Antifungal activity of AR-12 and its derivatives against clinically relevant fusarium solani isolates in keratitis

Keratitis infections caused by Fusarium species are on the rise globally, posing a significant challenge for treatment due to the intrinsic resistance mechanisms associated with these fungi. AR-12 (OSU-03012) is a celecoxib-derived protein kinase inhibitor with characteristic scaffold of 1,5-diaryl-3-trifluoropyrazole, originally developed as an antitumor agent that reached Phase I clinical trials, but has since shown activity against a broad spectrum of pathogens, including fungi, bacteria, and viruses. In an effort to expand the therapeutic options available for Fusarium keratitis, this study evaluated the Antifungal efficacy of AR-12 against Fusarium solani isolates responsible for keratitis infections. The results showed that the minimum inhibitory concentration (MIC) of AR-12 against these isolates ranged from 2 to 8 μg/mL, comparable to that of the control Antifungal agent voriconazole. Subsequently, we performed systematic chemical modifications of AR-12 and investigate the structure-activity relationships (SAR). Moreover, solubility measurements of the active derivatives identified compound B8 as exhibiting the optimal balance between Antifungal efficacy and hydrophobicity. Further investigations with B8 revealed morphological changes and the disruption of the cell membrane. This study underscores the potential of AR-12's chemical scaffold as a valuable foundation for the development of potent Antifungal drugs.

Antifungal; Drug-repurposing discovery; Fusarium solani; Lead optimization.