2. Academic Validation
  3. Benzamidine Conjugation Converts Expelled Potential Active Agents into Antifungals against Drug-Resistant Fungi

Benzamidine Conjugation Converts Expelled Potential Active Agents into Antifungals against Drug-Resistant Fungi

  • J Med Chem. 2023 Oct 12;66(19):13684-13704. doi: 10.1021/acs.jmedchem.3c01068.
Xue Wang 1,  Xueyang Jin 1,  Zhiyu Xie 2,  Hongyang Zhang 1,  Tiantian Liu 1,  Hongbo Zheng 1,  Xiaoyi Luan 1,  Yan Sun 1,  Wenjie Fang 3,  Wenqiang Chang 1,  Hongxiang Lou 1
Affiliations

Affiliations

  • 1 Department of Natural Product Chemistry, Key Lab of Chemical Biology of Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China.
  • 2 Key Laboratory of Micro-Nano Materials for Energy Storage and Conversion of Henan Province, Institute of Surface Micro and Nano Materials, College of Chemical and Materials Engineering, Xuchang University, Xuchang 461002, China.
  • 3 Shanghai Key Laboratory of Molecular Medical Mycology, Shanghai Institute of Mycology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200433, China.
PMID: 37787457 DOI: 10.1021/acs.jmedchem.3c01068
Abstract

Fungal infections present a growing global public health concern, necessitating the development of novel Antifungal drugs. However, many potential antifungals, particularly the expelled potential active agents (EPAAs), are often underestimated owing to their limitations in cellular entry or expulsion by efflux pumps. Herein, we identified 68 EPAAs out of 2322 candidates with activity against a Candida albicans efflux pump-deficient strain and no inhibitory activity against the wild-type strain. Using a novel conjugation strategy involving benzamidine (BM) as a mitochondrion-targeting warhead, we successfully converted EPAAs into potent antifungals against various urgent-threat azole-resistantCandida strains. Among the obtained EPAA-BM conjugates, IS-2-BM (11) exhibited excellent Antifungal activities and induced negligible drug resistance. Furthermore, IS-2-BM prevented biofilm formation, eradicated mature biofilms, and exhibited excellent therapeutic effects in a murine model of systemic candidiasis. These findings provide a promising strategy for increasing the possibilities of discovering more antifungals.

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