Novel quinoline derivatives: Synthesis, spectroscopic characterization, crystal structure, DFT calculations, Hirshfeld surface analysis, anti-tuberculosis activities and ADMET analysis

Using 4-methylaniline as a starting material, we synthesized 2-chloro-3-(chloromethyl)-6-methylquinoline through amidated on and Vilsmerier-Haack cyclization reactions. Subsequently, an esterification reaction with benzoic acid derivatives successfully converted the compound into the desired quinoline derivative compound 1. The structure of 1 was characterized using various spectroscopic techniques including UV-vis, FT-IR, FT-Raman, ¹H NMR, ¹³ C NMR, and HRMS. X-ray diffraction analysis was employed to determine the single crystal structure of the target molecule, revealing the presence of N-H^…O, N-H^…N, and C-H^…O hydrogen bonds between molecules, which play a crucial role in crystal stacking interactions. Additionally, geometric parameters, molecular electrostatic potential (MEP), and frontier molecular orbital (FMO) analysis were conducted to elucidate the physicochemical properties of the compounds under study. In addition, through Hirshfeld surface analysis, it was found that O^…H/H^…O contact has an important contribution to crystal packing. The title compound was tested for in vitro antituberculosis activity and its MIC value against Mycobacterium phlei was 3.125 μg/ml. Molecular docking results show that the title compound has strong binding ability to the tandem DEP domain of Mycobacterium phlei protein (4V1F), with a relative binding affinity of -13.97 kcal/mol. ADMET is used to estimate the ADME and toxicity of synthetic compounds 1 showed the highest drug score and became the lead compound, prompting further development of more effective and safer compounds.