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dc.contributor.authorAshton, TD
dc.contributor.authorNgo, A
dc.contributor.authorFavuzza, P
dc.contributor.authorBullen, HE
dc.contributor.authorGancheva, MR
dc.contributor.authorRomeo, O
dc.contributor.authorParkyn Schneider, M
dc.contributor.authorNguyen, N
dc.contributor.authorSteel, RWJ
dc.contributor.authorDuffy, S
dc.contributor.authorLowes, KN
dc.contributor.authorSabroux, HJ
dc.contributor.authorAvery, VM
dc.contributor.authorBoddey, JA
dc.contributor.authorWilson, DW
dc.contributor.authoret al.
dc.date.accessioned2021-11-03T01:46:49Z
dc.date.available2021-11-03T01:46:49Z
dc.date.issued2021
dc.identifier.issn0045-2068
dc.identifier.doi10.1016/j.bioorg.2021.105359
dc.identifier.urihttp://hdl.handle.net/10072/409698
dc.description.abstractMalaria 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.
dc.description.peerreviewedYes
dc.languageeng
dc.publisherElsevier BV
dc.relation.ispartofpagefrom105359
dc.relation.ispartofjournalBioorganic Chemistry
dc.relation.ispartofvolume117
dc.subject.fieldofresearchMedicinal and biomolecular chemistry
dc.subject.fieldofresearchcode3404
dc.subject.keywordsAntimalarial
dc.subject.keywordsMalaria
dc.subject.keywordsPlasmodium
dc.subject.keywordsQuinazoline
dc.titleProperty activity refinement of 2-anilino 4-amino substituted quinazolines as antimalarials with fast acting asexual parasite activity
dc.typeJournal article
dc.type.descriptionC1 - Articles
dcterms.bibliographicCitationAshton, TD; Ngo, A; Favuzza, P; Bullen, HE; Gancheva, MR; Romeo, O; Parkyn Schneider, M; Nguyen, N; Steel, RWJ; Duffy, S; Lowes, KN; Sabroux, HJ; Avery, VM; Boddey, JA; Wilson, DW; et al., Property activity refinement of 2-anilino 4-amino substituted quinazolines as antimalarials with fast acting asexual parasite activity, Bioorganic Chemistry, 2021, 117, pp. 105359
dcterms.dateAccepted2021-09-12
dc.date.updated2021-11-03T00:29:39Z
gro.hasfulltextNo Full Text
gro.griffith.authorDuffy, Sandra
gro.griffith.authorAvery, Vicky M.


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