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

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

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 s...

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Main Author: Godwin A. Dziwornu (22057544) (author)
Other Authors: Donald Seanego (18881995) (author), Stephen Fienberg (4710014) (author), Venkata S. Sypu (18881998) (author), Nicolaas Salomane (18882013) (author), Liezl Krugmann (21343901) (author), Dale Taylor (1463830) (author), Keabetswe Masike (3905104) (author), Mathew Njoroge (1463821) (author), Nonlawat Boonyalai (6053441) (author), Marcus C. S. Lee (7553543) (author), Luiz C. Godoy (614562) (author), Charisse Flerida Pasaje (9353757) (author), Jacquin C. Niles (304325) (author), Gregory S. Basarab (1550479) (author), Lauren B. Coulson (18882022) (author), Sandeep R. Ghorpade (1786699) (author), Kelly Chibale (503778) (author)
Published: 2025
Subjects:
Biochemistry
Cell Biology
Genetics
Molecular Biology
Physiology
Pharmacology
Sociology
Immunology
Cancer
Infectious Diseases
Biological Sciences not elsewhere classified
Chemical Sciences not elsewhere classified
Physical Sciences not elsewhere classified
shows low selectivity
shown suboptimal physicochemical
plasmodium falciparum malaria
pi4kβ ); however
kg qd doses
improved adme profiles
humanized nod -<
herg channel inhibition
improved physicochemical properties
improved pharmacokinetic profile
new frontrunner compound
kinase iiiβ 2
27 </ b
pharmacokinetic properties
2rγnull </
scid il
reduced parasitaemia
naphthyridine inhibitors
mouse model
map4k4 kinases
mammalian cytotoxicity
human mink1
high concentrations
good target
focused target
cell activities
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