Meshcheryakova Svetlana, Shumadalova Alina, Beylerli Ozal, Gareev Ilgiz
Bashkir State Medical University, Ufa, Russia.
ADMET DMPK. 2021 Feb 18;9(2):167-176. doi: 10.5599/admet.941. eCollection 2021.
The synthesis and antimicrobial evaluation of new 2-[6-methyl-4-(thietan-3-yloxy)pyrimidin-2-ylthio]acetohydrazide derivatives was investigated. According to the literature, there are a lot of antimicrobial agents among the pyrimidines and hydrazides, and therefore it seems promising to use 2-[6-methyl-4-(thietan-3-yloxy)pyrimidin-2-ylthio]acetohydrazide as a base object for synthesizing new biologically active substances. 2-[6-methyl-4-(thietan-3-yloxy)pyrimidin-2-ylthio]acetohydrazide was obtained by the hydrazinolysis of ethyl thioacetate, using a 3-fold molar excess of 85 % hydrazine hydrate in ethanol, at room temperature. Interaction of 2-[6-methyl-4-(thietan-3-yloxy)pyrimidin-2-ylthio]acetohydrazide with ketones during boiling in ethanol yielded N-ylidenehydrazides. The solid obtained by concentration was collected, and then purified by recrystallization. The new compounds were characterized by H, C NMR, IR spectroscopy and elemental analysis. The antibacterial and antifungal activities of the new compounds were analysed using agar diffusion and tenfold broth (pH 7.2 - 7.4) dilution methods, in comparison with the clinical used drugs, ceftriaxone and Pimafucin. The structure-activity studies showed that, depending on the nature of the hydrazide fragment, the newly synthesized compounds exhibited varying degrees of microbial inhibition. Within the same series the antimicrobial activity depends on the nature of the substituent attached to the benzene ring. The investigation of antibacterial screening data revealed that the compounds N'-[1-(4-aminophenyl)ethylidene]-2-[6-methyl-4-(thietan-3-yloxy)pyrimidin-2-ylthio]acetohydrazide, N'-[1-(4-hydroxyphenyl)ethylidene]-2-[6-methyl-4-(thietan-3-yloxy)pyrimidin-2-ylthio]acetohydrazide, N'-[1- (2,5-dihydroxyphenyl) ethylidene]-2-[6-methyl-4-(thietan-3-yloxy)-pyrimidin-2-ylthio]acetohydrazide were found to be more potent than the other synthesized analogues.
对新型2-[6-甲基-4-(硫杂环丁烷-3-氧基)嘧啶-2-基硫代]乙酰肼衍生物的合成及抗菌活性进行了研究。根据文献报道，嘧啶类和酰肼类化合物中有许多抗菌剂，因此，将2-[6-甲基-4-(硫杂环丁烷-3-氧基)嘧啶-2-基硫代]乙酰肼作为合成新型生物活性物质的基础对象似乎很有前景。2-[6-甲基-4-(硫杂环丁烷-3-氧基)嘧啶-2-基硫代]乙酰肼是通过硫代乙酸乙酯的肼解反应制得的，在室温下于乙醇中使用3倍摩尔过量的85%水合肼。2-[6-甲基-4-(硫杂环丁烷-3-氧基)嘧啶-2-基硫代]乙酰肼与酮在乙醇中沸腾时相互作用生成N-亚甲基酰肼。将浓缩得到的固体收集起来，然后通过重结晶进行纯化。通过氢谱、碳谱、红外光谱和元素分析对新化合物进行了表征。与临床使用的药物头孢曲松和匹美西林相比，采用琼脂扩散法和十倍肉汤（pH 7.2 - 7.4）稀释法分析了新化合物的抗菌和抗真菌活性。构效关系研究表明，根据酰肼片段的性质，新合成的化合物表现出不同程度的微生物抑制作用。在同一系列中，抗菌活性取决于连接在苯环上的取代基的性质。抗菌筛选数据研究表明，化合物N'-[1-(4-氨基苯基)亚乙基]-2-[6-甲基-4-(硫杂环丁烷-3-氧基)嘧啶-2-基硫代]乙酰肼、N'-[1-(4-羟基苯基)亚乙基]-2-[6-甲基-4-(硫杂环丁烷-3-氧基)嘧啶-2-基硫代]乙酰肼、N'-[1-(2,5-二羟基苯基)亚乙基]-2-[6-甲基-4-(硫杂环丁烷-3-氧基)嘧啶-2-基硫代]乙酰肼比其他合成类似物更具活性。
