Design, synthesis and SAR studies of N′-(Ethynylsalicylidene)arenecarbohydrazides as next-generation broad-spectrum antifungal agents

The present study investigated whether bromine could be replaced with its bioisostere, ethynyl group, without losing potency and selectivity toward fungi, and has found that the bioisosteric replacement strategy is successfully applied to the design, synthesis and SAR study of novel 2nd-generation N′-(salicylidene)arenecarbohydrazides, bearing ethynyl groups. This study particularly focused on the broad-spectrum antifungal activities against three critical priority fungal pathogens, C. neoformans, C. albicans, and A. fumigatus to select highly promising lead compounds. Reliable QSAR models for optimization and further drug development have been successfully created using the AutoQSAR program. Also, in silico ADME/Tox predictions were performed, which predicted considerably improved ClogP values (3.26–5.66), no mutagenicity (AMES test) except for 2 compounds (with low confidence) out of 31, no hERG toxicity, no lethal toxicity (LD₅₀ > 2 Mol/kg), no hepatotoxicity except for 2 compounds out of 31, and good Caco2 permeability. This study has identified 3 compounds, 8.1, 8.6 and 8.23 as the most promising leads for further drug development, which exhibited excellent broad-spectrum antifungal activities against the three fungal pathogens with high (SI >100) to extremely high (SI up to 17,066) selectivity indices and relevant ClogP values (3.26–4.40). Compounds 8.1 and 8.23 showed synergy in combination with 3 clinical antifungal drugs, especially 8.1 exhibited synergy with 3 clinical drugs against all 3 distinctly different fungal pathogens. Compound 8.23 will serve as the scaffold for developing a new series of bromine-free N′-(salicylidene)arene(or heteroarene)carbohydrazides.