Synthesis, Spectroscopic Characterization, Structural Analysis, Antimycobacterial Study, Molecular Docking, DFT, and...

The present study investigates the synthesis, characterization, and comprehensive analysis of a novel hybrid heterocyclic compound, (E)-1-(4-(1H-pyrrol-1-yl)-phenyl)-3-(3-methyl-5-(4-methylpiperazin-1-yl)-1-phenyl-1H-pyrazol-4-yl)-prop-2-en-1-one (3). The antitubercular evaluation against Mycobacterium tuberculosis H37Rv using the microplate Alamar Blue assay revealed that the compound exhibited a minimum inhibitory concentration (MIC) of 3.125 μg/mL, which is comparable to that of pyrazinamide but less potent than other reference drugs. This novel chalcone derivative (compound 3) and its precursors (1 and 2) were evaluated for their binding affinity with Mycobacterium tuberculosis enoyl-ACP reductase (InhA, PDB ID: 4TZK) using molecular docking. Compound 3 showed a superior binding affinity (-9.7 kcal/mol) compared to its precursors; 1 (-6.5 kcal/mol) and 2 (-7.3 kcal/mol), attributed to its extended conjugation and enhanced interactions with both the enzyme and the NAD cofactor. The density functional theory analysis provided crucial insights into the electronic structure, with the HOMO and LUMO energies calculated at -5.075 eV and -2.08 eV, respectively, resulting in a moderate energy gap of 2.995 eV, indicative of balanced chemical reactivity and kinetic stability. The molecular electrostatic potential plot highlighted electron-rich and electron-deficient regions, while the electron localization function and localized orbital locator plots revealed highly localized electrons and delocalized electron density. Reduced density gradient analysis further confirmed noncovalent interactions contributing to the compound's stability. The titled compound's nonlinear optical properties were also evaluated, showing promising values for mean polarizability (α₀) and first-order hyperpolarizability (β₀). The computed and experimental ¹H NMR and IR spectra showed good correlation, enabling the peak assignments.