Megally Abdo Nadia Youssef, Kamel Mona Monir
Chemistry Department, Faculty of Education, Alexandria University.
Chem Pharm Bull (Tokyo). 2015;63(5):369-76. doi: 10.1248/cpb.c15-00059.
A series of 5-(pyridin-4-yl)-N-substituted-1,3,4-oxadiazol-2-amines (3a-d), 5-(pyridin-4-yl)-N-substituted-1,3,4-thiadiazol-2-amines (4a-d) and 5-(pyridin-4-yl)-4-substituted-1,2,4-triazole-3-thiones (5a-d) were obtained by the cyclization of hydrazinecarbothioamide derivatives 2a-d derived from isonicotinic acid hydrazide. Aminoalkylation of compounds 5a-d with formaldehyde and various secondary amines furnished the Mannich bases 6a-p. The structures of the newly synthesized compounds were confirmed on the basis of their spectral data and elemental analyses. All the compounds were screened for their in vitro anticancer activity against six human cancer cell lines and normal fibroblast cells. Sixteen of the tested compounds exhibited significant cytotoxicity against most cell lines. Among these derivatives, the Mannich bases 6j, 6m and 6p were found to exhibit the most potent activity. The Mannich base 6m showed more potent cytotoxic activity against gastric cancer NUGC (IC50=0.021 µM) than the standard CHS 828 (IC50=0.025 µM). Normal fibroblast cells WI38 were affected to a much lesser extent (IC50>10 µM).
通过异烟肼衍生的肼基硫代甲酰胺衍生物2a - d环化反应，得到了一系列5 -（吡啶 - 4 - 基）- N - 取代 - 1,3,4 - 恶二唑 - 2 - 胺（3a - d）、5 -（吡啶 - 4 - 基）- N - 取代 - 1,3,4 - 噻二唑 - 2 - 胺（4a - d）和5 -（吡啶 - 4 - 基）- 4 - 取代 - 1,2,4 - 三唑 - 3 - 硫酮（5a - d）。化合物5a - d与甲醛及各种仲胺进行氨基烷基化反应，得到曼尼希碱6a - p。根据光谱数据和元素分析确定了新合成化合物的结构。对所有化合物针对六种人类癌细胞系和正常成纤维细胞进行了体外抗癌活性筛选。测试的化合物中有十六种对大多数细胞系表现出显著的细胞毒性。在这些衍生物中，发现曼尼希碱6j、6m和6p表现出最强的活性。曼尼希碱6m对胃癌NUGC的细胞毒性活性（IC50 = 0.021 μM）比标准品CHS 828（IC50 = 0.025 μM）更强。正常成纤维细胞WI38受到的影响程度要小得多（IC50>10 μM）。
