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

Lookup NU author(s): Professor Tiago OuteiroORCiD


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© 2015 HeteroCorporationHere, 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 2 and 3 displayed a better cytotoxic profile than the respective N-methylated benzimidazole congeners (5 and 7). The biodistribution of compound 2, which has shown the highest cytotoxic activity active in the U87 glioblastoma cells (IC50= 45.2 ± 13.0), was evaluated in CD1 mice using its18F-labeled counterpart ([18F]2). These studies showed that compound 2 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 2 against the U87 cells and the ability of its18F-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 chemotherapeutic agents, in particular, against highly aggressive brain tumors such as glioblastoma.

Publication metadata

Author(s): Morais GR, Palma E, Marques F, Gano L, Oliveira MC, Abrunhosa A, Miranda HV, Outeiro TF, Santos I, Paulo A

Publication type: Article

Publication status: Published

Journal: Journal of Heterocyclic Chemistry

Year: 2017

Volume: 54

Issue: 1

Pages: 255-267

Print publication date: 01/01/2017

Online publication date: 29/12/2015

Acceptance date: 18/10/2015

ISSN (print): 0022-152X

ISSN (electronic): 1943-5193

Publisher: Wiley-Blackwell


DOI: 10.1002/jhet.2575


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