Investigation of aryl isonitrile compounds with potent, broad-spectrum antifungal activity

Abstract

Invasive fungal infections present a formidable global public health challenge due to the limited number of approved antifungal agents and the emergence of resistance to the frontline treatment options, such as fluconazole. Three fungal pathogens of significant concern are Candida, Cryptococcus, and Aspergillus given their propensity to cause opportunistic infections in immunocompromised individuals. New antifungal agents composed of unique chemical scaffolds are needed to address this public health challenge. The present study examines the structure-activity relationship of a set of aryl isonitrile compounds that possess broad-spectrum antifungal activity primarily against species of Candida and Cryptococcus. The most potent derivatives are capable of inhibiting growth of these key pathogens at concentrations as low as 0.5 μM. Remarkably, the most active compounds exhibit an excellent safety profile and are nontoxic to mammalian cells even at concentrations up to 256 μM. The present study lays the foundation for further investigation of aryl isonitrile compounds as a new class of antifungal agents.

Natural product-inspired aryl isonitriles as a new class of antimalarial compounds against drug-resistant parasites

“…From this collection of compounds, we have through screening identified compounds with potent antibacterial 14 and antifungal activity. 15 Our most potent compounds (43 and 31) also demonstrated in vivo efficacy against methicillin-resistant Staphylococcus aureus (MRSA) in two different mouse models without showing any toxicity to the mice. 16 Our study further showed that these lead compounds are not toxic to mammalian cells at concentrations as high as 128 μM or 256 μM.…”

Medicinal Chemistry of Isocyanides

“…The most potent compound for this set displayed an SI of 512 (Table 22). 264,265 A simplified SAR for these isocyano stilbene derivatives as antibacterial and antifungal agents is represented in Figure 59.…”

Design, synthesis, and biological activity of novel 2‐(pyridin‐3‐yl)ethan‐1‐one oxime ethers bearing adamantane moiety

“…Pyridine and its derivatives are a kind of important nitrogen‐based heterocyclic compounds that are widely distribute in nature, such as nicotine, anabasine, pyridoxine (vitamin B6), nicotinic acid, and nicotinamide (vitamin PP). Many natural and synthetic pyridine derivatives display good biological activity, including antifungal, anticancer, antivirus, anti‐inflammatory, insecticidal, and herbicidal activities. On the other hand, pyridine is the bioisostere of benzene, but its electron density and hydrophobic constant are lower than that of benzene, so pyridine derivatives often have high bioactivity and notable systemic character .…”