Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt.
Medicinal Chemistry and Drug Discovery Research Laboratory, Pharmacy Group, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, Jawahar Nagar, Telangana 500078, India.
Bioorg Chem. 2020 Mar;96:103610. doi: 10.1016/j.bioorg.2020.103610. Epub 2020 Jan 25.
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.
尽管有强效的抗结核药物可用，但结核病仍然是一个主要的健康威胁。我们在此报告了各种包含吡嗪骨架和以前鉴定的各种抗分枝杆菌部分的杂合分子的设计和合成。使用 MABA 测定法，对 31 种化合物在体外对结核分枝杆菌 H37Rv 株的活性进行了筛选。结果表明，六种化合物（8a、8b、8c、8d、14b 和 18）对 Mtb 具有显著的活性，MIC 值≤6.25µg/ml，而吡嗪酰胺的 MIC 值为 6.25µg/ml。然后，用 MTT 测定法对最活跃的化合物进行了体外细胞毒性评估，对 PBMC 正常细胞系的 SI>200。已经进行了几项针对新型化合物的靶标筛选的计算研究，例如基于形状的相似性、药效团映射和反向对接。基于这项多步骤的靶标筛选研究，我们认为泛酸合成酶可能是这些化合物作用的可能靶标。然后，将最活跃的化合物成功对接进入泛酸合成酶酶的活性部位，并具有有利的结合相互作用。此外，还对化合物的物理化学、ADMET 和类药性进行了计算预测，表明化合物 8b、8c 和 8d 是具有增强活性和更好安全性的新型抗结核药物开发的有前途的候选药物。
