Jiménez Socha, María Alejandra

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    Discovery and in vitro characterization of bioactive compounds against human fungal pathogens
    (2023-07-07) Jiménez Socha, María Alejandra; Ortiz Bermúdez, Patricia; College of Engineering; Schüller, Andreas; Domenech García, Maribella; Rivera Portalatín, Nilka; Department of Chemical Engineering; Parés Matos, Elsie I.
    The Global Action for Fungal Infections has reported about 300 million cases of fungal infections worldwide, with two million deaths annually, mostly in immunocompromised patients. The scarcity of antifungal drugs and the increasing number of immunocompromised patients demand novel antifungal agents. We used a computational approach based on drug-drug-target networks to discover and characterize potential antifungal agents, determining the minimum inhibitory concentration (MIC) required to inhibit fungal growth. We identified 200 compounds with potential antifungal activity by adding a manually curated database of antifungal compounds using a drug repurposing approach and selected eight compounds with different clinical indications for experimental validation. Antifungal susceptibility assays demonstrated that Afimoxifene, Bithionol, Vortioxetine, and Zuclopenthixol inhibited the growth of human fungal pathogens within a concentration range of 8-64 µg/mL. We performed time-kill assays with Vortioxetine and Zuclopenthixol at 80% of their MIC, showing death rates of 0.417 h-1 and 0.253 h-1, respectively, against Candida albicans. In vitro cytotoxicity tests on NIH3T3 cells revealed cytotoxic effects of Vortioxetine and Zuclopenthixol over a concentration range of 12 -128 µg/mL. HepG2 cells exhibited higher resistance, with an IC25 of 104.856 ± 0.854 µg/mL for Vortioxetine and 52.280 ± 0.370 µg/mL for Zuclopenthixol. Our results corroborated the antifungal activity of the two new compounds and provided complementary information to the literature through in vitro assays. We performed combination treatments with Fluconazole to enhance efficacy by reducing the effective concentration. These findings highlight the potential of the selected compounds as promising candidates for the development of novel antifungal compounds.