Current therapy for primary amoebic meningoencephalitis (PAM), a highly lethal brain infection in humans caused by amoeba, is restricted to repurposed drugs with limited efficacy and success. Discovery of an antiamoebic benzylamine scaffold precipitated a medicinal chemistry effort to improve potency, cytotoxicity profile, and drug-like properties. Thirty-four compounds were prepared, leading to compound with significant gains in potency (EC = 0.92 μM), solubility, and microsomal stability and a demonstrated absence of cytotoxicity in SH-SY5Y human neuroblastoma cells (CC > 20 μM). The compounds demonstrated excellent blood-brain barrier permeability in an in vitro assay, thereby providing a new structural scaffold that inhibits viability and permits the investigation of therapeutic interventions in an understudied neglected disease.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10789148 | PMC |
| http://dx.doi.org/10.1021/acsmedchemlett.3c00440 | DOI Listing |
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