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 Marinez; Francisco 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

doi:10.1021/acs.jmedchem.6b00028

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 Marinez

Francisco Javier Gamo, Julie A. Frearson, David W. Gray, Alan H. Fairlamb, Elizabeth A. Winzeler, David Waterson, Simon F. Campbell, Paul Willis, Kevin D. Read (Lead / Corresponding author), Ian H. Gilbert (Lead / Corresponding author)

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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 language	English
Pages (from-to)	6101-6120
Number of pages	20
Journal	Journal of Medicinal Chemistry
Volume	59
Issue number	13
Early online date	17 Jun 2016
DOIs	https://doi.org/10.1021/acs.jmedchem.6b00028
Publication status	Published - 14 Jul 2016

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SDG 3 Good Health and Well-being

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This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see [insert ACS Articles on Request author-directed link to Published Work, see http://pubs.acs.org/page/policy/articlesonrequest/index.html].”
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© 2016 American Chemical Society. This is an open access article published under a Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
Final published version, 2.08 MBLicence: CC BY

A Translational Engine for Biomedical Discoveries (Strategic Grant)
Fairlamb, A. (Investigator) & Gilbert, I. (Investigator)
1/01/13 → 30/09/15
Project: Research

Gilbert, Ian
- Drug Discovery Unit - Professor/Head of the Drug Discovery Unit & Roscoe Chair in Drug Discovery
Person: Academic

Cite this

Norcross, N. R., Baragana, B., Wilson, C., Hallyburton, I., Osuna-Cabello, M., Norval, S., Riley, J., Stojanovski, L., Simeons, F. R. C., Porzelle, A., Grimaldi, R., Wittlin, S., Duffy, S., Avery, V. M., Meister, S., Sanz, L., Jimenez-Diaz, B., Angulo-Barturen, I., Ferrer, S., ... Gilbert, I. H. (2016). Trisubstituted Pyrimidines as Efficacious and Fast-acting Antimalarials. Journal of Medicinal Chemistry, 59(13), 6101-6120. https://doi.org/10.1021/acs.jmedchem.6b00028

@article{ec38528a8996402b81923942dc9e1ee1,

title = "Trisubstituted Pyrimidines as Efficacious and Fast-acting Antimalarials",

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. ",

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

year = "2016",

month = jul,

day = "14",

doi = "10.1021/acs.jmedchem.6b00028",

language = "English",

volume = "59",

pages = "6101--6120",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "13",

}

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

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

Y1 - 2016/7/14

N2 - 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.

AB - 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.

U2 - 10.1021/acs.jmedchem.6b00028

DO - 10.1021/acs.jmedchem.6b00028

M3 - Article

C2 - 27314305

SN - 0022-2623

VL - 59

SP - 6101

EP - 6120

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 13

ER -

Trisubstituted Pyrimidines as Efficacious and Fast-acting Antimalarials

Abstract

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Gilbert, Ian

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