Invasive fungal infections (IFIs) are an increasing global public health concern, particularly affecting people with underlying health problems or compromised immunity due to conditions such as cancer, organ transplantation, chronic lung disease, HIV, prior tuberculosis, and diabetes mellitus [1]. Approximately 90 % of IFIs are caused by three major pathogenic fungi, Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus [2,3]. In addition, the emergence of the multi-drug resistant fungi Candida auris has further exacerbated the threat IFIs pose. In 2022, the World Health Organization developed its first fungal priority pathogens list, in which C. neoformans, Candida auris, A. fumigatus and Candida albicans were categorized as “critical priority group” [4]. Currently, there are five drug classes, totaling 12 drugs, that have been approved for the treatment of IFIs: the azoles (fluconazole, voriconazole, itraconazole, posaconazole, isavuconazole, and oteseconazole), polyenes (amphotericin B), antimetabolite (flucytosine), echinocandins (micafungin, caspofungin, and anidufungin) and triterpenoid (ibrexafungerp) [5]. However, with the exception of the last resort, amphotericin B, no antifungal drug demonstrates clinical activity against all four of the "critical priority group" fungi, let alone rare pathogenic fungi. To highlight the lag in antifungal drug development, the standard of therapy for Cryptococcal meningitis has remained the combination of amphotericin B, flucytosine and fluconazole since 1990 [6]. New antifungal drugs with high potency, broad-spectrum of activity and novel mechanisms, especially anti-Cryptococcus agents, are urgently needed.

Deferasirox, developed by Novartis, is the first FDA-approved orally available iron chelator with an indication for the treatment of transfusion-related iron overload (Fig. 1) [7]. It had been reported that iron acquisition is essential for the growth and virulence of pathogenic fungi [[8], [9], [10], [11], [12], [13]]. When used alone or in combination with AmB, deferasirox is highly active against Mucorales in vitro and in vivo through iron starvation [10,14,15]. Although the results of a short-term Phase II study of Deferasirox-AmB treatment in patients who were acutely infected with Mucormycosis did not support the adjunctive deferasirox therapy for mucormycosis, the antifungal potential of deferasirox remains promising due to its safety and synergistic effects [12,16]. Notably, it has also been reported that esterification of the carboxyl group of deferasirox increases its antifungal activity, which suggested that structural optimization of deferasirox is feasible [17]. Therefore, investigations into the structural optimization to further enhance the antifungal potency of deferasirox with the aim of enabling this class of drugs to be used as an antifungal monotherapy in the future are warranted.

In this study, we retained the tridentate pharmacophore of deferasirox and focused on the amidation of the carboxylic acid in order to obtain highly active derivatives. We designed and synthesized a series of 58 deferasirox derivatives and evaluated their antifungal activity.