Synthesis, binding assays, cytotoxic activity and docking studies of benzimidazole and benzothiophene derivatives with selective affinity for the CB2 cannabinoid receptor

Eur J Med Chem. 2016 Nov 29:124:17-35. doi: 10.1016/j.ejmech.2016.08.005.

Javier Romero-Parra ¹, Jaime Mella-Raipán ², Vittoria Palmieri ³, Marco Allarà ³, Maria Jose Torres ¹, Hernán Pessoa-Mahana ⁴, Patricio Iturriaga-Vásquez ⁵, Rossy Escobar ¹, Mario Faúndez ¹, Vincenzo Di Marzo ³, C David Pessoa-Mahana ⁶

Affiliations

1 Department of Pharmacy, Faculty of Chemistry, Pontificia Universidad Católica de Chile, Vicuña Mackenna, 4860, Santiago, Chile.
2 Institute of Chemistry and Biochemistry, Universidad de Valparaíso, Gran Bretaña, 1111, Valparaíso, Chile.
3 Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 034, Napoli, Italy.
4 Department of Organic and Physical Chemistry, Faculty of Chemical and Pharmaceutical Sciences, Universidad de Chile, Sergio Livingstone, 1007, Santiago, Chile.
5 Faculty of Engineering and Sciences, University of La Frontera, Francisco Salazar, 1145, Temuco, Chile.
6 Department of Pharmacy, Faculty of Chemistry, Pontificia Universidad Católica de Chile, Vicuña Mackenna, 4860, Santiago, Chile. Electronic address: dvdpss91@gmail.com.

PMID: 27560280 DOI: 10.1016/j.ejmech.2016.08.005

Abstract

Herein we report the design, synthesis, bioinformatic and biological studies of benzimidazole and benzothiophene derivatives as new Cannabinoid Receptor ligands. To test the hypothesis that the lack of a hydrogen bond interaction between benzimidazole and benzothiophene derivatives with Lys192 reduces their affinity for CB1 receptors (as we previously reported) and leads to CB2 selectivity, most of the tested compounds do not exhibit hydrogen bond acceptors. All compounds displayed mostly CB2 selectivity, although this was more pronounced in the benzimidazoles derivatives. Furthermore, docking assays revealed a ∏-cation interaction with Lys109 which could play a key role for the CB2 selectivity index. The series displayed low toxicity on five different cell lines. Derivative 8f presented the best binding profile (Ki = 0.08 μM), high selectivity index (KiCB1/KiCB2) and a low citoxicity. Interestingly, in cell viability experiments, using HL-60 cells (expressing exclusively CB2 receptors), all synthesised compounds were shown to be cytotoxic, suggesting that a CB2 Agonist response may be involved.

Keywords

Benzimidazole; Benzothiophene; Binding; Cannabinoids; Cytotoxicity studies; Docking assays; HL-60 cells.

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