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

TD Ashton; A Ngo; P Favuzza; HE Bullen; MR Gancheva; O Romeo; M Parkyn Schneider; N Nguyen; RWJ Steel; S Duffy; KN Lowes; HJ Sabroux; VM Avery; JA Boddey; DW Wilson; AF Cowman; PR Gilson; BE Sleebs

Journal article

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

TD Ashton, A Ngo, P Favuzza, HE Bullen, MR Gancheva, O Romeo, M Parkyn Schneider, N Nguyen, RWJ Steel, S Duffy, KN Lowes, HJ Sabroux, VM Avery, JA Boddey, DW Wilson, AF Cowman, PR Gilson, BE Sleebs

Bioorganic Chemistry | Published : 2021

DOI: 10.1016/j.bioorg.2021.105359

Abstract

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 solub..

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University of Melbourne Researchers

Related Projects (1)

RETARGETING THE ANTIBIOTIC AZITHROMYCIN AS AN ANTIMALARIAL WITH DUAL MODALITY

Malaria parasites resistant to first-line treatments continue to spread in South East Asia. New drugs need to be developed urgently to ensur..

Grants

Awarded by National Health and Medical Research Council

Funding Acknowledgements

This work was funded by the National Health and Medical Research Council of Australia (Development Grant 1135421 to B.E.S., A.F.C., P.R. G., J.A.B. and V.M.A.; Project Grant 1143974 to D.W.W. and B.E.S.), the Australian Cancer Research Foundation, the Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS. We thank and acknowledge the Australian Red Cross Blood Bank for the provision of fresh red blood cells, without which this research could not have been performed. J.A.B was supported by NHMRC Investigator Grant 1176995, A.F.C. is a Howard Hughes International Scholar and an Australia Fellow of the NHMRC, D.W.W. is a Hospital Research Foundation Fellow and B.E.S. is a Corin Centenary Fellow. We thank Dr Andrew Powell from the Centre of Drug Candidate Optimisation for useful discussions.