Design, Synthesis, and Biological Evaluation of 7-Chloroquinoline Derivatives Against Mycobacterium tuberculosis H37Rv
摘要
Objective: To identify and evaluate novel 7-chloroquinoline-based derivatives as potential inhibitors of Mycobacterium tuberculosis H37Rv. Methods: A series of 7-chloroquinoline derivatives (IVa–IVn) was designed using a structure-based drug design approach. The compounds were synthesized and purified following standard organic synthesis procedures. In vitro biological activity was assessed through whole-cell screening using the microplate Alamar Blue assay (MABA) to determine minimum inhibitory concentrations (MIC) and half-maximal inhibitory concentrations (IC50). Computational studies, including molecular docking, molecular dynamics (MD) simulations, and MM-GBSA free energy calculations, were performed to elucidate binding interactions and complex stability. Quantum chemical calculations were also conducted to investigate the electronic properties and conformational preferences of the most active compounds. Results and Discussion: Among the synthesized derivatives, compounds IVm, IVl, and IVn demonstrated potent antitubercular activity with IC50 values ranging from 0.7 to 25 µg/mL. Notably, compounds IVm and IVl, bearing 4-methylthiophene and 4-bromothiophene substituents, respectively, exhibited the highest activity, with MIC values of 0.7 and 3.1 µg/mL. Molecular docking studies revealed that IVm forms stable interactions with key residues ARG324 and TYR60 in the active site, yielding a docking score of –8.44, glide energy of –71.24 kcal/mol, and an MM-GBSA ΔGbind of –72.41 kcal/mol. MD simulations confirmed the stability of the IVm–protein complex, while quantum chemical analysis provided insights into the conformational features contributing to the observed activity. Conclusions: The integrated in vitro and in silico approach successfully identified 7-chloroquinoline derivatives, particularly IVl and IVm, as promising lead compounds for further optimization in antitubercular drug discovery. These findings contribute valuable insights into quinoline-based drug design and support the continued exploration of thiophene-substituted analogs for tuberculosis therapy.