Design, synthesis, and biological evaluation of novel dual-functional NMT/IDO-1 inhibitors with fungicidal and immunomodulatory activities.

Abstract

Invasive fungal infections, particularly those caused by fluconazole- resistant strains, remain a major clinical challenge owing to the limited therapeutic options currently available and the immunosuppressive state induced by the infection. Herein, we report the rational design of a series of dual-targeting small molecules capable of simultaneously inhibiting fungal N-myristoyltransferase and host indoleamine 2,3-dioxygenase-1. The representative compounds 8a-4 and 14a-2 exhibited potent inhibitory activities against both targets, broad antifungal efficacy across clinical isolates of Candida albicans including fluconazole-resistant strains, and extremely low cytotoxicity toward host cells. Mechanistic investigations revealed that 14a-2 could induce rapid accumulation of reactive oxygen species in the fungal pathogen, trigger mitochondrial dysfunction, and provoke a cell death process resembling apoptosis, while simultaneously modulating the tryptophan-kynurenine metabolic pathway in macrophages, downregulating the expression of indoleamine 2,3-dioxygenase-1, and restoring the production of proinflammatory cytokines. In a mouse model of cutaneous and pulmonary candidiasis, 14a-2 significantly reduced fungal burden, alleviated histopathological damage, accelerated wound healing, and reshaped the local immune microenvironment by enhancing the infiltration of cluster of differentiation 4-positive and cluster of differentiation 8-positive T cells. Collectively, this work establishes a dual-target strategy that couples pathogen elimination with immune activation, thereby providing a promising therapeutic framework for the next generation of antifungal immunotherapies.