Berillo Dmitriy A, Dyusebaeva Moldyr A
Division of Chemistry, Al-Farabi Kazakh National University, Almaty 050040, Kazakhstan.
Department of Pharmaceutical and Toxicological Chemistry, Pharmacognosy and Botany School of Pharmacy Asfendiyarov Kazakh National Medical University, Almaty 050000, Kazakhstan.
Saudi Pharm J. 2022 Jul;30(7):1036-1043. doi: 10.1016/j.jsps.2022.04.009. Epub 2022 Apr 26.
Un unsolvable issue of a significant number increase of drug multi resistant strains of microorganisms including Mycobacterium tuberculosis force researchers for continuous design novel pharmaceuticals. The purpose of the study is the establishment of the correlation between the structure of novel heterocyclic hydrazide derivatives and their biological activity. Several hydrazide derivatives of N-piperidinyl and N-morpholinyl and propionic acids and N-piperidinyl acetic and their derivatives were synthesized via condensation of corresponding esters with hydrazine hydrate.The structure of synthesized compounds were confirmed by the use of FTIR, H1NMR, Mass-spectroscopy and element analysis. Investigation of synthesized substances using PASS software was carried out to predict probability of pharmacological activity in silico. The antibacterial, antifungal and spasmolytic activity as well as acute toxicity of obtained compounds were evaluated in vivo. 2-(N-piperidinyl)acetic acid hydrazide and 2-methyl-3-N-piperidinyl)propanacid hydrazide revealed antibacterial and spasmolytic activities comparable to the model drugs (drotaverin) study. Synthesized compounds in in vivo experiment showed significantly low acute toxicity (LD50 520-5750 mg/kg) compared to commercially available drugs (streptomicine, ciprofloxacinum and drotaverin LD50 100-215 mg/kg). The structure- activity relationship was established that the increasing of the length of the linker between heterocyclic amine and hydrazide group results in a decrease of antimicrobial activity against studied strains ).
包括结核分枝杆菌在内的微生物耐药菌株数量大幅增加这一无法解决的问题，促使研究人员不断设计新型药物。本研究的目的是建立新型杂环酰肼衍生物的结构与其生物活性之间的相关性。通过相应的酯与水合肼缩合，合成了几种N - 哌啶基、N - 吗啉基和丙酸的酰肼衍生物以及N - 哌啶基乙酸及其衍生物。通过傅里叶变换红外光谱（FTIR）、氢核磁共振（H1NMR）、质谱和元素分析确定了合成化合物的结构。使用PASS软件对合成物质进行研究，以预测其在计算机模拟中的药理活性概率。在体内评估了所得化合物的抗菌、抗真菌和解痉活性以及急性毒性。2 -（N - 哌啶基）乙酸酰肼和2 - 甲基 - 3 -（N - 哌啶基）丙酸酰肼显示出与模型药物（屈他维林）相当的抗菌和解痉活性。与市售药物（链霉素、环丙沙星和屈他维林的半数致死量LD50为100 - 215mg/kg）相比，合成化合物在体内实验中显示出显著较低的急性毒性（LD50为520 - 5750mg/kg）。建立了构效关系，即杂环胺与酰肼基团之间连接链长度的增加会导致对所研究菌株的抗菌活性降低。
