2. Academic Validation
  3. Optimization of 2-Anilino 4-Amino Substituted Quinazolines into Potent Antimalarial Agents with Oral in Vivo Activity

Optimization of 2-Anilino 4-Amino Substituted Quinazolines into Potent Antimalarial Agents with Oral in Vivo Activity

  • J Med Chem. 2017 Feb 9;60(3):1171-1188. doi: 10.1021/acs.jmedchem.6b01673.
Paul R Gilson 1 2,  Cyrus Tan 3 4,  Kate E Jarman 3 4,  Kym N Lowes 3 4,  Joan M Curtis 3,  William Nguyen 3 4,  Adrian E Di Rago 3,  Hayley E Bullen 1,  Boris Prinz 1,  Sandra Duffy 5,  Jonathan B Baell 6,  Craig A Hutton 7,  Helene Jousset Subroux 3 4,  Brendan S Crabb 4 1 2,  Vicky M Avery 5,  Alan F Cowman 3 4,  Brad E Sleebs 3 4
Affiliations

Affiliations

  • 1 Macfarlane Burnet Institute for Medical Research and Public Health , Melbourne, 3004, Australia.
  • 2 Monash University , Clayton, Victoria 3800, Australia.
  • 3 The Walter and Eliza Hall Institute of Medical Research , Parkville 3052, Australia.
  • 4 Department of Medical Biology, The University of Melbourne , Parkville 3010, Australia.
  • 5 Discovery Biology, Eskitis Institute for Drug Discovery, Griffith University , Nathan, Queensland 4111, Australia.
  • 6 Monash Institute of Pharmaceutical Sciences, Monash University , Parkville, Victoria 3052, Australia.
  • 7 School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne , Parkville, Victoria 3010, Australia.
PMID: 28080063 DOI: 10.1021/acs.jmedchem.6b01673
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.

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