Structural analysis, in vitro anti-tubercular activities, and in silico ADMET evaluation of ethyl 7-methoxy-3-(4-substituted benzoyl)indolizine-1-carboxylates

Within the context of crucial exploration for innovative tuberculosis drugs, especially to counteract emerging drug resistance, we present a newly developed series of ethyl 3-(4-substituted benzoyl)-7-methoxyindolizine-1-carboxylate analogues with various substituents (5a–p) to analyze their anti-tubercular efficacy. The synthesized indolizine derivatives were characterized by several spectroscopic methods such as FT-IR, 1 H-NMR, and 13 C-NMR. The structural aspects of these derivatives (5a, 5b, 5d, 5h, 5l, 5n, and 5p) were elucidated using single-crystal X-ray diffraction. Hirshfeld surface analysis and 2D fingerprint plots aided in investigating intermolecular hydrogen bonding and non-covalent interactions, and their impact on crystal packing. Moreover, computational analyses such as MEP, and energy framework calculations have identified the compound's interaction sites and inter-molecular interaction energies. FMO analysis was carried out to determine the global reactivity parameters of the synthesized compounds. NCI and QTAIM studies were conducted to evaluate the nature as well as qualitative and quantitative descriptions of intra and inter-molecular hydrogen bonding interactions present in these molecules and their crystal packing. The in vitro whole-cell anti-tubercular activity of the indolizine derivatives (5a–p) was evaluated against Mycobacterium tuberculosis H37Rv (susceptible), multidrug-resistant, and extensively drug-resistant strains (ATCC 27294 – American type cell culture). It is worth mentioning that some of these molecules (5a–5h, 5l, 5n, and 5p) exhibited potent activity against H37Rv and MDR-MTB strains, with minimum inhibitory concentrations ranging from 4–32 μg mL −1 . In the case of the XDR-MTB strain, only compounds 5d, 5e, 5f, 5h, 5l, and 5n, showed moderate to good activities with MIC values ranging from 16–128 μg mL −1 . Additionally, ADMET ( in silico ) studies of the potent compounds emphasized their drug-likeness, reinforcing their potential as promising compounds for further development as anti-TB agents.