Development of dihydroquinazoline compounds as novel therapeutics against Naegleria fowleri

Abstract

Primary amoebic meningoencephalitis (PAM) is a brain infection caused by the free-living amoebae Naegleria fowleri. There are few viable treatment options for the infection, resulting in a >97 % fatality rate. Small molecules are being increasingly investigated as treatment options for this deadly infection. This work details the discovery of a dihydroquinazoline that was toxic to the amoeba and subsequent structure–activity relationship (SAR) development of compounds with increasingly potent activity, yielding several early lead candidates exhibiting submicromolar activity (EC₅₀ = 0.62–0.84 μM) and limited cytotoxicity (CC₅₀ > 10 μM).