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, 9 (12), 2045-2054
eCollection

Exploring the Effectiveness of Novel Benzimidazoles as CB2 Ligands: Synthesis, Biological Evaluation, Molecular Docking Studies and ADMET Prediction

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Exploring the Effectiveness of Novel Benzimidazoles as CB2 Ligands: Synthesis, Biological Evaluation, Molecular Docking Studies and ADMET Prediction

Michele Tonelli et al. Medchemcomm.

Abstract

Herein we continued our previous work on the development of CB2 ligands, reporting the design and synthesis of a series of benzimidazole-containing derivatives that were explored as selective CB2 ligands with binding affinity towards both CB1 and CB2 receptors. Seven out of eighteen compounds exhibited preferential binding ability to CB2 over CB1 receptors with potencies in the 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: K i = 0.42 μM) and the inverse agonist/antagonist 1-butyl-2-(3,4-dichlorobenzyl)-5-trifluoromethylbenzimidazole (11) (CB2: K i = 0.37 μM). Docking studies also performed on other benzimidazoles reported in the literature supported the structure-activity relationship observed in this series of compounds and allowed the key contacts involved in the agonist and/or inverse agonist behaviour displayed by these derivatives to be determined. 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.

Figures

Fig. 1
Fig. 1. Chemical structures and binding affinity values of the agonist WIN-55,212-2 and the inverse agonist/antagonist AM630.
Fig. 2
Fig. 2. Chemical structures and binding affinity values of known CB1/CB2 indole-containing agonists.
Fig. 3
Fig. 3. Chemical structures and binding affinity values of CB2 benzimidazole-containing agonists and antagonists.
Fig. 4
Fig. 4. Chemical structure of the investigated benzimidazole derivatives.
Scheme 1
Scheme 1. Reagents and conditions: a) EtOH/H2O, NH2NH2·H2O (1.15 equiv.), 120 °C, 5 h.
Fig. 5
Fig. 5. Concentration–response curves of compounds 3 and 11 measured using the cAMP Hunter™ assay enzyme fragment complementation chemiluminescence detection kit. (A) Effect of increasing concentrations of compounds on NKH-477-induced cAMP levels. (B) Effect of compound on the stimulus of NKH-477 in the presence of a challenge of known agonist (3 μM JWH-133).
Fig. 6
Fig. 6. Docking mode of agonists 2b (C atom, green) and 3b (C atom, yellow) within the homology model of the human CB2 receptor.
Fig. 7
Fig. 7. Docking mode of agonist 2b (C atom, gray) and inverse agonist 5b (C atom, green) within the homology model of the human CB2 receptor.
Fig. 8
Fig. 8. Docking mode of agonist 2b (C atom, gray) and benzimidazole 3 (C atom, coral) within the homology model of the human CB2 receptor.

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