# Optimization of 2,8-Diaryl-1,5-naphthyridines as Plasmodium falciparum Phosphatidylinositol 4‑Kinase Inhibitors with Improved ADME Profiles and In Vivo Efficacy

## TL;DR

Researchers optimized a new compound that inhibits a key malaria parasite enzyme, showing improved drug properties and effectiveness in a mouse model.

## Contribution

A new 2,8-diaryl-1,5-naphthyridine compound with improved ADME and in vivo efficacy against Plasmodium falciparum is identified.

## Key findings

- Compound 27 reduced parasitaemia by 91% in a humanized mouse model of malaria.
- Compound 27 shows no hERG inhibition or mammalian cytotoxicity.
- Compound 27 has low selectivity against some human lipid kinases but higher selectivity against others.

## Abstract

Previously reported antimalarial Plasmodium phosphatidylinositol 4-kinase IIIβ 2,8-diaryl-1,5-naphthyridine
inhibitors have shown suboptimal physicochemical and pharmacokinetic
properties. A focused target-based structure–activity relationship
and structure–property optimization studies identified several
compounds with good target and whole-cell activities and improved
physicochemical properties. A new frontrunner compound 27 showed an improved pharmacokinetic profile and reduced parasitaemia
(91% at 4 × 50 mg/kg QD doses) in the humanized NOD-scid
IL-2Rγnull mouse model of Plasmodium
falciparum malaria. Compound 27 poses
no hERG channel inhibition at high concentrations or mammalian cytotoxicity
but shows low selectivity against related human lipid kinases (PI3Kα
and PI4Kβ); however, significantly higher selectivity margins
were observed against the human MINK1 and MAP4K4 kinases.