Abstract
Novel series of diversely substituted indolizines were designed, synthesized, and evaluated for their in vitro anti-mycobacterial activity against H37Rv and multi-drug-resistant (MDR) strains of Mycobacterium tuberculosis (MTB). Many compounds exhibited significant inhibitory activity against MTB H37Rv strains. Indolizines 2d, 2e, and 4 were also found to be active against MTB clinical isolates with multi-resistance to rifampicin and isoniazid. Indolizine 4 was identified as the most promising anti-mycobacterial agent, displaying minimum inhibitory concentration (MIC) values of 4 and 32 μg/mL against H37Rv and MDR strains, respectively. Furthermore, an in silico study was carried out for prospective molecular target identification and revealed favorable interactions with the target enzymes CYP 121, malate synthase, and DNA GyrB ATPase. None of the potent molecules presented toxicity against peripheral blood mononuclear (PBM) cell lines, demonstrating their potentiality to be used for drug-sensitive and drug-resistant tuberculosis therapy.
Highlights
Mycobacterium tuberculosis (MTB) is responsible for the development of the disease tuberculosis (TB), which is airborne and highly contagious
Multicomponent reactions (MCRs) are associated with various advantages such as single operation, synthetic efficiency, and a diversity of inputs, both economic and ecological
We recently reported an efficient, convenient, one-pot MCR for the preparation of diversely substituted indolizines at high yields [14]
Summary
Mycobacterium tuberculosis (MTB) is responsible for the development of the disease tuberculosis (TB), which is airborne and highly contagious. Treating the MDR-TB and XDR-TB has proven to be more challenging, as second-line drugs have largely become less effective [4]. This problem has worsened given the emergence of totally drug-resistant (TDR) strains of MTB [5]. According to the literature search from the last 40 years of academic and pharmaceutical drug discovery industry inventions, the US Food and Drug Administration (US FDA) in December 2012 approved only bedaquiline as the first novel anti-TB drug for the treatment of MDR-TB [6], while the European Medicine Agency in late 2013 approved delamanid as the second anti-TB agent [7]
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