Synthesis of Novel Chloro-Benzo [d]imidazole Regioisomers as Selective CB2 Receptor Agonists: Indirect Functional Evaluation and Molecular Insights

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dc.catalogadorvdr
dc.contributor.authorZuñiga Salazar, Valeria
dc.contributor.authorBurgos Ravanal, Renato
dc.contributor.authorSoto Flores, Jonathan
dc.contributor.authorSabadini, Gianfranco
dc.contributor.authorGonzález, José Vicente
dc.contributor.authorMella, Jaime
dc.contributor.authorRomero Parra, Javier
dc.date.accessioned2025-10-30T19:43:48Z
dc.date.available2025-10-30T19:43:48Z
dc.date.issued2025
dc.description.abstractThe cannabinoid type 2 receptor (CB2 receptor) has been extensively studied in recent years due to the benefits associated with its modulation, including the regulation of the inflammatory response, neuroimmunomodulatory properties, and antitumor effects, all with the advantage of lacking significant psychoactive effects. Herein, we report the design, synthesis, characterization, biological assays, and molecular modelling analyses of novel (5/6-chloro-2-aryl-1H-benzo [d]imidazol-1-yl)(4-methoxyphenyl)methanone and 5/6-chloro-1-(4-methoxybenzyl)-2-aryl-1H-benzo [d]imidazole regioisomers as potential cannabinoid type 2 receptor ligands. Methods: The compounds were evaluated for their presumed CB2 agonist activity using an indirect receptor-dependent apoptotic cell death assay exerted by cannabinoids, using the cell lines HEK293 (low CB1/CB2 expression), U-87 MG (high CB1 expression), and HL-60 (exclusive CB2 expression), and including the known cannabinoid ligands WIN-55,212-2 and AM630 as reference ligands. Flow cytometry was performed to assess apoptosis. Molecular docking and molecular dynamics simulations were used to explore ligand-receptor interactions at the CB2 active site. Results: Compounds 3a, 3b’, 3c, and 4b selectively reduced HL-60 cell viability, similar to WIN-55,212-2, while showing no toxicity toward HEK293 or U-87 MG cells. Flow cytometry indicated that compounds 3a and 3c induced apoptosis in HL-60 cells comparable to WIN-55,212-2. Computational studies suggested that both compounds bind within the CB2 receptor active site predominantly through π–π and hydrophobic interactions involving their benzo [d]imidazole cores, 2-aryl moieties, and 4-methoxybenzoyl scaffolds, resembling the binding patterns of established CB2 ligands. Conclusions: Compounds 3a and 3c exert selective cytotoxicity against HL-60 cells, likely via a CB2 agonist-mediated apoptotic mechanism. The applied combined experimental and computational approach provides a rapid, informative strategy for preliminary evaluation of CB2 ligands and guides subsequent detailed pharmacological studies.
dc.fechaingreso.objetodigital2025-10-30
dc.format.extent28 páginas
dc.fuente.origenORCID
dc.identifier.doi10.3390/ph18111599
dc.identifier.eissn1424-8247
dc.identifier.urihttps://doi.org/10.3390/ph18111599
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/106451
dc.information.autorucEscuela de Química; Burgos Ravanal, Renato; S/I; 195210
dc.information.autorucEscuela de Química; González, José Vicente; 0000-0001-7856-9211; 17164
dc.issue.numero11
dc.language.isoen
dc.nota.accesoContenido completo
dc.pagina.final28
dc.pagina.inicio1
dc.revistaPharmaceuticals
dc.rightsacceso abierto
dc.rights.licenseCC BY 4.0 Attribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subject.ddc610
dc.subject.deweyMedicina y saludes_ES
dc.subject.ods03 Good health and well-being
dc.subject.odspa03 Salud y bienestar
dc.titleSynthesis of Novel Chloro-Benzo [d]imidazole Regioisomers as Selective CB2 Receptor Agonists: Indirect Functional Evaluation and Molecular Insights
dc.typeartículo
dc.volumen18
sipa.codpersvinculados195210
sipa.codpersvinculados17164
sipa.trazabilidadORCID;2025-10-27
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