Department of Chemistry, Acharya Nagarjuna University, Guntur-AP, India.
Natsol Laboratories Private Limited, II Floor, Research & Development Building, Ramky Commercial Hub, J. N. Pharmacity, Visakhapatnam-AP, India.
Curr Top Med Chem. 2019;19(9):662-682. doi: 10.2174/1568026619666190305124954.
Hispolons are natural products known to possess cytoprotective, antioxidant and anti-cancer activities. We have found recently anti TB activity in these compounds. Efforts were made to optimize the structure with bioisosteric replacement of 1,3-diketo functional group with the corresponding pyrazole and isoxazole moieties.
The goal of this paper is designing new hispolon isoxazole and pyrazole and the evaluation of their biological activities.
The designed compounds were prepared using classical organic synthesis methods. The anti- TB activity was evaluated using the MABA method.
A total of 44 compounds were synthesized (1a- 1v and 2a-2v) and screened for anti TB activity and antibacterial activity. The compounds 1b and 1n showed the highest potency with MIC 1.6µg/mL against M. tuberculosis H37Rv.
Bioisosteric replacement of 1,3-diketo functional group in hispolons with pyrazole or isoxazole rings have resulted in potent anti TB molecules. Docking simulations of these compounds on mtFabH enzyme resulted in a clear understanding of bioactivity profiles of these compounds. Docking scores are in good agreement with the anti TB activity obtained for these compounds. Computational studies and in vitro screening results indicate mtFabH as the probable target of these compounds.
Hispolon 是一种天然产物，已知具有细胞保护、抗氧化和抗癌活性。我们最近在这些化合物中发现了抗结核活性。我们努力通过用相应的吡唑和异噁唑取代 1,3-二酮官能团来优化结构。
本文的目的是设计新的 Hispolon 异噁唑和吡唑，并评估它们的生物学活性。
使用经典的有机合成方法制备设计的化合物。采用 MABA 法评价抗结核活性。
共合成了 44 种化合物（1a-1v 和 2a-2v），并对其抗结核活性和抗菌活性进行了筛选。化合物 1b 和 1n 对结核分枝杆菌 H37Rv 的抑菌活性最强，MIC 为 1.6µg/mL。
用吡唑或异噁唑环替代 Hispolon 中的 1,3-二酮官能团得到了具有高效抗结核活性的分子。这些化合物对 mtFabH 酶的对接模拟结果清楚地表明了这些化合物的生物活性特征。对接评分与这些化合物的抗结核活性一致。计算研究和体外筛选结果表明 mtFabH 可能是这些化合物的靶标。
