Synthesis and Evaluation of Benzylamine Inhibitors of Neuropathogenic Naegleria fowleri "Brain-Eating" Amoeba
- ACS Med Chem Lett. 2023 Dec 29;15(1):87-92. doi: 10.1021/acsmedchemlett.3c00440.
- 1. Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706, United States.
- 2. School of Pharmacy, Division of Pharmaceutical Sciences, University of Wisconsin-Madison, Madison, Wisconsin 53705, United States.
- 3. Eukaryotic Pathogens Innovation Center, Department of Genetics and Biochemistry, Clemson University, Clemson, South Carolina 29634, United States.
Current therapy for primary amoebic meningoencephalitis (PAM), a highly lethal brain Infection in humans caused by Naegleria fowleri amoeba, is restricted to repurposed drugs with limited efficacy and success. Discovery of an antiamoebic benzylamine scaffold 2 precipitated a medicinal chemistry effort to improve potency, cytotoxicity profile, and drug-like properties. Thirty-four compounds were prepared, leading to compound 28 with significant gains in potency (EC50 = 0.92 μM), solubility, and microsomal stability and a demonstrated absence of cytotoxicity in SH-SY5Y human neuroblastoma cells (CC50 > 20 μM). The compounds demonstrated excellent blood-brain barrier permeability in an in vitro assay, thereby providing a new structural scaffold that inhibits N. fowleri viability and permits the investigation of therapeutic interventions in an understudied neglected disease.