Pharmacophore Establishment and Optimization of Saturated 1,6-Naphthyridine-Fused Quinazolinones that Inhibit
Matthew S Lish1, Jillian E M McKeon2, Caroline M Palmentiero2
1Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706, United States.
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 (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.
Insights
New quinazolinone compounds show promise in inhibiting Naegleria fowleri, the cause of primary amoebic meningoencephalitis (PAM). The most potent compound, BDGR-20237, demonstrated high brain penetration but limited efficacy in mice.
Area of Science:
- Medicinal Chemistry
- Neuroscience
- Parasitology
Background:
- Primary amoebic meningoencephalitis (PAM) is a rare but nearly always fatal brain infection caused by Naegleria fowleri.
- Quinazolinones have emerged as potential inhibitors against this deadly amoeba.
Purpose of the Study:
- To identify and synthesize novel quinazolinone analogs with improved antiamoebic properties.
- To establish a pharmacophore model for enhanced potency, solubility, and metabolic stability.
Main Methods:
- Synthesis of 53 quinazolinone analogs using Mannich protocol and late-stage functionalization.
- Determination of effective concentrations and assessment of solubility and microsomal stability.
- Enantiomeric separation and pharmacokinetic profiling of lead compounds in mice.
Main Results:
- A pharmacophore model was established, identifying key structural features for antiamoebic activity.
- Compound (±)-trans-57b and its enantiomer (4aS,13bR)-57b (BDGR-20237) showed significant potency.
- BDGR-20237 exhibited high brain penetrance in mice but a short half-life, leading to no significant survival benefit in a pilot efficacy study.
Conclusions:
- The established quinazolinone pharmacophore provides a strong foundation for further drug development against Naegleria fowleri.
- Optimized quinazolinones, including BDGR-20237, warrant further investigation despite limitations in current efficacy studies.
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