Pharmacophore Establishment and Optimization of Saturated 1,6-Naphthyridine-Fused Quinazolinones that Inhibit Meningoencephalitis-Causing <i>Naegleria fowleri</i>.

ABSTRACT: Primary amoebic meningoencephalitis (PAM) is a human brain infection caused by Naegleria fowleri with a 97% mortality rate. Quinazolinones resulting from a Mannich-coupled domino rearrangement were recently identified as inhibitors of the amoeba. Herein, we resolved the effective concentrations for 25 pilot compounds and then, using the Mannich protocol and a key late-stage, N-demethylation/functionalization, we synthesized 53 additional analogs to improve potency, solubility and microsomal stability. We established an antiamoebic quinazolinone pharmacophore, culminating in (±)-trans-57b which featured the best combination of potency, selectivity index, solubility, and microsomal stability. Enantiomeric separation afforded (4aS,13bR)-57b (

SUBMITTER: Lish MS 

PROVIDER: S-EPMC11577639 | biostudies-literature | 2024 Oct

REPOSITORIES: biostudies-literature