Property activity refinement of 2-anilino 4-amino substituted quinazolines as antimalarials with fast acting asexual parasite activity.

Autor: Ashton TD; The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia., Ngo A; The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia., Favuzza P; The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia., Bullen HE; Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, 3004, Australia; Monash University, Clayton, Victoria 3800, Australia., Gancheva MR; Research Centre for Infectious Diseases, School of Biological Sciences, University of Adelaide, Adelaide, Australia., Romeo O; Research Centre for Infectious Diseases, School of Biological Sciences, University of Adelaide, Adelaide, Australia., Parkyn Schneider M; Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, 3004, Australia; Monash University, Clayton, Victoria 3800, Australia., Nguyen N; The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia., Steel RWJ; The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia., Duffy S; Discovery Biology, Griffith Institute for Drug Discovery, Griffith University, Nathan, Queensland 4111, Australia., Lowes KN; The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia., Sabroux HJ; The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia., Avery VM; Discovery Biology, Griffith Institute for Drug Discovery, Griffith University, Nathan, Queensland 4111, Australia., Boddey JA; The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia., Wilson DW; Research Centre for Infectious Diseases, School of Biological Sciences, University of Adelaide, Adelaide, Australia., Cowman AF; The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia., Gilson PR; Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, 3004, Australia; Monash University, Clayton, Victoria 3800, Australia., Sleebs BE; The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia. Electronic address: sleebs@wehi.edu.au.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2021 Dec; Vol. 117, pp. 105359. Date of Electronic Publication: 2021 Sep 21.
DOI: 10.1016/j.bioorg.2021.105359
Abstrakt: Malaria is a devastating disease caused by Plasmodium parasites. Emerging resistance against current antimalarial therapeutics has engendered the need to develop antimalarials with novel structural classes. We recently described the identification and initial optimization of the 2-anilino quinazoline antimalarial class. Here, we refine the physicochemical properties of this antimalarial class with the aim to improve aqueous solubility and metabolism and to reduce adverse promiscuity. We show the physicochemical properties of this class are intricately balanced with asexual parasite activity and human cell cytotoxicity. Structural modifications we have implemented improved LipE, aqueous solubility and in vitro metabolism while preserving fast acting P. falciparum asexual stage activity. The lead compounds demonstrated equipotent activity against P. knowlesi parasites and were not predisposed to resistance mechanisms of clinically used antimalarials. The optimized compounds exhibited modest activity against early-stage gametocytes, but no activity against pre-erythrocytic liver parasites. Confoundingly, the refined physicochemical properties installed in the compounds did not engender improved oral efficacy in a P. berghei mouse model of malaria compared to earlier studies on the 2-anilino quinazoline class. This study provides the framework for further development of this antimalarial class.
(Copyright © 2021 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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