Trisubstituted Pyrimidines as Efficacious and Fast-acting Antimalarials

Neil R. Norcross, Beatriz Baragana, Caroline Wilson, Irene Hallyburton, Maria Osuna-Cabello, Suzanne Norval, Jennifer Riley, Laste Stojanovski, Frederick R. C. Simeons, Achim Porzelle, Raffaella Grimaldi, Sergio Wittlin, Sandra Duffy, Vicky M. Avery, Stephan Meister, Laura Sanz, Belen Jimenez-Diaz, Inigo Angulo-Barturen, Santiago Ferrer, Maria Santos MarinezFrancisco Javier Gamo, Julie A. Frearson, David W. Gray, Alan H. Fairlamb, Elizabeth A. Winzeler, David Waterson, Simon F. Campbell, Paul Willis, Kevin D. Read, Ian H. Gilbert

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Abstract

In this paper we describe the optimisation of a phenotypic hit against Plasmodium falciparum, based on a tri-substituted pyrimidine scaffold. This led to compounds with good pharmacokinetics and oral activity in a P. berghei mouse model of malaria. The most promising compound (13) showed a reduction in parasitaemia of 96% when dosed at 30 mg/kg orally, once a day for 4 days in the P. berghei mouse model of malaria. It also demonstrated a rapid rate of clearance of the erythrocytic stage of P. falciparum in the SCID mouse model with an ED90 11.7 mg/kg when dosed orally. Unfortunately, the compound is a potent inhibitor of cytochrome P450 enzymes, probably due to a 4-pyridyl substituent. Nevertheless, this is a lead molecule with a potentially useful antimalarial profile, which could either be further optimised or used for target hunting.
Original languageEnglish
Pages (from-to)6101-6120
Number of pages20
JournalJournal of Medicinal Chemistry
Volume59
Issue number13
Early online date17 Jun 2016
DOIs
Publication statusPublished - 14 Jul 2016

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Pyrimidines
Antimalarials
Plasmodium falciparum
Malaria
SCID Mice
Parasitemia
Cytochrome P-450 Enzyme System
Pharmacokinetics
Lead
pyrimidine
Cytochrome P-450 Enzyme Inhibitors

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Norcross, Neil R. ; Baragana, Beatriz ; Wilson, Caroline ; Hallyburton, Irene ; Osuna-Cabello, Maria ; Norval, Suzanne ; Riley, Jennifer ; Stojanovski, Laste ; Simeons, Frederick R. C. ; Porzelle, Achim ; Grimaldi, Raffaella ; Wittlin, Sergio ; Duffy, Sandra ; Avery, Vicky M. ; Meister, Stephan ; Sanz, Laura ; Jimenez-Diaz, Belen ; Angulo-Barturen, Inigo ; Ferrer, Santiago ; Santos Marinez, Maria ; Javier Gamo, Francisco ; Frearson, Julie A. ; Gray, David W. ; Fairlamb, Alan H. ; Winzeler, Elizabeth A. ; Waterson, David ; Campbell, Simon F. ; Willis, Paul ; Read, Kevin D. ; Gilbert, Ian H. / Trisubstituted Pyrimidines as Efficacious and Fast-acting Antimalarials. In: Journal of Medicinal Chemistry. 2016 ; Vol. 59, No. 13. pp. 6101-6120.
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abstract = "In this paper we describe the optimisation of a phenotypic hit against Plasmodium falciparum, based on a tri-substituted pyrimidine scaffold. This led to compounds with good pharmacokinetics and oral activity in a P. berghei mouse model of malaria. The most promising compound (13) showed a reduction in parasitaemia of 96{\%} when dosed at 30 mg/kg orally, once a day for 4 days in the P. berghei mouse model of malaria. It also demonstrated a rapid rate of clearance of the erythrocytic stage of P. falciparum in the SCID mouse model with an ED90 11.7 mg/kg when dosed orally. Unfortunately, the compound is a potent inhibitor of cytochrome P450 enzymes, probably due to a 4-pyridyl substituent. Nevertheless, this is a lead molecule with a potentially useful antimalarial profile, which could either be further optimised or used for target hunting.",
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Norcross, NR, Baragana, B, Wilson, C, Hallyburton, I, Osuna-Cabello, M, Norval, S, Riley, J, Stojanovski, L, Simeons, FRC, Porzelle, A, Grimaldi, R, Wittlin, S, Duffy, S, Avery, VM, Meister, S, Sanz, L, Jimenez-Diaz, B, Angulo-Barturen, I, Ferrer, S, Santos Marinez, M, Javier Gamo, F, Frearson, JA, Gray, DW, Fairlamb, AH, Winzeler, EA, Waterson, D, Campbell, SF, Willis, P, Read, KD & Gilbert, IH 2016, 'Trisubstituted Pyrimidines as Efficacious and Fast-acting Antimalarials', Journal of Medicinal Chemistry, vol. 59, no. 13, pp. 6101-6120. https://doi.org/10.1021/acs.jmedchem.6b00028

Trisubstituted Pyrimidines as Efficacious and Fast-acting Antimalarials. / Norcross, Neil R.; Baragana, Beatriz; Wilson, Caroline; Hallyburton, Irene; Osuna-Cabello, Maria; Norval, Suzanne; Riley, Jennifer; Stojanovski, Laste; Simeons, Frederick R. C.; Porzelle, Achim; Grimaldi, Raffaella; Wittlin, Sergio; Duffy, Sandra; Avery, Vicky M.; Meister, Stephan; Sanz, Laura; Jimenez-Diaz, Belen; Angulo-Barturen, Inigo; Ferrer, Santiago; Santos Marinez, Maria; Javier Gamo, Francisco; Frearson, Julie A.; Gray, David W.; Fairlamb, Alan H.; Winzeler, Elizabeth A.; Waterson, David; Campbell, Simon F.; Willis, Paul; Read, Kevin D. (Lead / Corresponding author); Gilbert, Ian H. (Lead / Corresponding author).

In: Journal of Medicinal Chemistry, Vol. 59, No. 13, 14.07.2016, p. 6101-6120.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Trisubstituted Pyrimidines as Efficacious and Fast-acting Antimalarials

AU - Norcross, Neil R.

AU - Baragana, Beatriz

AU - Wilson, Caroline

AU - Hallyburton, Irene

AU - Osuna-Cabello, Maria

AU - Norval, Suzanne

AU - Riley, Jennifer

AU - Stojanovski, Laste

AU - Simeons, Frederick R. C.

AU - Porzelle, Achim

AU - Grimaldi, Raffaella

AU - Wittlin, Sergio

AU - Duffy, Sandra

AU - Avery, Vicky M.

AU - Meister, Stephan

AU - Sanz, Laura

AU - Jimenez-Diaz, Belen

AU - Angulo-Barturen, Inigo

AU - Ferrer, Santiago

AU - Santos Marinez, Maria

AU - Javier Gamo, Francisco

AU - Frearson, Julie A.

AU - Gray, David W.

AU - Fairlamb, Alan H.

AU - Winzeler, Elizabeth A.

AU - Waterson, David

AU - Campbell, Simon F.

AU - Willis, Paul

AU - Read, Kevin D.

AU - Gilbert, Ian H.

PY - 2016/7/14

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DO - 10.1021/acs.jmedchem.6b00028

M3 - Article

C2 - 27314305

VL - 59

SP - 6101

EP - 6120

JO - Journal of Medicinal Chemistry

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