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Delamanid ( Figure 1) was the second anti-TB agent approved by European Medicine Agency in late 2013. However, bedaquiline suffered from various adverse effects such as nausea, elongation of QT interval, and drug interaction with Cytochrome P3A4 inducers and inhibitors 11. Bedaquiline (approved in late 2012 under the FDA’s accelerated review program) ( Figure 1) was found to exhibit favourable anti-TB effects and promising anti-TB action against MDR and XDR-TB when combined with first-line or second-line anti-TB drugs, resulting in a shorter duration of treatment. Several therapeutics have been approved by the US Food and Drug Administration (US-FDA) to enhance the treatment of TB. This includes the development of drug resistance such as multidrug-resistant tuberculosis (MDR-TB), extensively drug-resistant tuberculosis (XDR-TB) 5, and totally drug-resistant tuberculosis (TDR-TB) 6 the co-morbidities with acquired immunodeficiency syndrome (AIDS) 7, 8 and the risks involved in developing diabetes mellitus among TB patients 9, 10.
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Several factors have contributed to the continuous health threat of TB globally. 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.
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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).
#Smbx 1.4.4 anti gravity series
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.