Primary amoebic meningoencephalitis (PAM) is a human brain infection caused by 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, -demethylation/functionalization, we synthesized 53 additional analogs to improve potency, solubility and microsomal stability. We established an antiamoebic quinazolinone pharmacophore, culminating in (±)-- which featured the best combination of potency, selectivity index, solubility, and microsomal stability. Enantiomeric separation afforded (4a,13b)- () with a 41-fold potency advantage over its enantiomer. ADME and mouse pharmacokinetic profiling for revealed high brain penetrance but a limited half-life which did not statistically enhance the mouse survival in a pilot efficacy study. The pharmacophoric model, supported by 88 quinazolinones, several of which exhibit subnanomolar potency, will guide further scaffold optimization.
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| http://dx.doi.org/10.1021/acs.jmedchem.4c01630 | DOI Listing |
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