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Property and Activity Refinement of Dihydroquinazolinone-3-carboxamides as Orally Efficacious Antimalarials that Target PfATP4.

Authors :
Ashton TD
Calic PPS
Dans MG
Ooi ZK
Zhou Q
Palandri J
Loi K
Jarman KE
Qiu D
Lehane AM
Maity BC
De N
Giannangelo C
MacRaild CA
Creek DJ
Mao EY
Gancheva MR
Wilson DW
Chowdury M
de Koning-Ward TF
Famodimu MT
Delves MJ
Pollard H
Sutherland CJ
Baud D
Brand S
Jackson PF
Cowman AF
Sleebs BE
Source :
Journal of medicinal chemistry [J Med Chem] 2024 Aug 22; Vol. 67 (16), pp. 14493-14523. Date of Electronic Publication: 2024 Aug 12.
Publication Year :
2024

Abstract

To contribute to the global effort to develop new antimalarial therapies, we previously disclosed initial findings on the optimization of the dihydroquinazolinone-3-carboxamide class that targets PfATP4. Here we report on refining the aqueous solubility and metabolic stability to improve the pharmacokinetic profile and consequently in vivo efficacy. We show that the incorporation of heterocycle systems in the 8-position of the scaffold was found to provide the greatest attainable balance between parasite activity, aqueous solubility, and metabolic stability. Optimized analogs, including the frontrunner compound S -WJM992, were shown to inhibit PfATP4-associated Na <superscript>+</superscript> -ATPase activity, gave rise to a metabolic signature consistent with PfATP4 inhibition, and displayed altered activities against parasites with mutations in PfATP4. Finally, S -WJM992 showed appreciable efficacy in a malaria mouse model and blocked gamete development preventing transmission to mosquitoes. Importantly, further optimization of the dihydroquinazolinone class is required to deliver a candidate with improved pharmacokinetic and risk of resistance profiles.

Details

Language :
English
ISSN :
1520-4804
Volume :
67
Issue :
16
Database :
MEDLINE
Journal :
Journal of medicinal chemistry
Publication Type :
Academic Journal
Accession number :
39134060
Full Text :
https://doi.org/10.1021/acs.jmedchem.4c01241