HIV-infected patients are 19 times more likely to develop TB than HIV-negative subjects 3, 4. In 2019, TB resulted in nearly 1.4 million deaths, including 208,000 deaths among human immunodeficiency virus (HIV) positive patients 2. According to the World Health Organisation (WHO), TB is considered as one of the top 10 causes of death worldwide, and the leading cause of death from a single infectious agent 1. It is caused by the opportunistic bacillus Mycobacterium tuberculosis (MTB) which primarily attacks the lungs (pulmonary) but may later affect other parts (extra-pulmonary) of the body 1. Tuberculosis (TB) is a communicable infectious disease and a major cause of illness, particularly in low-income countries. Thus, the indolizines warrant further development and may represent a novel promising class of InhA inhibitors and multi-targeting agents to combat drug-sensitive and drug-resistant MTB strains. Further, a safety study ( in silico and in vitro) demonstrated no toxicity for these compounds. The X-ray diffraction analysis of the compound 4b was also carried out.
In silico docking study revealed the enoyl-acyl carrier protein reductase (InhA) and anthranilate phosphoribosyltransferase as potential molecular targets for the indolizines. Compounds 2b–2d, 3a–3d, and 4a–4c were active against the H37Rv-MTB strain with minimum inhibitory concentration (MIC) ranging from 4 to 32 µg/mL, whereas the indolizines 4a–4c, with ethyl ester group at the 4-position of the benzoyl ring also exhibited anti-MDR-MTB activity (MIC = 16–64 µg/mL).
Journal of Structural Chemistry Springer Journals A series of 1,2,3-trisubstituted indolizines ( 2a–2f, 3a–3d, and 4a–4c) were screened for in vitro whole-cell anti-tubercular activity against the susceptible H37Rv and multidrug-resistant (MDR) Mycobacterium tuberculosis (MTB) strains. Found that with a bulky substituent at the nitrogen atom, the formation of chelates is hindered due to the intraligand repulsion between the atoms of this substituent and the tert-butyl group.
Using a quantum chemical hybrid M06 method, the structures of copper(II) chelates with the H, CH3, CH2CH3, CH(CH3)2, and C(CH3)3 substituents at the nitrogen atom are calculated. The complexes have the molecular structures formed from isolated molecules bonded by van der Waals interactions. The complexes are isostructural the coordination polyhedron of metal atoms is a flattened tetrahedron formed from two O atoms (Cu-O of 1.901(2) Å, 1.892(2) Å, Ni-O of 1.845(2) Å, 1.833(2) Å) and two N atoms (Cu-N of 1.976(3) Å, 1.972(3) Å, Ni-N of 1.911(2) Å, 1.920(2) Å) of the ligand the chelate OMN angles (M = Cu(II), Ni(II)) are in the 87.4–93.1° range the OMO and NMN angles are 162.2° and 167.2° in I, 171.1° and 173.2° in II. Two bis-chelates M(tmih)2 (M = Cu(II), Ni(II), tmih = (CH3)3C(NCH3)CHCOC(CH3)3)− are synthesized and their crystal structures are determined using XRD (Bruker APEX-II diffractometer with a CCD detector, λMoK Crystal and molecular structures of bis(2,2,6,6-tetramethyl-3-methylaminoheptan-5-onate) copper(II) and nickel(II) Crystal and molecular structures of bis(2,2,6,6-tetramethyl-3-methylaminoheptan-5-onate).