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

Autor: Ashton TD; Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Victoria, Australia.; Department of Medical Biology, University of Melbourne, Parkville, 3010, Victoria, Australia., Calic PPS; Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Victoria, Australia.; Department of Medical Biology, University of Melbourne, Parkville, 3010, Victoria, Australia., Dans MG; Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Victoria, Australia.; Department of Medical Biology, University of Melbourne, Parkville, 3010, Victoria, Australia., Kang Ooi Z; Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Victoria, Australia., Zhou Q; Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Victoria, Australia., Loi K; Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Victoria, Australia.; Department of Medical Biology, University of Melbourne, Parkville, 3010, Victoria, Australia., Jarman KE; Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Victoria, Australia.; Department of Medical Biology, University of Melbourne, Parkville, 3010, Victoria, Australia., Palandri J; Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Victoria, Australia.; Department of Medical Biology, University of Melbourne, Parkville, 3010, Victoria, Australia., Qiu D; Research School of Biology, Australian National University, Canberra, 2601, Australia., Lehane AM; Research School of Biology, Australian National University, Canberra, 2601, Australia., Maity B; TCG Lifesciences, Kolkata, West Bengal, 700091, India., De N; TCG Lifesciences, Kolkata, West Bengal, 700091, India., Famodimu MT; Department of Infection Biology, London School of Hygiene and Tropical Medicine, London, WC1E 7HT, UK., Delves MJ; Department of Infection Biology, London School of Hygiene and Tropical Medicine, London, WC1E 7HT, UK., Mao EY; Research Centre for Infectious Diseases, School of Biological Sciences, University of Adelaide, Adelaide, 5005, Australia., Gancheva MR; Research Centre for Infectious Diseases, School of Biological Sciences, University of Adelaide, Adelaide, 5005, Australia., Wilson DW; Research Centre for Infectious Diseases, School of Biological Sciences, University of Adelaide, Adelaide, 5005, Australia., Chowdury M; School of Medicine, Deakin University, Waurn Ponds, Victoria, 3216, Australia.; Institute for Mental and Physical Health and Clinical Translation, Deakin University, Geelong, Victoria, 3216, Australia., de Koning-Ward TF; School of Medicine, Deakin University, Waurn Ponds, Victoria, 3216, Australia.; Institute for Mental and Physical Health and Clinical Translation, Deakin University, Geelong, Victoria, 3216, Australia., Baud D; MMV Medicines for Malaria Venture, ICC, Route de Pré-Bois 20, 1215, Geneva, Switzerland., Brand S; MMV Medicines for Malaria Venture, ICC, Route de Pré-Bois 20, 1215, Geneva, Switzerland., Jackson PF; Emerging Science & Innovation, Discovery Sciences, Janssen R&D LLC, La Jolla, California, 92121, USA., Cowman AF; Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Victoria, Australia.; Department of Medical Biology, University of Melbourne, Parkville, 3010, Victoria, Australia., Sleebs BE; Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Victoria, Australia.; Department of Medical Biology, University of Melbourne, Parkville, 3010, Victoria, Australia.
Jazyk: angličtina
Zdroj: ChemMedChem [ChemMedChem] 2024 Aug 30, pp. e202400549. Date of Electronic Publication: 2024 Aug 30.
DOI: 10.1002/cmdc.202400549
Abstrakt: 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.
(© 2024 The Authors. ChemMedChem published by Wiley-VCH GmbH.)
Databáze: MEDLINE
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