Multifaceted Evaluation of Anticancer, Antibacterial, Antifungal, and Anti-Candida Properties of Novel Cannabinoid Receptor 2 (CB2R) Ligands: An Integrated In Vitro and In Silico Analysis

Background: Cannabinoid Receptor 2 (CB2R) is a key target in cancer therapy, with several potential therapeutic applications still to be explored. CB2R ligands, including agonists, antagonists, and inverse agonists, represent a diverse class of compounds with promising effects in various biological contexts. However, their full therapeutic potential remains underexplored. In this study, we investigate the effects of the CB2R agonist CB65 and the inverse agonist JTE907 for antibacterial, antifungal, anti-Candida, and anticancer activities using both in vitro and in silico approaches. Method: In vitro assays were conducted to evaluate the antibacterial, antifungal, anti-Candida, and anticancer effects of CB65 and JTE907. Antibacterial activity was assessed against Gram-positive and Gram-negative bacteria. Antifungal and anti-Candida effects were tested on various fungal and Candida species. Anticancer activity was measured using the MTT assay on MDA-MB231 breast cancer cells. Additionally, in silico docking simulations were carried out using Maestro software to investigate the compounds’ mechanisms of action. Result:Both CB65 and JTE907 showed negligible antibacterial activity against E.coli, K. pneumoniae, and S.aureus. However, both compounds demonstrated significant antifungal activity against filamentous fungi, including Alternaria sp., Sclerotinia sclerotiorum, and Fusarium equiseti. The mean growth inhibition values were 2.61 ± 0.18, 2.26 ± 0.13, and 3.15 ± 0.24 for CB65, and 2.90 ± 0.05, 2.73 ± 0.19, and 2.64 ± 0.15 for JTE907. Neither compound exhibited anti-Candida activity against Candida albicans, Candida dubliniensis, or Candida parapsilosis. For anticancer activity, CB65 and JTE907 showed IC50 values of 59.38 µM and 18.23 µM, respectively, in MDA-MB231 breast cancer cells. In silico docking results supported the experimental data, revealing possible mechanisms of action for both compounds. Conclusion: CB65 and JTE907 exhibited significant antifungal activity against filamentous fungi and anticancer potential in MDA-MB231 cells, but showed limited antibacterial and anti-Candida effects. These findings were supported by in silico studies, which suggested underlying mechanisms of action.