Optimization of 2-anilino 4-amino substituted quinazolines into potent antimalarial agents with oral in vivo activity

Paul R Gilson, Cyrus Tan, Kate E Jarman, Kym N. Lowes, Joan M. Curtis, William Nguyen, Adrian E. Di Rago, Hayley E. Bullen, Boris Prinz, Sandra Duffy, Jonathan B Baell, Craig A. Hutton, Helene Jousset Subroux, Brendan S Crabb, Vicky M. Avery, Alan F. Cowman, Brad E. Sleebs

Research output: Contribution to journalArticle

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.

LanguageEnglish
Pages1171-1188
Number of pages18
JournalJournal of Medicinal Chemistry
Volume60
Issue number3
DOIs
StatePublished - 9 Feb 2017

Cite this

Gilson, Paul R ; Tan, Cyrus ; Jarman, Kate E ; Lowes, Kym N. ; Curtis, Joan M. ; Nguyen, William ; Di Rago, Adrian E. ; Bullen, Hayley E. ; Prinz, Boris ; Duffy, Sandra ; Baell, Jonathan B ; Hutton, Craig A. ; Jousset Subroux, Helene ; Crabb, Brendan S ; Avery, Vicky M. ; Cowman, Alan F. ; Sleebs, Brad E./ Optimization of 2-anilino 4-amino substituted quinazolines into potent antimalarial agents with oral in vivo activity. In: Journal of Medicinal Chemistry. 2017 ; Vol. 60, No. 3. pp. 1171-1188
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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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Gilson, PR, Tan, C, Jarman, KE, Lowes, KN, Curtis, JM, Nguyen, W, Di Rago, AE, Bullen, HE, Prinz, B, Duffy, S, Baell, JB, Hutton, CA, Jousset Subroux, H, Crabb, BS, Avery, VM, Cowman, AF & Sleebs, BE 2017, 'Optimization of 2-anilino 4-amino substituted quinazolines into potent antimalarial agents with oral in vivo activity' Journal of Medicinal Chemistry, vol 60, no. 3, pp. 1171-1188. DOI: 10.1021/acs.jmedchem.6b01673

Optimization of 2-anilino 4-amino substituted quinazolines into potent antimalarial agents with oral in vivo activity. / Gilson, Paul R; Tan, Cyrus; Jarman, Kate E; Lowes, Kym N.; Curtis, Joan M.; Nguyen, William; Di Rago, Adrian E.; Bullen, Hayley E.; Prinz, Boris; Duffy, Sandra; Baell, Jonathan B; Hutton, Craig A.; Jousset Subroux, Helene; Crabb, Brendan S; Avery, Vicky M.; Cowman, Alan F.; Sleebs, Brad E.

In: Journal of Medicinal Chemistry, Vol. 60, No. 3, 09.02.2017, p. 1171-1188.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Optimization of 2-anilino 4-amino substituted quinazolines into potent antimalarial agents with oral in vivo activity

AU - Gilson,Paul R

AU - Tan,Cyrus

AU - Jarman,Kate E

AU - Lowes,Kym N.

AU - Curtis,Joan M.

AU - Nguyen,William

AU - Di Rago,Adrian E.

AU - Bullen,Hayley E.

AU - Prinz,Boris

AU - Duffy,Sandra

AU - Baell,Jonathan B

AU - Hutton,Craig A.

AU - Jousset Subroux,Helene

AU - Crabb,Brendan S

AU - Avery,Vicky M.

AU - Cowman,Alan F.

AU - Sleebs,Brad E.

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AB - 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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DO - 10.1021/acs.jmedchem.6b01673

M3 - Article

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SP - 1171

EP - 1188

JO - Journal of Medicinal Chemistry

T2 - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 3

ER -