Design, synthesis and biological evaluation of natural product echinocandin derivatives

Fungal pathogen infections impose a great challenge for global public health, causing approximately 1.6 million deaths annually. Echinocandin-class drugs, with unique mechanism and favorable safety profile, have become the first-line anti-fungal therapeutic option for candidemia and invasive candidiasis. The present study successfully designed and synthesized a series of novel echinocandin derivatives, among which SIPI-18333 and SIPI-18334 exhibited a minimum inhibitory concentration (MIC) of 0.03125 μg/mL against Candida krusei in vitro, significantly surpassing existing echinocandin drugs. Furthermore, these optimized compounds demonstrated minimal dependence on CYP450 metabolism in liver microsomes, resulting in significantly reduced risk of drug-drug interactions. Meanwhile, plasma stability experiments indicated that the optimized compounds exhibited better stability in plasma compared with Micafungin. Subsequent pharmacokinetic studies in rats showed significantly higher plasma exposure levels [Cmax, AUC(0-t)] of the optimized compounds than those of Rezafungin. To sum up, SIPI-18333 and SIPI-18334 exhibit superior anti-fungal activity and enhanced bioavailability, which are promising candidates for the next-generation anti-fungal agents and warrant further development.