Often overlooked, fungal infections claim nearly 1.7 million lives annually. Current antifungal agents possess severe drawbacks such as drug-drug interactions, toxicity, and a narrow spectrum of activity. With an increase in the emergence of resistant strains of fungi to these drugs, there is an urgent need to develop new antifungal agents with novel mechanisms of action. We have recently reported an extensive SAR study by synthesizing a library of ~300 N-(aromatic acyl)-2-hydroxyarylhydrazones. We identified several lead compounds that displayed excellent MIC80, in vitro killing activity, and high selectivity indices. Multi-brominated compounds could seldom be seen as drug candidates. However, our current lead molecules contain one or more bromine atoms, making the molecule heavy and further leading to solubility problems. Therefore, we investigated whether bromine could be replaced with its bioisostere – ethynyl (acetylene) functional group. Here, we have synthesized a series of structurally diverse hydroxyacylhydrazones containing ethynyl groups to investigate their antifungal activity. Broad-spectrum in vitro studies involving C. neoformans, C. albicans, and A. fumingatus indicated that replacing bromine with an ethynyl group enhanced their antifungal activity. Computer-aided drug design (CADD) that involves AutoQSAR and pkCSM programs were used in this work to enhance the affinity to target and desirable pharmacological properties. We will present the QSAR-based design and synthesis of a series of novel ethynyl-hydroxyacylhydrazones, as well as their antifungal activities and SAR for lead optimization.

Computer-aided drug design, synthesis, antifungal activity, and SAR studies of novel hydroxyacylhydrazones as a new class of antifungal agents

ACS Spring 2022

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