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Design, Synthesis and Biological Evaluation of Novel Spiro-[Chroman-2,4′-Piperidin]-4-One Analogs as Anti-Tubercular Agents
Chemistry & Biodiversity ( IF 2.3 ) Pub Date : 2022-07-12 , DOI: 10.1002/cbdv.202200304 Surendar Chitti 1 , Adinarayana Nandikolla 1 , Yogesh Mahadu Khetmalis 1 , Kevin Van Calster 2 , Boddupalli Venkata Siva Kumar 1 , Banoth Karan Kumar 3 , Sankaranarayanan Murugesan 3 , Davie Cappoen 2 , Kondapalli Venkata Gowri Chandra Sekhar 1
Chemistry & Biodiversity ( IF 2.3 ) Pub Date : 2022-07-12 , DOI: 10.1002/cbdv.202200304 Surendar Chitti 1 , Adinarayana Nandikolla 1 , Yogesh Mahadu Khetmalis 1 , Kevin Van Calster 2 , Boddupalli Venkata Siva Kumar 1 , Banoth Karan Kumar 3 , Sankaranarayanan Murugesan 3 , Davie Cappoen 2 , Kondapalli Venkata Gowri Chandra Sekhar 1
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A series of novel spiro-[chromane-2,4′-piperidin]-4(3H)-one derivatives were designed, synthesized and structures were confirmed by analytical methods, viz., 1H-NMR, 13C-NMR and mass spectrometry. The synthetic derivatives were evaluated for their anti-tuberculosis (anti-TB) activity against Mycobacterium tuberculosis (Mtb) strain H37Ra. Among all the evaluated Compounds, PS08 exhibited significant inhibition with MIC value of 3.72 μM while MIC values of the remaining Compounds ranged from 7.68 to 230.42 μM in comparison to the standard drug INH (MIC 0.09 μM). The two most active Compounds however showed acute cytotoxicity towards the human MRC-5 lung fibroblast cell lines. The in silico ADMET profiles of the titled Compounds were predicted and found within the prescribed limits of the Lipinski and Jorgenson rules. Molecular docking study of the notably active Compound (PS08) was also carried out after performing validation in order to understand the putative binding position of the test ligand at the active site of selected target protein Mtb tyrosine phosphatase (PtpB).
中文翻译：
新型 Spiro-[Chroman-2,4'-Piperidin]-4-One 类似物作为抗结核药物的设计、合成和生物学评价
设计、合成了一系列新型螺-[chromane-2,4'-哌啶]-4(3 H ) -one衍生物，并通过1 H-NMR、13 C-NMR和质谱。评估了合成衍生物对结核分枝杆菌(Mtb) 菌株 H37Ra的抗结核 (抗结核) 活性。在所有评估的化合物中，与标准药物 INH (MIC 0.09 μM) 相比，PS08表现出显着的抑制作用，MIC 值为 3.72 μM，而其余化合物的 MIC 值范围为 7.68 至 230.42 μM。然而，两种最活跃的化合物对人 MRC-5 肺成纤维细胞系显示出急性细胞毒性。这在Lipinski 和 Jorgenson 规则的规定范围内预测并发现了标题化合物的计算机 ADMET 谱。为了了解测试配体在选定靶蛋白Mtb酪氨酸磷酸酶 (PtpB)活性位点的推定结合位置，还对显着活性化合物 ( PS08 ) 进行了分子对接研究。
更新日期：2022-07-12
中文翻译：
新型 Spiro-[Chroman-2,4'-Piperidin]-4-One 类似物作为抗结核药物的设计、合成和生物学评价
设计、合成了一系列新型螺-[chromane-2,4'-哌啶]-4(3 H ) -one衍生物，并通过1 H-NMR、13 C-NMR和质谱。评估了合成衍生物对结核分枝杆菌(Mtb) 菌株 H37Ra的抗结核 (抗结核) 活性。在所有评估的化合物中，与标准药物 INH (MIC 0.09 μM) 相比，PS08表现出显着的抑制作用，MIC 值为 3.72 μM，而其余化合物的 MIC 值范围为 7.68 至 230.42 μM。然而，两种最活跃的化合物对人 MRC-5 肺成纤维细胞系显示出急性细胞毒性。这在Lipinski 和 Jorgenson 规则的规定范围内预测并发现了标题化合物的计算机 ADMET 谱。为了了解测试配体在选定靶蛋白Mtb酪氨酸磷酸酶 (PtpB)活性位点的推定结合位置，还对显着活性化合物 ( PS08 ) 进行了分子对接研究。
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