Pharmacophore Establishment and Optimization of Saturated 1,6-Naphthyridine-Fused Quinazolinones that Inhibit Meningoencephalitis-Causing Naegleria fowleri

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...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2024-10, Vol.67 (20), p.18265-18289
Main Authors: Lish, Matthew S., McKeon, Jillian E. M., Palmentiero, Caroline M., Pomeroy, Julia M., Roster, Colm P., Guzei, Ilia A., Morris, James C., Golden, Jennifer E.
Format: Article
Language:English
Subjects:
Animals
Antiprotozoal Agents - chemical synthesis
Antiprotozoal Agents - chemistry
Antiprotozoal Agents - pharmacokinetics
Antiprotozoal Agents - pharmacology
Antiprotozoal Agents - therapeutic use
Humans
Meningoencephalitis - drug therapy
Meningoencephalitis - parasitology
Mice
Naegleria fowleri - drug effects
Pharmacophore
Quinazolinones - chemical synthesis
Quinazolinones - chemistry
Quinazolinones - pharmacokinetics
Quinazolinones - pharmacology
Quinazolinones - therapeutic use
Stereoisomerism
Structure-Activity Relationship
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Summary: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 (BDGR-20237) with a 41-fold potency advantage over its enantiomer. ADME and mouse pharmacokinetic profiling for BDGR-20237 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.
ISSN:0022-2623
1520-4804
1520-4804
DOI:10.1021/acs.jmedchem.4c01630