Rychtarčíková Zuzana, Krátký Martin, Gazvoda Martin, Komlóová Markéta, Polanc Slovenko, Kočevar Marijan, Stolaříková Jiřina, Vinšová Jarmila
Department of Inorganic and Organic Chemistry, Faculty of Pharmacy, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic.
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5, SI-1000 Ljubljana, Slovenia.
Molecules. 2014 Mar 28;19(4):3851-68. doi: 10.3390/molecules19043851.
This report presents a new modification of the isoniazid (INH) structure linked with different anilines via a carbonyl group obtained by two synthetic procedures and with N-substituted 5-(pyridine-4-yl)-1,3,4-oxadiazole-2-amines prepared by their cyclisation. All synthesised derivatives were characterised by IR, NMR, MS and elemental analyses and were evaluated in vitro for their antimycobacterial activity against Mycobacterium tuberculosis H37Rv, Mycobacterium avium 330/88, Mycobacterium kansasii 235/80 and one clinical isolated strain of M. kansasii 6509/96. 2-Isonicotinoyl-N-(4-octylphenyl)hydrazinecarboxamide displayed an in vitro efficacy comparable to that of INH for M. tuberculosis with minimum inhibitory concentrations (MICs) of 1-2 μM. Among the halogenated derivatives, the best anti-tuberculosis activity was found for 2-isonicotinoyl-N-(2,4,6-trichlorophenyl)hydrazinecarboxamide (MIC=4 μM). In silico modelling on the enoyl-acyl carrier protein reductase InhA confirmed that longer alkyl substituents are advantageous for the interactions and affinity to InhA. Most of the hydrazinecarboxamides, especially those derived from 4-alkylanilines, exhibited significant activity against INH-resistant nontuberculous mycobacteria.
本报告介绍了异烟肼（INH）结构的一种新修饰，该修饰通过两种合成方法获得的羰基与不同苯胺相连，并与通过环化制备的N-取代的5-（吡啶-4-基）-1,3,4-恶二唑-2-胺相连。所有合成衍生物均通过红外光谱、核磁共振、质谱和元素分析进行表征，并在体外评估其对结核分枝杆菌H37Rv、鸟分枝杆菌330/88、堪萨斯分枝杆菌235/80和一株堪萨斯分枝杆菌临床分离株6509/96的抗分枝杆菌活性。2-异烟酰基-N-（4-辛基苯基）肼甲酰胺对结核分枝杆菌的体外疗效与INH相当，最低抑菌浓度（MIC）为1-2μM。在卤代衍生物中，2-异烟酰基-N-（2,4,6-三氯苯基）肼甲酰胺的抗结核活性最佳（MIC = 4μM）。对烯酰基-酰基载体蛋白还原酶InhA的计算机模拟证实，较长的烷基取代基有利于与InhA的相互作用和亲和力。大多数肼甲酰胺，尤其是那些衍生自4-烷基苯胺的肼甲酰胺，对耐INH的非结核分枝杆菌表现出显著活性。
