title: Synthesis, binding assays, cytotoxic activity and docking studies of benzimidazole and benzothiophene derivatives with selective affinity for the CB2 cannabinoid receptor.
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.
authors: Department of Pharmacy, Faculty of Chemistry, Pontificia Universidad Católica de Chile, Vicuña Mackenna, 4860, Santiago, Chile.
authors: Javier
authors: J
authors: Romero-Parra
authors: Institute of Chemistry and Biochemistry, Universidad de Valparaíso, Gran Bretaña, 1111, Valparaíso, Chile.
authors: Jaime
authors: J
authors: Mella-Raipán
authors: Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 034, Napoli, Italy.
authors: Vittoria
authors: V
authors: Palmieri
authors: Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 034, Napoli, Italy.
authors: Marco
authors: M
authors: Allarà
authors: Department of Pharmacy, Faculty of Chemistry, Pontificia Universidad Católica de Chile, Vicuña Mackenna, 4860, Santiago, Chile.
authors: Maria Jose
authors: MJ
authors: Torres
authors: Department of Organic and Physical Chemistry, Faculty of Chemical and Pharmaceutical Sciences, Universidad de Chile, Sergio Livingstone, 1007, Santiago, Chile.
authors: Hernán
authors: H
authors: Pessoa-Mahana
authors: Faculty of Engineering and Sciences, University of La Frontera, Francisco Salazar, 1145, Temuco, Chile.
authors: Patricio
authors: P
authors: Iturriaga-Vásquez
authors: Department of Pharmacy, Faculty of Chemistry, Pontificia Universidad Católica de Chile, Vicuña Mackenna, 4860, Santiago, Chile.
authors: Rossy
authors: R
authors: Escobar
authors: Department of Pharmacy, Faculty of Chemistry, Pontificia Universidad Católica de Chile, Vicuña Mackenna, 4860, Santiago, Chile.
authors: Mario
authors: M
authors: Faúndez
authors: Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 034, Napoli, Italy.
authors: Vincenzo
authors: V
authors: Di Marzo
authors: Department of Pharmacy, Faculty of Chemistry, Pontificia Universidad Católica de Chile, Vicuña Mackenna, 4860, Santiago, Chile. Electronic address: dvdpss91@gmail.com.
authors: C David
authors: CD
authors: Pessoa-Mahana
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D006801:Humans; D062105:Molecular Docking Simulation; D011485:Protein Binding; D011487:Protein Conformation; D043885:Receptor, Cannabinoid, CB2 / Q000737:chemistry / Q000378:metabolism*; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D043885:Receptor, Cannabinoid, CB2; D013876:Thiophenes; C088015:benzothiophene
keywords: Benzimidazole; Benzothiophene; Binding; Cannabinoids; Cytotoxicity studies; Docking assays; HL-60 cells