Focused library of phenyl-fused macrocyclic amidinoureas as antifungal agents

Abstract

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.

The impact of counterions in biological activity: case study of antibacterial alkylguanidino ureas

“…Then, a different strategy starting from the synthesis of the TF-Acetate salt 1a [10,37] (ii., Table 1) and the counterion exchange with the chloride anion was implemented. To confirm the completion of the anion exchange, we resorted to the detection of the presence/disappearance of the TF-Acetate in the samples by 19 F NMR since its fluorine atoms show a characteristic singlet signal at 77 ppm in CD 3 OD [17,38].…”

Violacein and its antifungal activity: comments and potentialities

“…The current review focused on data available in the scientific literature about violacein's activity against medically important fungi, since this natural pigment has already been described as presenting antimicrobial activities (Dodou et al 2020) and because there is a need to develop new antifungal drugs as the consequence of low availability of different compound classes accountable for this activity (Balestri et al 2022), and given the resurgence on fungal resistance to drugs (Mart ınez-Herrera et al 2021).…”

“…2020) and because there is a need to develop new antifungal drugs as the consequence of low availability of different compound classes accountable for this activity (Balestri et al . 2022), and given the resurgence on fungal resistance to drugs (Martínez‐Herrera et al . 2021).…”

Guanidine-Containing Antifungal Agents against Human-Relevant Fungal Pathogens (2004–2022)—A Review

“…In 2022 novel derivatives of ( 13 ) were described by Dreassi et al [ 26 ]. In this work an additional aromatic ring was incorporated in to the macrocycle of ( 13 ) so as to explore the chemical space of the macrocyclic core.…”