Importantly, compounds 2d, 2e, and 4 were observed to exert anti-TB activity against MTB clinical isolates with multi-resistance to first-line anti-TB agents (rifampicin and isoniazid). demonstrating their potentiality to be used for drug-sensitive and drug-resistant tuberculosis therapy. (MTB) is responsible for the development of the disease tuberculosis (TB), which is definitely airborne and highly contagious. TB is one of the leading causes of death worldwide and is produced by a single infectious agent. According to the 2019 global tuberculosis statement, TB resulted in nearly 1.5 million deaths, including 251,000 people that were HIV-positive [1]. The increase in the prevalence of multi-drug-resistant (MDR)-TB [2] and extensively drug-resistant (XDR)-TB [3] offers increased the requirement for more effective restorative regimens with fewer side effects. Treating the MDR-TB and XDR-TB offers proven to be more demanding, as second-line medicines possess mainly become less effective [4]. This problem offers worsened given the emergence of totally drug-resistant (TDR) strains of MTB [5]. TDR cannot be treated using the currently available anti-TB medicines. According to the literature search from your last 40 years of academic and pharmaceutical drug finding market inventions, the US Food and Drug Administration (US FDA) in December 2012 approved only bedaquiline as the 1st 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]. Indolizine represents an interesting heterocyclic scaffold Dynarrestin in which nitrogen belongs to both fused six- and five-membered rings. It is a well-known pharmacophore responsible for various promising pharmacological properties. For instance, indolizines were found to exhibit analgesic [8], anticancer [9,10], antidiabetic [11], antihistaminic [12], anti-inflammatory [13,14], antileishmanial [15], antimicrobial [16], antimutagenic [17], antioxidant [18], antiviral [19], larvicidal [20,21], and herbicidal [22] activities. However, the anti-TB activity of indolizine is usually poorly documented in the literature [23,24,25,26]. Recently, our group started investigating multifunctionalized indolizine pharmacophores for their chemistry, structural elucidation, and pharmacological properties, including their anticancer properties [10], cyclooxygenase-2 (COX-2) inhibition properties [14,27], and larvicidal activity against [21]. In continuation of our effort to identify novel potent anti-TB brokers of cyclic depsipeptides [28] and heterocyclic origin [29,30,31,32,33,34], we previously identified a series of 7-acetyl indolizines Dynarrestin exhibiting interesting anti-mycobacterial activity. A preliminary structureCactivity relationship was determined to demonstrate that this indolizine (1) displayed the most potent activity at 11 g/mL against both H37Rv and MDR strains of MTB (Physique 1) [31]. In the present investigation, we explore the impacts of the functionalization at positions 2 and Dynarrestin 7 of a novel series of 3-substituted benzoylindolizine (2) around the anti-tubercular activity against H37Rv and MDR strains of MTB. The whole-cell anti-TB screening process will help to identify the key substituents responsible for the biological activity, thereby facilitating the discovery of potential molecular target(s) through a computational docking study. Open in a separate window Physique 1 VCA-2 Chemical structure of anti-tuberculosis (TB) indolizine compound (1) and the proposed poly-functionalized indolizines (2) as potential anti-TB brokers. 2. Results and Discussion 2.1. Chemistry Multicomponent reactions Dynarrestin (MCRs) have gained considerable prominence in the drug-discovery process in both academia and industry. MCRs provide medicinal chemists with the opportunity to rapidly access novel scaffolds with a high degree of structural functionality and complexity, accelerating lead compound identification [21]. MCRs are associated with various advantages such as single operation, synthetic efficiency, and a diversity of inputs, both economic Dynarrestin and ecological. We recently reported an efficient, convenient, one-pot MCR for the preparation of diversely substituted indolizines at high yields [14]. The reaction involved condensing three components: substituted pyridine, substituted bromoacetophenone, and ethyl propiolate/ethyl but-2-ynoate/ethyl hex-2-ynoate/methyl 3-phenylpropiolate. This method was highly convergent and flexible, allowing functionalization construction. The use of this synthetic development process allowed us to prepare a variety of indolizine derivatives. The chemical synthesis of the indolizine 1aCe, 2aCe, and 3aCe were achieved by employing a one-pot MCR using a microwave method (Scheme 1) [21]. This method was ecofriendly, and the yield of the test samples was found to be in the range of 85C94%. Two novel compounds, 7-formyl-2-methylindolizine derivative 4 and 7-methyl-2-phenylindolizine derivative 5, were synthesized using the reported microwave method, and their chemical structures were confirmed by FTCIR, nuclear magnetic resonance (NMR; 1H and 13C), LCCMS, and elemental analysis (Table 1). Table 1 Physicochemical characteristics of ethyl 3-(4-substitutedbenzoyl)-7-substituted-2-substitutedindolizine-1-carboxylates (4 and 5). Yield of the product was calculated after column chromatography purification. cLogof the title compounds was calculated using ChemDraw Professional 16.0. m.p.: melting point. 2.2. Anti-Tubercular Activity All synthesized indolizine derivatives (1aCe, 2aCe, 3aCe, 4, and 5) were assessed for in.