Drug Discovery Division, Southern Research Institute, 2000 Ninth Avenue South, Birmingham, AL 35205, USA.
Tuberculosis (Edinb). 2013 Jul;93(4):398-400. doi: 10.1016/j.tube.2013.04.002. Epub 2013 May 4.
High throughput phenotypic screening of large commercially available libraries through two NIH programs has produced thousands of potentially interesting hits for further development as antitubercular agents. Unfortunately, these screens do not supply target information, and further follow up target identification is required to allow optimal rational design and development of highly active and selective clinical candidates. Cheminformatic analysis of the quinoline and quinazoline hits from these HTS screens suggested a hypothesis that certain compounds in these two classes may target the mycobacterial tubulin homolog, FtsZ. In this brief communication, activity of a lead quinoline against the target FtsZ from Mycobacterium tuberculosis (Mtb) is confirmed as well as good in vitro whole cell antibacterial activity against Mtb H37Rv. The identification of a putative target of this highly tractable pharmacophore should help medicinal chemists interested in targeting FtsZ and cell division develop a rational design program to optimize this activity toward a novel drug candidate.
通过 NIH 计划中的两个项目，对大型商业文库进行高通量表型筛选，产生了数千种有潜力的抗结核药物进一步开发的潜在靶点。不幸的是，这些筛选没有提供靶点信息，需要进一步进行后续靶点鉴定，以便对高度有效和选择性的临床候选药物进行最佳的合理设计和开发。对这些高通量筛选中得到的喹啉和喹唑啉化合物的计算化学分析表明，这两个化合物类别中的某些化合物可能针对分枝杆菌微管蛋白同源物 FtsZ。在本简要报告中，确认了一种先导喹啉化合物对结核分枝杆菌（Mtb）的靶标 FtsZ 的活性，以及对 Mtb H37Rv 的体外全细胞抗菌活性良好。鉴定出该高可及性药效团的潜在靶标，应有助于对 FtsZ 和细胞分裂感兴趣的药物化学家制定合理的设计方案，以优化该活性，从而获得新的候选药物。
