| Summary: | The occurrence of invasive fungal infections represents a substantial threat to human health that is particularly serious in immunocompromised patients. The limited number of antifungal agents, devoid of unwanted toxic effects, has resulted in an increased demand for new drugs. Herein, the chalcone framework was functionalized to develop new antifungal agents able to interfere with cell growth and with the infection process. Thus, a small library of chalcone-based analogues was evaluated in vitro against <i>C. albicans</i> ATCC 10231 and a number of compounds strongly inhibited yeast growth at non-cytotoxic concentrations. Among these, <b>5</b> and <b>7</b> interfered with the expression of two key virulence factors in <i>C. albicans</i> pathogenesis, namely, hyphae and biofilm formation, while <b>28</b> emerged as a potent and broad spectrum antifungal agent, enabling the inhibition of the tested <i>Candida</i> spp. and non-<i>Candida</i> species. Indeed, these compounds combine two modes of action by selectively interfering with growth and, as an added value, weakening microbial virulence. Overall, these compounds could be regarded as promising antifungal candidates worthy of deeper investigation. They also provide a chemical platform through which to perform an optimization process, addressed at improving potency and correcting liabilities.
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