Olaru Anda-Mihaela, Vasilache Violeta, Danac Ramona, Mangalagiu Ionel I
a Faculty of Chemistry , " Alexandru Ioan Cuza" University of Iasi , Iasi , Romania.
b "Alexandru Ioan Cuza" University of Iasi, CERNESIM Research Centre , Iasi , Romania.
J Enzyme Inhib Med Chem. 2017 Dec;32(1):1291-1298. doi: 10.1080/14756366.2017.1375483.
A series of 13 compounds having a monoindolizine mono-salt skeleton was designed and synthesised in order to evaluate their antimycobacterial activity. The synthesis is efficient, involving only three steps: two alkylations and one 3 + 2 dipolar cycloaddition. The antimicrobial activity against Mycobacterium tuberculosis H37Rv grown under aerobic conditions was evaluated, eight compounds showing a very good antimycobacterial activity. SAR correlation reveals a certain influence of the R substituent from the para position of benzoyl moiety at position 3 of indolizine. The most active five compounds passed the second stage of anti-TB testing, the assay demonstrating that they are potent against both replicating and non-replicating Mtb, have a bactericidal mechanism of action, are active against drug-resistant Mtb strains, present a moderate to good activity against nontuberculous mycobacteria, a good intracellular activity, and a moderate to high cytotoxicity. For one compound showing a promising anti-TB profile, a complete ADMET study has been performed.
为了评估一系列具有中氮茚单盐骨架的13种化合物的抗分枝杆菌活性，对其进行了设计与合成。该合成方法高效，仅涉及三个步骤：两次烷基化反应和一次3+2偶极环加成反应。评估了这些化合物对在有氧条件下生长的结核分枝杆菌H37Rv的抗菌活性，其中八种化合物表现出非常好的抗分枝杆菌活性。构效关系研究表明，中氮茚3位苯甲酰基部分对位的R取代基有一定影响。活性最强的五种化合物通过了抗结核测试的第二阶段，该试验表明它们对复制型和非复制型结核分枝杆菌均有强效，具有杀菌作用机制，对耐药结核分枝杆菌菌株有活性，对非结核分枝杆菌具有中度至良好的活性、良好的细胞内活性以及中度至高细胞毒性。对于一种显示出有前景的抗结核特性的化合物，已进行了完整的药物代谢及药物动力学性质（ADMET）研究。
