Pflégr Václav, Stolaříková Jiřina, Vinšová Jarmila, Krátký Martin
Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 500 05, Hradec Králové, Czech Republic.
Laboratory for Mycobacterial Diagnostics and Tuberculosis, Regional Institute of Public Health in Ostrava, Partyzánské náměstí 7, 702 00, Ostrava, Czech Republic.
Curr Top Med Chem. 2022;22(32):2695-2706. doi: 10.2174/1568026622666220805152811.
There is an urgent need for new antitubercular compounds. Modification of antimycobacterial isonicotinohydrazide at hydrazide N2 provided antimycobacterial active compounds.
Combining this scaffold with various aliphatic amines that are also frequently present in antitubercular compounds, we have designed, synthesized, and evaluated twenty-three N- (cyclo)alkyl-2-(2-isonicotinoylhydrazineylidene)propanamides and their analogues as potential antimycobacterial compounds. By increasing lipophilicity, we intended to facilitate the penetration of mycobacteria's highly impermeable cell wall.
The target amides were prepared via condensation of isoniazid and pyruvic acid, followed by carbodiimide-mediated coupling with yields from 35 to 98 %. The compounds were screened against Mycobacterium tuberculosis H37Rv and two nontuberculous mycobacteria (M. avium, M. kansasii).
All the derivatives exhibited low minimum inhibitory concentrations (MIC) from ≤0.125 and 2 μM against M. tuberculosis and nontuberculous mycobacteria, respectively. The most active molecules were substituted by a longer n-alkyl from C8 to C14. Importantly, the compounds showed comparable or even several-fold lower MIC than parent isonicotinohydrazide. Based on in silico predictions, a vast majority of the derivatives share suitable physicochemical properties and structural features for drug-likeness.
Presented amides are promising antimycobacterial agents.
迫切需要新的抗结核化合物。在酰肼N2处对抗分枝杆菌异烟酰肼进行修饰可得到具有抗分枝杆菌活性的化合物。
将该骨架与抗结核化合物中也经常出现的各种脂肪胺相结合，我们设计、合成并评估了23种N-（环）烷基-2-（2-异烟酰肼叉）丙酰胺及其类似物作为潜在的抗分枝杆菌化合物。通过增加亲脂性，我们旨在促进药物穿透高度不透水的分枝杆菌细胞壁。
通过异烟肼与丙酮酸缩合制备目标酰胺，然后通过碳二亚胺介导的偶联反应，产率为35%至98%。对这些化合物针对结核分枝杆菌H37Rv和两种非结核分枝杆菌（鸟分枝杆菌、堪萨斯分枝杆菌）进行筛选。
所有衍生物对结核分枝杆菌和非结核分枝杆菌的最低抑菌浓度（MIC）均较低，分别≤0.125 μM和2 μM。活性最高的分子被C8至C14的较长正烷基取代。重要的是，这些化合物的MIC比母体异烟酰肼低几倍甚至相当。基于计算机预测，绝大多数衍生物具有适合类药物的理化性质和结构特征。
所呈现的酰胺是有前景的抗分枝杆菌药物。
