Department of Chemistry, School of Chemical and Life science, Jamia Hamdard, New Delhi 110062, India.
Department of Biological Sciences (Pharmacology and Toxicology), National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana 500037, India.
ACS Infect Dis. 2024 Sep 13;10(9):3320-3331. doi: 10.1021/acsinfecdis.4c00415. Epub 2024 Aug 16.
Benzothiazole-bearing compounds have emerged as potential noncovalent DprE1 (decaprenylphosphoryl-β-d-ribose-2'-epimerase) inhibitors active against . Based on structure-based virtual screening (PDB ID: 4KW5), a focused library of thirty-one skeletally diverse benzothiazole amides was prepared, and the compounds were assessed for their antitubercular activity against H37Ra. Most potent compounds and were further evaluated against the H37Rv strain by the microdilution assay method. Among the compounds evaluated, bisbenzothiazole amide emerged as a hit molecule and demonstrated promising antitubercular activity with minimum inhibitory concentration (MIC) values of 0.45 μg/mL and 8.0 μg/mL against HRa and HRv, respectively. Based on the preliminary hit molecule (, a focused library of 12 more bis-benzothiazole amide derivatives was further prepared by varying the substituents on either side to obtain new leads and generate a structure-activity relationship (SAR). Among these compounds, , and demonstrated remarkable antitubercular activity with MIC values of 0.5 μg/mL against H37Ra and 1.0, 2.0, and 8.0 μg/mL against HRv, respectively. The most active compound, , also displayed significant efficacy against four drug-resistant tuberculosis strains. Compound was assessed for cytotoxicity against the HepG2 cell line, and it displayed insignificant cytotoxicity. Furthermore, time-kill kinetic studies demonstrated time- and dose-dependent bactericidal activity of this compound. The GFP release assay revealed that compound targets the inhibition of a cell wall component. SNPs in gene assessment revealed that compound binds to tyrosine at position 314 of DprE1 and replaces it with histidine, causing resistance similar to that of standard TCA1. docking studies further suggest that the strong noncovalent interactions of these compounds may lead to the development of potent noncovalent DprE1 inhibitors.
苯并噻唑类化合物已成为潜在的非共价 DprE1（去甲戊二酰磷酸-β-d-核糖-2'-差向异构酶）抑制剂，对 有效。基于基于结构的虚拟筛选（PDB ID：4KW5），制备了 31 种骨架多样的苯并噻唑酰胺的聚焦文库，并评估了这些化合物对 H37Ra 的抗结核活性。最有效的化合物 和 进一步通过微量稀释法评估了对 H37Rv 菌株的活性。在所评估的化合物中，双苯并噻唑酰胺 成为一个有效分子，并表现出有希望的抗结核活性，对 HRa 和 HRv 的最低抑菌浓度（MIC）值分别为 0.45 μg/mL 和 8.0 μg/mL。基于初步的有效分子（ ，进一步通过改变两侧的取代基来制备 12 种更多的双苯并噻唑酰胺衍生物的聚焦文库，以获得新的先导化合物并产生构效关系（SAR）。在这些化合物中， 、 和 对 H37Ra 的 MIC 值分别为 0.5 μg/mL，对 HRv 的 MIC 值分别为 1.0、2.0 和 8.0 μg/mL，表现出显著的抗结核活性。最活跃的化合物 ，也对四种耐药结核菌株显示出显著疗效。化合物 对 HepG2 细胞系的细胞毒性进行了评估，结果显示其无显著细胞毒性。此外，时间杀伤动力学研究表明该化合物具有时间和剂量依赖性的杀菌活性。GFP 释放试验表明该化合物靶向细胞壁成分的抑制。 基因中 SNPs 的评估表明，化合物 结合 DprE1 上的酪氨酸 314 位并将其替换为组氨酸，导致与标准 TCA1 相似的耐药性。 对接研究进一步表明，这些化合物的强非共价相互作用可能导致开发出有效的非共价 DprE1 抑制剂。
