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Exploring the effectiveness of novel benzimidazoles as CB2 ligands: synthesis, biological evaluation, molecular docking studies and ADMET prediction

Abstract

Herein we continued our previous work on the developmente of CB2 ligands reporting the design and synthesis of a series of benzimidazole-containing derivatives that were explored as selective CB2 ligands in binding affinity towards both CB1 and CB2 receptors. Seven out of eighteen compounds featured selective binding ability to CB2 over CB1 receptor with potencies in sub-micromolar or low micromolar range. In particular, we identified two promising hit compounds, the agonist 1-[2-(N,N-diethylamino)ethyl]-2-(4-ethoxybenzyl)-5-trifluoromethylbenzimidazole 3 (CB2: Ki= 0.42 µM) and the inverse agonist/antagonist 1-butyl-2-(3,4-dichlorobenzyl)-5-trifluoromethylbenzimidazole (11) (CB2: Ki= 0.37 µM). Docking studies also performed on other benzimidazoles reported in the literature supported the structure-activity relationship observed within this series of compounds and allow to reveal the key contacts involved in the agonist and/or inverse agonist behaviour displayed by these derivatives. The in silico evaluation of ADMET properties suggested a favorable pharmacokinetic and safety profile, promoting the drug-likeness of these compounds towards a further optimization process.

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Publication details

The article was accepted on 07 Oct 2018 and first published on 10 Oct 2018


Article type: Research Article
DOI: 10.1039/C8MD00461G
Citation: Med. Chem. Commun., 2018, Accepted Manuscript
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    Exploring the effectiveness of novel benzimidazoles as CB2 ligands: synthesis, biological evaluation, molecular docking studies and ADMET prediction

    M. TONELLI, E. Cichero, A. M. Mahmoud, A. Rabbito, B. Tasso, P. Fossa and A. Ligresti, Med. Chem. Commun., 2018, Accepted Manuscript , DOI: 10.1039/C8MD00461G

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