Novel pyrazine based anti-tubercular agents: Design, synthesis, biological evaluation and in silico studies.,Bioorganic Chemistry

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Novel pyrazine based anti-tubercular agents: Design, synthesis, biological evaluation and in silico studies.
Bioorganic Chemistry ( IF 4.5 ) Pub Date : 2020-01-25 , DOI: 10.1016/j.bioorg.2020.103610
Nayera W Hassan ₁ , Manal N Saudi ₁ , Yasser S Abdel-Ghany ₁ , Azza Ismail ₁ , Perihan A Elzahhar ₁ , Dharmarajan Sriram ₂ , Rasha Nassra ₃ , Marwa M Abdel-Aziz ₄ , Soad A El-Hawash ₁

Affiliation

TB continues to be a leading health threat despite the availability of powerful anti-TB drugs. We report herein the design and synthesis of various hybrid molecules comprising pyrazine scaffold and various formerly identified anti-mycobacterial moieties. Thirty-one compounds were screened in vitro for their activity against Mycobacterium tuberculosis H37Rv strain using MABA assay. The results revealed that six compounds (8a, 8b, 8c, 8d, 14b and 18) displayed significant activity against Mtb with MIC values ≤6.25 µg/ml versus 6.25 µg/ml for pyrazinamide. The most active compounds were then assessed for their in vitro cytotoxicity against PBMC normal cell line using MTT assay and showed SI > 200. Several in silico studies have been carried out for target fishing of the novel compounds such as shape-based similarity, pharmacophore mapping and inverse docking. Based on this multi-step target fishing study, we suggest that pantothenate synthetase could be the possible target responsible for the action of these compounds. The most active compounds were then successfully docked into the active site of pantothenate synthetase enzyme with favorable binding interactions. In addition, in silico prediction of physicochemical, ADMET and drug-like properties were also determined indicating that compounds 8b, 8c and 8d are promising candidates for the development of new anti-TB agents with enhanced activity and better safety profile.

中文翻译：

基于吡嗪的新型抗结核药：设计，合成，生物学评估和计算机研究。

尽管有强大的抗结核药物，结核病仍然是主要的健康威胁。我们在本文中报道了包括吡嗪支架和各种先前鉴定的抗分枝杆菌部分的各种杂合分子的设计和合成。使用MABA分析在体外筛选了31种化合物对结核分枝杆菌H37Rv菌株的活性。结果表明，六种化合物（8a，8b，8c，8d，14b和18）显示出对Mtb的显着活性，MIC值≤6.25µg / ml，而吡嗪酰胺为6.25 µg / ml。然后使用MTT分析法评估活性最高的化合物对PBMC正常细胞系的体外细胞毒性，并显示SI>200。已针对新化合物的目标捕捞进行了多项计算机研究，例如基于形状的相似性，药效团映射和反向对接。基于此多步骤目标捕捞研究，我们建议泛酸合成酶可能是负责这些化合物作用的目标。然后将活性最高的化合物成功地对接至具有良好结合相互作用的泛酸合成酶的活性位点。此外，还对物理化学的计算机模拟预测，ADMET和类药物特性进行了测定，表明化合物8b，8c和8d是开发具有增强活性和更好安全性的新型抗结核药物的有希望的候选者。然后将活性最高的化合物成功地对接至具有良好结合相互作用的泛酸合成酶的活性位点。此外，还对物理化学的计算机模拟预测，ADMET和类药物特性进行了测定，表明化合物8b，8c和8d是开发具有增强活性和更好安全性的新型抗结核药物的有希望的候选者。然后将活性最高的化合物成功地对接至具有良好结合相互作用的泛酸合成酶的活性位点。此外，还对物理化学的计算机模拟预测，ADMET和类药物特性进行了测定，表明化合物8b，8c和8d是开发具有增强活性和更好安全性的新型抗结核药物的有希望的候选者。

更新日期：2020-01-26

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