bacillus cereus ATCC 10876), Gram-negative (Escherichia coli ATCC 25922, Pseudomonas aeruginosa clinical isolate), and Candida albicans ATCC 10231 strains using standardized CLSI protocols. Computational studies employed molecular docking (MolDock) and binding free energy calculations against PLC-γ (PDB ID:5EG3). Results: Among the tested compounds, compounds 2-c and 2-e showed strong antibacterial activity against Staphylococcus aureus, even surpassing gentamicin. Compounds 2-b and 2-d, on the other hand, showed significant antifungal activity against Candida albicans, equivalent to that of DEPTIL BFC. Molecular docking revealed compound 2d (L4) as the most potent PLC-γ inhibitor (ΔG=- 116.127 kcal/mol), forming π-alkyl interactions with Ala 567 in the catalytic pocket. discussion: Among the five Aryl-CTTQ compounds tested, all samples demonstrated strong antibacterial activity, with MICs ranging from 6.25 to 25 µg/mL in DMSO. Additionally, only compounds 2-b and 2-d demonstrated moderate antifungal activity against Candida albicans. The in silico analysis identified compound L4 as the most promising, displaying the highest binding affinity and a stable interaction with the target phospholipase C-γ. This systematic, computer-aided design approach not only pinpointed potential biological targets but also provided valuable insights into the structural features driving the compounds' activity. Discussion: The structure-activity relationship demonstrates that chloro-substitution at position 9 enhances antimicrobial potency, while aryl modifications at position 2 influence PLC-γ binding affinity. These findings suggest a unique dual mechanism of action distinct from conventional antimicrobials. Conclusion: his study highlights the biological potential of [Aryl-CTTQ] derivatives (2a-e), in particular their marked antibacterial activity and, for some, moderate antifungal activity. Compound 2d (L4) is distinguished by its high affinity for phospholipase C-γ, identified through in vitro and in silico analyses. These results validate the effectiveness of a computer-aided design approach to develop new therapeutic agents.