Lactam Truncation Yields a Dihydroquinazolinone Scaffold with Potent Antimalarial Activity that Targets PfATP4
Year: 2024
Type: article
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.
Source: ChemMedChem
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, Nirupam De, 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
Institutions: The University of Melbourne, Walter and Eliza Hall Institute of Medical Research, Australian National University, TCG Lifesciences (India), London School of Hygiene & Tropical Medicine, The University of Adelaide, Deakin University, Medicines for Malaria Venture, Janssen Research & Development (United States)
Language: English
Topic: Malaria Research and Control
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,950
Awards: Multidisciplinary catalyst to discover and progress novel antimalarial drugs, Optimisation of a potent and fast acting antimalarial class that is orally efficacious in vivo, Can malaria transmission be prevented through catastrophic failure of gametocyte quiescence?, G6278674949, G689834564, G8067893058
OpenAlex ID: W4402066803