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Design, synthesis and anti-mycobacterial evaluation of imidazo[1,2-a]pyridine analogues
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2022-01-03 , DOI: 10.1039/d1md00367d Yogesh Mahadu Khetmalis 1 , Surendar Chitti 1 , Anjani Umarani Wunnava 2 , Banoth Karan Kumar 3 , Muthyala Murali Krishna Kumar 2 , Sankaranarayanan Murugesan 3 , Kondapalli Venkata Gowri Chandra Sekhar 1
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2022-01-03 , DOI: 10.1039/d1md00367d Yogesh Mahadu Khetmalis 1 , Surendar Chitti 1 , Anjani Umarani Wunnava 2 , Banoth Karan Kumar 3 , Muthyala Murali Krishna Kumar 2 , Sankaranarayanan Murugesan 3 , Kondapalli Venkata Gowri Chandra Sekhar 1
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Based on the molecular hybridization strategy, thirty-four imidazo[1,2-a]pyridine amides (IPAs) and imidazo[1,2-a]pyridine sulfonamides (IPSs) were designed and synthesized. The structures of the target compounds were characterized using 1H NMR, 13C NMR, LCMS, and elemental analyses. The synthesized compounds were evaluated in vitro for anti-tubercular activity using the microplate Alamar Blue assay against Mycobacterium tuberculosis H37Rv strain and the MIC was determined. The evaluated compounds exhibited MIC in the range 0.05–≤100 μg mL−1. Among these derivatives, IPA-6 (MIC 0.05 μg mL−1), IPA-9 (MIC 0.4 μg mL−1), and IPS-1 (MIC 0.4 μg mL−1) displayed excellent anti-TB activity, whereas compounds IPA-5, IPA-7 and IPS-16 showed good anti-TB activity (MIC 0.8–3.12 μg mL−1). The most active compounds with MIC of <3.125 μg mL−1 were screened against human embryonic kidney cells to check their cytotoxicity to normal cells. It was observed that these compounds were nontoxic (SI value ≥66). The ADMET characteristics of the final compounds were also predicted in silico. Further, using the Glide module of Schrodinger software, a molecular docking study of IPA-6 was carried out to estimate the binding pattern at the active site of enoyl acyl carrier protein reductase from Mycobacterium tuberculosis (PDB 4TZK). Finally, molecular dynamics simulations were performed for 100 ns to elucidate the stability, conformation, and intermolecular interactions of the co-crystal ligand and significantly active compound IPA-6 on the selected target protein. IPA-6, the most active compound, was found to be 125 times more potent than the standard drug ethambutol (MIC 6.25 μg mL−1).
中文翻译：
咪唑并[1,2-a]吡啶类似物的设计、合成及抗分枝杆菌评价
基于分子杂交策略，设计并合成了 34 种咪唑并[1,2- a ]吡啶酰胺 (IPA) 和咪唑并[1,2- a ] 吡啶磺酰胺 (IPS)。使用1 H NMR、13 C NMR、LCMS 和元素分析对目标化合物的结构进行了表征。使用微孔板 Alamar Blue 测定抗结核分枝杆菌H37Rv 菌株，在体外评估合成化合物的抗结核活性，并确定 MIC。评估化合物的 MIC 范围为 0.05–≤100 μg mL -1。在这些衍生物中，IPA - 6 (MIC 0.05 μg mL -1 )，IPA - 9（MIC 0.4 μg mL -1）和IPS- 1（MIC 0.4 μg mL -1）表现出优异的抗结核活性，而化合物IPA - 5、IPA - 7和IPS - 16表现出良好的抗结核活性（MIC 0.8–3.12 微克·毫升-1）。针对人胚肾细胞筛选MIC <3.125 μg mL -1的最具活性的化合物，以检查它们对正常细胞的细胞毒性。据观察，这些化合物是无毒的（SI 值≥66）。最终化合物的 ADMET 特征也在计算机中预测. 此外，使用Schrodinger软件的Glide模块，进行了IPA - 6的分子对接研究，以估计来自结核分枝杆菌(PDB 4TZK)的烯酰基载体蛋白还原酶在活性位点的结合模式。最后，进行了 100 ns 的分子动力学模拟，以阐明共晶配体和显着活性化合物IPA - 6在所选目标蛋白上的稳定性、构象和分子间相互作用。IPA- 6是最活跃的化合物，被发现比标准药物乙胺丁醇 (MIC 6.25 μg mL -1 )效力高 125 倍。
更新日期：2022-02-02
中文翻译：
咪唑并[1,2-a]吡啶类似物的设计、合成及抗分枝杆菌评价
基于分子杂交策略，设计并合成了 34 种咪唑并[1,2- a ]吡啶酰胺 (IPA) 和咪唑并[1,2- a ] 吡啶磺酰胺 (IPS)。使用1 H NMR、13 C NMR、LCMS 和元素分析对目标化合物的结构进行了表征。使用微孔板 Alamar Blue 测定抗结核分枝杆菌H37Rv 菌株，在体外评估合成化合物的抗结核活性，并确定 MIC。评估化合物的 MIC 范围为 0.05–≤100 μg mL -1。在这些衍生物中，IPA - 6 (MIC 0.05 μg mL -1 )，IPA - 9（MIC 0.4 μg mL -1）和IPS- 1（MIC 0.4 μg mL -1）表现出优异的抗结核活性，而化合物IPA - 5、IPA - 7和IPS - 16表现出良好的抗结核活性（MIC 0.8–3.12 微克·毫升-1）。针对人胚肾细胞筛选MIC <3.125 μg mL -1的最具活性的化合物，以检查它们对正常细胞的细胞毒性。据观察，这些化合物是无毒的（SI 值≥66）。最终化合物的 ADMET 特征也在计算机中预测. 此外，使用Schrodinger软件的Glide模块，进行了IPA - 6的分子对接研究，以估计来自结核分枝杆菌(PDB 4TZK)的烯酰基载体蛋白还原酶在活性位点的结合模式。最后，进行了 100 ns 的分子动力学模拟，以阐明共晶配体和显着活性化合物IPA - 6在所选目标蛋白上的稳定性、构象和分子间相互作用。IPA- 6是最活跃的化合物，被发现比标准药物乙胺丁醇 (MIC 6.25 μg mL -1 )效力高 125 倍。
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