The cyclooxygenase-2 (COX-2) enzyme is an important target for drug discovery and development of novel anti-inflammatory agents. Selective COX-2 inhibitors have the advantage of reduced side-effects, which result from COX-1 inhibition that is usually observed with nonselective COX inhibitors. In this study, the design and synthesis of a new series of 7-methoxy indolizines as bioisostere indomethacin analogues (5a–e) were carried out and evaluated for COX-2 enzyme inhibition. All the compounds showed activity in micromolar ranges, and the compound diethyl 3-(4-cyanobenzoyl)-7-methoxyindolizine-1,2-dicarboxylate (5a) emerged as a promising COX-2 inhibitor with an IC₅₀ of 5.84 µM, as compared to indomethacin (IC₅₀ = 6.84 µM). The molecular modeling study of indolizines indicated that hydrophobic interactions were the major contribution to COX-2 inhibition. The title compound diethyl 3-(4-bromobenzoyl)-7-methoxyindolizine-1,2-dicarboxylate (5c) was subjected for single-crystal X-ray studies, Hirshfeld surface analysis, and energy framework calculations. The X-ray diffraction analysis showed that the molecule (5c) crystallizes in the monoclinic crystal system with space group P 2₁/n with a = 12.0497(6)Å, b = 17.8324(10)Å, c = 19.6052(11)Å, α = 90.000°, β = 100.372(1)°, γ = 90.000°, and V = 4143.8(4)ų. In addition, with the help of Crystal Explorer software program using the B3LYP/6-31G(d, p) basis set, the theoretical calculation of the interaction and graphical representation of energy value was measured in the form of the energy framework in terms of coulombic, dispersion, and total energy.

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, ¹H-NMR, and ¹³C-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.