Fig 1.
Chemical structure of clinically approved anti-TB drugs bedaquiline (1) and delamanid (2).
Fig 2.
Molecular structure of compounds ethyl 7-acetyl-3-benzoyl-2-methyl-indolizine-1-carboxylate (3), ethyl 7-acetyl-3-benzoyl-2-ethyl-indolizine-1-carboxylate (4), ethyl 7-acetyl-3-(4-chlorobenzoyl)-2-ethyl-indolizine-1-carboxylate (5), and diethyl 3-(4-fluorobenzoyl)indolizine-1,2-dicarboxylate (6) for their anti-TB activity against MDR strains of MTB [10].
Fig 3.
Chemical structures of substituted 7-methoxy-indolizine analogues tested for their anti-TB activity against H37Rv and MDR MTB strains.
Fig 4.
Indolizine lead compounds identified for their anticancer (7) [14] and anti-tubercular (8) properties [10] against MDR strains of MTB, as well as for their COX-2 inhibition (9) [18] and larvicidal activity (10) [25] against Anopheles arabiensis.
Fig 5.
Synthetic scheme for the construction of substituted 7-methoxy-indolizine analogues.
Table 1.
Physicochemical parameters of ethyl 7-methoxy-3-(substituted benzoyl)-indolizine-1-carboxylate 5a–5j.
Table 2.
Single crystal data and structure refinement parameters for 5c and 5d.
Table 3.
In vitro whole-cell anti-TB activity of 7-methoxy-indolizine analogues (5a–j) against H37RV and MDR-MTB isolates.
Fig 6.
Thermal ellipsoidal plots drawn at the 50% probability level for the crystal structures of (a) 5c (second symmetry independent molecule has been omitted for clarity, Z' = 2) and (b) 5d. Dotted lines indicate intramolecular interactions.
Fig 7.
Formation of (a) dimer by two symmetry-independent molecules (black and green) in the asymmetric unit of 5c utilizing C-H···O, C-H···N and C-H···π interactions. (b) Crystal packing for 5c molecules via the association of dimeric motifs (light red) through C-H···O and π···π stacking interactions. (c) Packing arrangement of 5d molecules stabilized via various strong to weak C-H···O (light blue) and C-H···F (light green) dimers. Different-colored carbon atoms indicate different symmetry-independent molecules. Non-interacting hydrogen atoms were removed in the case of 5d to clarify the packing view.
Table 4.
List of intra- and intermolecular interactions present in compounds 5c and 5d.
Fig 8.
Intermolecular interactions of docked 7-methoxy-indolizine analogues 5a–5j at the active site of the enoyl-[acyl-carrier] protein-reductase enzyme.
Table 5.
Docking free energy and estimated inhibition constant (Ki) of the docked indolizine analogues 5a–j.
Fig 9.
RMSD graph computed for 3.5 ns; the black line represents compound 5i and the red line represents compound 5j.
Fig 10.
The interaction of ligands 5i and 5j at the active site of the enoyl-[acyl-carrier] protein-reductase enzyme following simulation.
Table 6.
MM/PBSA and MM/GBSA calculations for compounds 5i and 5j.