Due to the increased morbidity and mortality by fungal infections and the emergence of severe antifungal resistance, there is an urgent need for new antifungal agents. Here, we screened for antifungal activity in our in-house library through the minimum inhibitory concentration test and derived two hit compounds with moderate antifungal activities. The hit compounds' antifungal activities and drug-like properties were optimized by substituting various aryl ring, alkyl chain, and methyl groups. Among the optimized compounds, 22h was the most promising candidate with good drug-like properties and exhibited potent fast-acting fungicidal antifungal effects against various fungal pathogens and synergistic antifungal activities with some known antifungal drugs. Additionally, 22h was further confirmed to disturb fungal cell wall integrity by activating multiple cell wall integrity pathways. Furthermore, 22h exerted significant antifungal efficacy in both the subcutaneous infection mouse model and ex vivo human nail infection model.
Bibliographical noteFunding Information:
This study was supported by a National Research Council of Science & Technology grant by the South Korean government (MSIP, no. CRC-15-04-KIST to K.D.P.), the National Research Foundation of Korea (NRF-2018M3A9C8016849 to K.D.P.; 2021M3A9I4021434 and 2021R1A2B5B03086596 to Y.-S.B.), and Korea Health Technology R&D Project (HI20C0326 to J.-S.L. and K.-T.L.) by the Ministry of Health and Welfare, Republic of Korea.
© 2021 American Chemical Society.
All Science Journal Classification (ASJC) codes
- Molecular Medicine
- Drug Discovery