Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 500 05, Hradec Králové, Czech Republic.
Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 500 05, Hradec Králové, Czech Republic; Department of Chemistry, Faculty of Science, J. E. Purkinje University, České mládeže 8, 400 96, Ústí nad Labem, Czech Republic.
Eur J Med Chem. 2018 May 10;151:824-835. doi: 10.1016/j.ejmech.2018.04.017. Epub 2018 Apr 10.
The development of novel drugs is essential for the treatment of tuberculosis and other mycobacterial infections in future. A series of N-alkyl-2-isonicotinoylhydrazine-1-carboxamides was synthesized from isoniazid (INH) and then cyclized to N-alkyl-5-(pyridin-4-yl)-1,3,4-oxadiazole-2-amines. All derivatives were characterised spectroscopically. The compounds were screened for their in vitro antimycobacterial activity against susceptible and multidrug-resistant Mycobacterium tuberculosis (Mtb.) and nontuberculous mycobacteria (NTM; M. avium, M. kansasii). The most active carboxamides were substituted by a short n-alkyl, their activity was comparable to INH with minimum inhibitory concentrations (MICs) against Mtb. of 0.5-2 μM. Moreover, they are non-toxic for HepG2, and some of them are highly active against INH-resistant NTM (MICs ≥4 μM). Their cyclization to 1,3,4-oxadiazoles did not increase the activity. The experimentally proved mechanism of action of 2-isonicotinoylhydrazine-1-carboxamides consists of the inhibition of enoyl-ACP reductase (InhA) in a way similar to INH, which is blocking the biosynthesis of mycolic acids. N-Dodecyl-5-(pyridin-4-yl)-1,3,4-oxadiazol-2-amine as the most efficacious oxadiazole inhibits growth of both susceptible and drug-resistant Mtb. strains with uniform MIC values of 4-8 μM with no cross-resistance to antitubercular drugs including INH. The mechanism of action is not elucidated but it is different from INH. Obtained results qualify these promising derivatives for further investigation.
新型药物的开发对于未来结核病和其他分枝杆菌感染的治疗至关重要。从异烟肼（INH）合成了一系列 N-烷基-2-异烟酰基肼-1-甲酰胺，然后环化成 N-烷基-5-（吡啶-4-基）-1,3,4-噁二唑-2-胺。所有衍生物均通过光谱学进行了表征。这些化合物在体外针对敏感和耐多药结核分枝杆菌（Mtb.）和非结核分枝杆菌（NTM；M. avium、M. kansasii）进行了抗分枝杆菌活性筛选。最活跃的羧酰胺被短的 n-烷基取代，其活性与 INH 相当，对 Mtb 的最小抑菌浓度（MIC）为 0.5-2 µM。此外，它们对 HepG2 无毒性，其中一些对 INH 耐药的 NTM 具有高度活性（MIC≥4 µM）。它们环化成 1,3,4-噁二唑并没有增加活性。实验证明，2-异烟酰基肼-1-甲酰胺的作用机制包括以类似于 INH 的方式抑制烯酰基-ACP 还原酶（InhA），从而阻断了分枝酸的生物合成。作为最有效的噁二唑的 N-十二烷基-5-（吡啶-4-基）-1,3,4-噁二唑-2-胺抑制了敏感和耐药 Mtb 菌株的生长，MIC 值均匀为 4-8 µM，与包括 INH 在内的抗结核药物无交叉耐药性。作用机制尚未阐明，但与 INH 不同。获得的结果证明这些有前途的衍生物值得进一步研究。
