Lactam Truncation Yields a Dihydroquinazolinone Scaffold with Potent Antimalarial Activity that Targets PfATP4.

Published in: ChemMedChem, Pages: e202400549, Journal; Article, 2024

DOI: 10.1002/cmdc.202400549

Authors: Trent D. Ashton, Petar P. S. Calic, Madeline G. Dans, Zi Kang Ooi, Qingmiao Zhou, Katie Loi, Kate E. Jarman, Josephine Palandri, Deyun Qiu, Adele M. Lehane, Bikash Maity (TCGLS Member), Nirupam De (TCGLS Member), Mufuliat T. Famodimu, Michael J. Delves, Emma Y. Mao, Maria R. Gancheva, Danny W. Wilson, Mrittika Chowdury, Tania F. de Koning-Ward, Delphine Baud, Stephen Brand, Paul F. Jackson, Alan F. Cowman, Brad E Sleebs

Abstract: The emergence of resistance against current antimalarial treatments has necessitated the need for the development of novel antimalarial chemotypes. Toward this goal, we recently optimised the antimalarial activity of the dihydroquinazolinone scaffold and showed it targeted PfATP4. Here, we deconstruct the lactam moiety of the tricyclic dihydroquinazolinone scaffold and investigate the structure-activity relationship of the truncated scaffold. It was shown that SAR between scaffolds was largely transferrable and generated analogues with potent asexual stage activity. Evaluation of the truncated analogues against PfATP4 mutant drug resistant parasite strains and in assays measuring PfATP4-associated ATPase activity demonstrated retention of PfATP4 as the molecular target. Analogues exhibited activity against both male and female gametes and multidrug resistant parasites. Limited efficacy of analogues in a P. berghei asexual stage mouse model was attributed to their moderate metabolic stability and low aqueous stability. Further development is required to address these attributes toward the potential use of the dihydroquinazolinone class in a curative and transmission blocking combination antimalarial therapy.