Isoxazole derivatives as multi-target agents: virucidal, antibacterial, and antiproliferative effects on skin cancer cells.

Abstract

Background: The convergence of microbial infections and cancer risk in inflammatory skin diseases demands novel, multi-functional therapeutics. This challenge is exacerbated by the rise in antimicrobial resistance and the lack of approved drugs for pathogens like human adenovirus (HAdV).

Methods: Here, we investigated a series of isoxazole derivatives to identify lead candidates with combined antibacterial, antiviral, and anticancer properties for dermatological applications. The tests performed include antibacterial agar diffusion assay, antiviral quantitative suspension test, in silico and in vitro assays such as MTT, Rho-123, DCF-DA, Griess, as well as ELISA tests (Caspase-3, IL-6, TNF-α, COX), and detection of apoptosis in a microchip.

Results: Our study identified compound MO3 with significant antibacterial action against Staphylococcus aureus and the zoonotic pathogen Staphylococcus pseudintermedius. In antiviral assays, MO10 and MO7 demonstrated exceptionally high virucidal potency against HSV-1 (100-fold greater than the threshold) and AdV-5 (10-fold greater than the threshold), respectively, while remaining non-toxic to human fibroblasts. Critically, MO10 also exhibited multi-modal anticancer effects in melanoma, inducing NO-mediated apoptosis, reducing pro-inflammatory cytokines, and acting in strong synergy with doxorubicin to enhance its chemotherapeutic effect.

Conclusion: In conclusion, this work validates specific isoxazole derivatives as highly promising candidates for development: MO3 for resistant bacterial infections, MO7 for otherwise untreatable adenovirus infections, and MO10 as a dual-action agent against HSV-1 and an adjunct to melanoma chemotherapy.