title: Optimization of 2-Anilino 4-Amino Substituted Quinazolines into Potent Antimalarial Agents with Oral in Vivo Activity.
abstract: Novel antimalarial therapeutics that target multiple stages of the parasite lifecycle are urgently required to tackle the emerging problem of resistance with current drugs. Here, we describe the optimization of the 2-anilino quinazoline class as antimalarial agents. The class, identified from publicly available antimalarial screening data, was optimized to generate lead compounds that possess potent antimalarial activity against P. falciparum parasites comparable to the known antimalarials, chloroquine and mefloquine. During the optimization process, we defined the functionality necessary for activity and improved in vitro metabolism and solubility. The resultant lead compounds possess potent activity against a multidrug resistant strain of P. falciparum and arrest parasites at the ring phase of the asexual stage and also gametocytogensis. Finally, we show that the lead compounds are orally efficacious in a 4 day murine model of malaria disease burden.
authors.affiliation: Macfarlane Burnet Institute for Medical Research and Public Health , Melbourne, 3004, Australia.|Monash University , Clayton, Victoria 3800, Australia.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Gilson
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research , Parkville 3052, Australia.|Department of Medical Biology, The University of Melbourne , Parkville 3010, Australia.
authors.forename: Cyrus
authors.initials: C
authors.lastname: Tan
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research , Parkville 3052, Australia.|Department of Medical Biology, The University of Melbourne , Parkville 3010, Australia.
authors.forename: Kate E
authors.initials: KE
authors.lastname: Jarman
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research , Parkville 3052, Australia.|Department of Medical Biology, The University of Melbourne , Parkville 3010, Australia.
authors.forename: Kym N
authors.initials: KN
authors.lastname: Lowes
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research , Parkville 3052, Australia.
authors.forename: Joan M
authors.initials: JM
authors.lastname: Curtis
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research , Parkville 3052, Australia.|Department of Medical Biology, The University of Melbourne , Parkville 3010, Australia.
authors.forename: William
authors.initials: W
authors.lastname: Nguyen
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research , Parkville 3052, Australia.
authors.forename: Adrian E
authors.initials: AE
authors.lastname: Di Rago
authors.affiliation: Macfarlane Burnet Institute for Medical Research and Public Health , Melbourne, 3004, Australia.
authors.forename: Hayley E
authors.initials: HE
authors.lastname: Bullen
authors.affiliation: Macfarlane Burnet Institute for Medical Research and Public Health , Melbourne, 3004, Australia.
authors.forename: Boris
authors.initials: B
authors.lastname: Prinz
authors.affiliation: Discovery Biology, Eskitis Institute for Drug Discovery, Griffith University , Nathan, Queensland 4111, Australia.
authors.forename: Sandra
authors.initials: S
authors.lastname: Duffy
authors.affiliation: Monash Institute of Pharmaceutical Sciences, Monash University , Parkville, Victoria 3052, Australia.
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Baell
authors.affiliation: School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne , Parkville, Victoria 3010, Australia.
authors.forename: Craig A
authors.identifier: 0000-0002-2353-9258
authors.initials: CA
authors.lastname: Hutton
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research , Parkville 3052, Australia.|Department of Medical Biology, The University of Melbourne , Parkville 3010, Australia.
authors.forename: Helene
authors.initials: H
authors.lastname: Jousset Subroux
authors.affiliation: Department of Medical Biology, The University of Melbourne , Parkville 3010, Australia.|Macfarlane Burnet Institute for Medical Research and Public Health , Melbourne, 3004, Australia.|Monash University , Clayton, Victoria 3800, Australia.
authors.forename: Brendan S
authors.initials: BS
authors.lastname: Crabb
authors.affiliation: Discovery Biology, Eskitis Institute for Drug Discovery, Griffith University , Nathan, Queensland 4111, Australia.
authors.forename: Vicky M
authors.initials: VM
authors.lastname: Avery
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research , Parkville 3052, Australia.|Department of Medical Biology, The University of Melbourne , Parkville 3010, Australia.
authors.forename: Alan F
authors.initials: AF
authors.lastname: Cowman
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research , Parkville 3052, Australia.|Department of Medical Biology, The University of Melbourne , Parkville 3010, Australia.
authors.forename: Brad E
authors.identifier: 0000-0001-9117-1048
authors.initials: BE
authors.lastname: Sleebs
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D051379:Mice; D010963:Plasmodium falciparum / Q000187:drug effects; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D011799:Quinazolines