Synthetic Derivatives of Ciclopirox are Effective Inhibitors ofCryptococcus neoformans

Abstract

Opportunistic fungal infections caused by Cryptococcus neoformans are a significant source of mortality in immunocompromised patients. They are challenging to treat because of a limited number of antifungal drugs, and novel and more effective anticryptococcal therapies are needed. Ciclopirox olamine, a N-hydroxypyridone, has been in use as an approved therapeutic agent for the treatment of topical fungal infections for more than two decades. It is a fungicide, with broad activity across multiple fungal species. We synthesized 10 N-hydroxypyridone derivatives to develop an initial structure–activity understanding relative to efficacy as a starting point for the development of systemic antifungals. We screened the derivatives for antifungal activity against C. neoformans and Cryptococcus gattii and counter-screened for specificity in Candida albicans and two Malassezia species. Eight of the ten show inhibition at 1–3 μM concentration (0.17–0.42 μg per mL) in both Cryptococcus species and in C. albicans, but poor activity in the Malassezia species. In C. neoformans, the N-hydroxypyridones are fungicides, are not antagonistic with either fluconazole or amphotericin B, and are synergistic with multiple inhibitors of the mitochondrial electron transport chain. They appear to function primarily by chelating iron within the active site of iron-dependent enzymes. This preliminary structure–activity relationship points to the need for a lipophilic functional group at position six of the N-hydroxypyridone ring and identifies positions four and six as sites where further substitution may be tolerated. These molecules provide a clear starting point for future optimization for efficacy and target identification.

Antifungal Activity of Aniba canelilla (Kunth) Mez Essential Oil and Its Main Compound 1-Nitro-2-Phenylethane against Dermatophytes

“…It is important to note that ciclopirox olamine is, structurally, the N-oxide of a 2-hydroxypyridine derivative. On the other hand, 1-nitro-2-phenylethane, the main compound of EOAC, is an aromatic nitro compound formed through the biotransformation of phenylalanine [ 23 , 24 ]. The structural similarity between these substances with the presence of nitro groups may be an explanation for their antifungal activity.…”

Repurposing of Ciclopirox to Overcome the Limitations of Zidovudine (Azidothymidine) against Multidrug-Resistant Gram-Negative Bacteria

“…In addition, synthetic derivatives of CPX can be utilized to increase its specificity. This possibility was proved in a recent study, in which synthesized CPX derivatives effectively inhibited the growth of Cryptococcus neoformans [ 62 ]. It would be worth to assess such chemicals for antibacterial activity against specific bacteria with different antibiotic resistance statuses.…”

Ferroptosis inhibitors: past, present and future

“…Thymus β4 is an endogenous iron chelator that regulates ferroptosis by affecting free iron ions and ROS ( Lachowicz et al, 2022 ). Ciclopirox (CPX) ( Eberhard et al, 2009 ; Lin J. et al, 2021 ; Lu et al, 2022 ) has been approved by the FDA for antifungal therapy, and in recent years it has been found that intraperitoneal injection can significantly inhibit the growth of non-small cell lung cancer (NSCLC). Therefore, the use of iron chelation therapy in clinical practice still holds great promise.…”