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

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

Author(s): 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;
Details: Publication Year 2024-08-12,Volume 67,Issue #16,Page 14493-14523
Journal Title: Journal of Medicinal Chemistry
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(+)-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.
Publisher: ACS
Keywords: *Antimalarials/pharmacology/chemistry/pharmacokinetics; Animals; *Plasmodium falciparum/drug effects; *Quinazolinones/pharmacology/chemistry/pharmacokinetics; Mice; Administration, Oral; Structure-Activity Relationship; Humans; Malaria/drug therapy; Female; Solubility
Research Division(s): Chemical Biology; Advanced Technology And Biology; Infectious Diseases And Immune Defence; Advanced Technology and Biology; Infectious Diseases and Immune Defence
PubMed ID: 39134060
Publisher's Version: https://doi.org/10.1021/acs.jmedchem.4c01241
Open Access at Publisher's Site: https://doi.org/10.1021/acs.jmedchem.4c01241
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-08-14 09:49:30

Last Modified: 2024-08-23 02:56:05