Semelková Lucia, Janďourek Ondřej, Konečná Klára, Paterová Pavla, Navrátilová Lucie, Trejtnar František, Kubíček Vladimír, Kuneš Jiří, Doležal Martin, Zitko Jan
Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic.
Department of Clinical Microbiology, University Hospital, Sokolská 581, 500 05 Hradec Králové, Czech Republic.
Molecules. 2017 Mar 21;22(3):495. doi: 10.3390/molecules22030495.
A series of substituted -benzyl-3-chloropyrazine-2-carboxamides were prepared as positional isomers of 5-chloro and 6-chloro derivatives, prepared previously. During the aminolysis of the acyl chloride, the simultaneous substitution of chlorine with benzylamino moiety gave rise to -benzyl-3-(benzylamino)pyrazine-2-carboxamides as side products, in some cases. Although not initially planned, the reaction conditions were modified to populate this double substituted series. The final compounds were tested against four mycobacterial strains. -(2-methylbenzyl)-3-((2-methylbenzyl)amino)pyrazine-2-carboxamide () and -(3,4-dichlorobenzyl)-3-((3,4-dichlorobenzyl)amino)pyrazine-2-carboxamide () proved to be the most effective against H37Rv, with MIC = 12.5 μg·mL. Compounds were screened for antibacterial activity. The most active compound was 3-chloro--(2-chlorobenzyl)pyrazine-2-carboxamide () against with MIC = 7.81 μM, and with MIC = 15.62 μM. HepG2 in vitro cytotoxicity was evaluated for the most active compounds; however, no significant toxicity was detected. Compound was docked to several conformations of the enoyl-ACP-reductase of . In some cases, it was capable of -bond interactions, typical for most of the known inhibitors.
制备了一系列取代苄基-3-氯吡嗪-2-甲酰胺，作为先前制备的5-氯和6-氯衍生物的位置异构体。在酰氯的氨解过程中，在某些情况下，苄基氨基部分会同时取代氯，生成苄基-3-(苄基氨基)吡嗪-2-甲酰胺作为副产物。尽管最初没有计划，但对反应条件进行了修改以得到这个双取代系列。对最终化合物针对四种分枝杆菌菌株进行了测试。(2-甲基苄基)-3-((2-甲基苄基)氨基)吡嗪-2-甲酰胺()和(3,4-二氯苄基)-3-((3,4-二氯苄基)氨基)吡嗪-2-甲酰胺()被证明对H37Rv最有效，MIC = 12.5 μg·mL。对化合物进行了抗菌活性筛选。活性最高的化合物是3-氯-(2-氯苄基)吡嗪-2-甲酰胺()，对的MIC = 7.81 μM，对的MIC = 15.62 μM。对活性最高的化合物进行了HepG2体外细胞毒性评估；然而，未检测到明显毒性。化合物与的烯酰-ACP还原酶的几种构象进行了对接。在某些情况下，它能够形成氢键相互作用，这是大多数已知抑制剂的典型特征。
