Focused library of phenyl-fused macrocyclic amidinoureas as antifungal agents

• DOI: 10.1007/s11030-022-10388-7
• Publication Date: 2022-02-10T09:02:51Z
• Authors: Lorenzo J. I. Bal...; Ilaria D’Agostino; Enrico Rango; Chiara Vagaggini; Rosalba Marchitiello; Melinda Mariotti; Alexandru Casian; Davide Deodato; Giuseppina I. Tru...; Francesco Orofino; Maurizio Sanguinetti; Francesca Bugli; Lorenzo Botta; Elena Dreassi
• Keywords: 0301 basic medicine; 0303 health sciences; Antifungal Agents; Amidinourea · Antifungal agents · Candida · Cryptococcus · Macrocycles · PAMPA; Short Communication; 610; COVID-19; Microbial Sensitivity Tests; 540; 3. Good health; PAMPA; 03 medical and health sciences; Macrocycle; Amidinourea; Antifungal agents; Candida; Cryptococcus; Macrocycles; PAMPA; Cryptococcus neoformans; Amidinourea; Cryptococcu; Antifungal agent; Candida

The rise of antimicrobial-resistant phenotypes and the spread of the global pandemic of COVID-19 are worsening the outcomes of hospitalized patients for invasive fungal infections. Among them, candidiases are seriously worrying, especially since the currently available drug armamentarium is extremely limited. We recently reported a new class of macrocyclic amidinoureas bearing a guanidino tail as promising antifungal agents. Herein, we present the design and synthesis of a focused library of seven derivatives of macrocyclic amidinoureas, bearing a second phenyl ring fused with the core. Biological activity evaluation shows an interesting antifungal profile for some compounds, resulting to be active on a large panel of Candida spp. and C. neoformans. PAMPA experiments for representative compounds of the series revealed a low passive diffusion, suggesting a membrane-based mechanism of action or the involvement of active transport systems. Also, compounds were found not toxic at high concentrations, as assessed through MTT assays.