Karaaslan Cigdem, Duydu Yalcin, Ustundag Aylin, Yalcin Can O, Kaskatepe Banu, Goker Hakan
Department of Pharmaceutical Chemistry, Ankara University, Ankara, Turkey.
Department of Pharmaceutical Toxicology, Ankara University, Ankara, Turkey.
Med Chem. 2019;15(3):287-297. doi: 10.2174/1573406414666180711130012.
The benzazole nucleus is found in many promising small molecules such as anticancer and antibacterial agents. Bendamustine (Alkylating agent), Nocodazole (Mitotic inhibitor), Veliparib (PARP inhibitor), and Glasdegib (SMO inhibitor) are being clinically used as anticancer therapeutic which bear benzimidazole moiety. Based on the principle of bioisosterism, in the present work, 23 compounds belonging to 2-(3,4-dimethoxyphenyl)benzazoles and imidazopyridine series were synthesized and evaluated for their anticancer and antimicrobial activities.
A series of new 2-(3,4-dimethoxyphenyl)-1H-benz(or pyrido)azoles were synthesized and evaluated for their anticancer and antimicrobial activities.
N-(5-chloro-2-hdroxyphenyl)-3,4-dimethoxybenzamide 1, was obtained by the amidation of 2-hydroxy-5-chloroaniline with 3,4-dimethoxybenzoic acid by using 1,1'-carbonyldiimidazole. Cyclization of 1 to benzoxazole derivative 2, was achieved by p-toluenesulfonic acid. Other 1H-benz(or pyrido)azoles were prepared by the reaction between 2-aminothiophenol, ophenylenediamine, o-pyridinediamine with sodium metabisulfite adduct of 3,4-dimethoxybenzaldehyde. The NMR assignments of the dimethoxy groups were established by the NOESY spectra.
Compound 12, bearing two chlorine atoms at the 5(4) and 7(6) positions of the benzene moiety of benzimidazole was found the most potent analogue against A549 cells with the GI50 value of 1.5 μg/mL. Moreover, 24 showed remarkable cell growth inhibition against MCF-7 and HeLa cells with the GI50 values of 7 and 5.5 μg/mL, respectively. The synthesized compounds have no important antibacterial and antifungal activities.
It could be concluded that the introduction of di-chloro atoms at the phenyl ring of 2-(3,4-dimethoxyphenyl)-1H-benzimidazoles increases significant cytotoxicity to selected human tumor cell lines in comparison to other all benzazoles synthesized. Unsubstituted 2-(3,4- dimethoxyphenyl)-imidazopyridines also gave good inhibitory profile against A549 and HeLa cells.
苯并唑核存在于许多有前景的小分子中，如抗癌和抗菌剂。苯达莫司汀（烷化剂）、诺考达唑（有丝分裂抑制剂）、维利帕尼（PARP抑制剂）和格拉斯吉布（SMO抑制剂）作为带有苯并咪唑部分的抗癌治疗药物正在临床使用。基于生物电子等排原理，在本研究中，合成了23种属于2-(3,4-二甲氧基苯基)苯并唑和咪唑并吡啶系列的化合物，并对其抗癌和抗菌活性进行了评估。
合成一系列新型2-(3,4-二甲氧基苯基)-1H-苯并（或吡啶并）唑，并对其抗癌和抗菌活性进行评估。
通过使用1,1'-羰基二咪唑使2-羟基-5-氯苯胺与3,4-二甲氧基苯甲酸酰胺化得到N-(5-氯-2-羟基苯基)-3,4-二甲氧基苯甲酰胺1。通过对甲苯磺酸使1环化得到苯并恶唑衍生物2。其他1H-苯并（或吡啶并）唑通过2-氨基苯硫酚、邻苯二胺、邻吡啶二胺与3,4-二甲氧基苯甲醛的焦亚硫酸钠加合物反应制备。通过NOESY光谱确定二甲氧基的核磁共振归属。
在苯并咪唑苯部分的5(4)和7(6)位带有两个氯原子的化合物12被发现是对A549细胞最有效的类似物，其GI50值为1.5μg/mL。此外，化合物24对MCF-7和HeLa细胞显示出显著的细胞生长抑制作用，GI50值分别为7和5.5μg/mL。合成的化合物没有重要的抗菌和抗真菌活性。
可以得出结论，与其他所有合成的苯并唑相比，在2-(3,4-二甲氧基苯基)-1H-苯并咪唑的苯环上引入二氯原子会增加对选定人类肿瘤细胞系的显著细胞毒性。未取代的2-(3,4-二甲氧基苯基)-咪唑并吡啶对A549和HeLa细胞也有良好的抑制作用。
