Synthesis and Biological Evaluation of Novel 2-Aryl Benzimidazoles as Chemotherapeutic Agents

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• 作者：Goreti Ribeiro Morais ; Elisa Palma ; Fernanda Marques ; Lurdes Gano ; Maria Cristina Oliveira ; Antero Abrunhosa ; Hugo Vicente Miranda ; Tiago F. Outeiro ; Isabel Santos and Antonio Paulo
• 刊名：Journal of Heterocyclic Chemistry
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：54
• 期：1
• 页码：255-267
• 全文大小：700K
• ISSN：1943-5193

文摘

Here, we describe the synthesis and preliminary biological evaluation of novel N-unsubstituted and N-methylated 2-aryl benzimidazole derivatives that contain fluorinated or hydroxylated alkyl substituents in the 4-N-aryl position and different substitution patterns (H vs Br vs I) in the benzimidazole ring. For the selected compounds and for comparison purposes, the congener benzothiazoles were also tested. The cytotoxic effect of 11 benzazole derivatives was evaluated in a panel of human cancer cell lines, such as breast (MCF7), melanoma (A375), cervix (HeLa), and glioblastoma (U87). In general, the compounds exerted a moderate cytotoxic activity against all cells tested. In particular, for the A375 and HeLa cells, the N-unsubstituted benzimidazoles ces:#jhet2575-eo-0002"> and ces:#jhet2575-eo-0003"> displayed a better cytotoxic profile than the respective N-methylated benzimidazole congeners (ces:#jhet2575-eo-0005"> and ces:#jhet2575-eo-0007">). The biodistribution of compound ces:#jhet2575-eo-0002">, which has shown the highest cytotoxic activity active in the U87 glioblastoma cells (IC₅₀ = 45.2 ± 13.0), was evaluated in CD1 mice using its ¹⁸F-labeled counterpart (ces:#jhet2575-eo-0036">). These studies showed that compound ces:#jhet2575-eo-0002"> can cross the blood brain barrier with a reasonable brain uptake (1.24 and 2.81%I.A./g at 5 and 60 min p.i., respectively), which is a crucial issue for systemic chemotherapy of glioblastoma. Altogether, the in vitro antitumoral activity of benzimidazole ces:#jhet2575-eo-0002"> against the U87 cells and the ability of its ¹⁸F-congener to cross the blood brain barrier provide a strong rationale to consider the reported fluoroalkylated 2-aryl benzimidazoles as lead candidates for the generation of class="TH_term6">chemotherapeutic agents, in particular, against highly aggressive brain tumors such as glioblastoma.