Ambernath Organics Pvt. Ltd., 222, The Summit Business Bay, Andheri (E), Mumbai, 400 093, India.
Department of Pharmaceutical Chemistry, Bombay College of Pharmacy, Kalina, Santacruz (E), Mumbai, 400 098, India.
Mol Divers. 2022 Feb;26(1):73-96. doi: 10.1007/s11030-020-10158-3. Epub 2021 Jan 1.
N-furfuryl piperazine ureas disclosed by scientists at GSK Tres Cantos were chosen as antimycobacterial hits from a phenotypic whole-cell screen. Bioisosteric replacement of the furan ring in the GSK Tres Cantos molecules with a phenyl ring led to molecule (I) with an MIC of 1 μM against Mtb H37Rv, low cellular toxicity (HepG2 IC ~ 80 μM), good DMPK properties and specificity for Mtb. With the aim of delineating the SAR associated with (I), fifty-five analogs were synthesized and screened against Mtb. The SAR suggests that the piperazine ring, benzyl urea and piperonyl moieties are essential signatures of this series. Active compounds in this series are metabolically stable, have low cellular toxicity and are valuable leads for optimization. Molecular docking suggests these molecules occupy the Q0 site of QcrB like Q203. Bioisosteric replacement of N-furfuryl piperazine-1-carboxamides yielded molecule (I) a novel lead with satisfactory PD, metabolism, and toxicity profiles.
葛兰素史克特雷斯·坎托斯的科学家们披露的 N-糠基哌嗪脲类化合物是从表型全细胞筛选中作为抗分枝杆菌命中物选择的。用苯环替代 GSK Tres Cantos 分子中的呋喃环，得到了化合物（I），其对 Mtb H37Rv 的 MIC 为 1μM，细胞毒性低（HepG2 IC~80μM），具有良好的 DMPK 性质和对 Mtb 的特异性。为了阐明与（I）相关的 SAR，合成了 55 个类似物并对 Mtb 进行了筛选。SAR 表明，哌嗪环、苄基脲和哌啶基部分是该系列的重要特征。该系列中的活性化合物代谢稳定，细胞毒性低，是优化的有价值的先导化合物。分子对接表明这些分子像 Q203 一样占据 QcrB 的 Q0 位。N-糠基哌嗪-1-羧酰胺的生物等排体替代得到了化合物（I），这是一种具有令人满意的 PD、代谢和毒性特征的新型先导化合物。
