Synthesis of new N-(3-oxo-1-thia-4-azaspiro[4.5]decan-4-yl)pyridine-3-carboxamide derivatives and evaluation of their anti-influenza virus and antitubercular activities,Archiv der Pharmazie

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Synthesis of new N-(3-oxo-1-thia-4-azaspiro[4.5]decan-4-yl)pyridine-3-carboxamide derivatives and evaluation of their anti-influenza virus and antitubercular activities
Archiv der Pharmazie ( IF 4.3 ) Pub Date : 2022-07-18 , DOI: 10.1002/ardp.202200224
Gökçe Cihan-Üstündağ ₁ , Çiğdem Acar ₁ , Lieve Naesens ₂ , Gonca Erköse-Genç ₃ , Dilek Şatana ₃

Affiliation

We here report the synthesis, structural characterization, and evaluation of the antiviral and antitubercular activities of a novel series of hybrid spirothiazolidinone derivatives (2a–f and 3a–f) containing the nicotinohydrazide moiety, which is an isomer form of the approved antitubercular drug isoniazid. When evaluated for activity against influenza A/H1N1, A/H3N2, and B viruses, three of the new compounds proved to possess specific antiviral activity against the influenza A/H3N2 virus. The most active analog 3a, bearing a 2,8-dimethyl group at the spiro ring, displayed an antiviral EC₅₀ value of 5.2 µM. Compound 3a produced no cytotoxicity at 100 µM, the highest concentration tested, giving a selectivity index of at least 19. Structure–activity relationship analysis indicated that the absence of the methyl substituent at the 2-position and the presence of a bulky substituent at the 8-position of the spirothiazolidinone system caused a significant decrease in antiviral activity. The in vitro antitubercular activity of compounds 2a–f and 3a–f was determined for six different drug-sensitive/drug-resistant laboratory strains and clinical isolates of Mycobacterium tuberculosis. Compounds 2c, 2d, 3b, 3c, and 3d showed weak antitubercular activity against different strains, with MIC values of 125–250 μM.

中文翻译：

新型 N-(3-oxo-1-thia-4-azaspiro[4.5]decan-4-yl)pyridine-3-carboxamide 衍生物的合成及其抗流感病毒和抗结核活性的评价

我们在此报告了一系列新型杂合螺噻唑烷酮衍生物（2a-f和3a-f）的合成、结构表征和抗病毒和抗结核活性评估，该衍生物含有烟酰肼部分，这是已批准的抗结核药物异烟肼的异构体形式. 在评估对甲型/H1N1、A/H3N2 和 B 型流感病毒的活性时，三种新化合物证明对甲型/H3N2 流感病毒具有特异性抗病毒活性。最活跃的类似物3a，在螺环上带有 2,8-二甲基基团，显示出 5.2 µM 的抗病毒 EC ₅₀值。化合物3a在 100 µM（测试的最高浓度）下没有产生细胞毒性，选择性指数至少为 19。构效关系分析表明，在 2 位不存在甲基取代基，而在 8 位存在庞大的取代基。螺噻唑烷酮系统的位置导致抗病毒活性显着降低。化合物2a-f和3a-f的体外抗结核活性对六种不同的药物敏感/耐药实验室菌株和结核分枝杆菌临床分离株进行了测定。化合物2c、2d、3b、3c和3d对不同菌株显示出较弱的抗结核活性，MIC 值为 125-250 μM。

更新日期：2022-07-18

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