Substituted Aminoacetamides as Novel Leads for Malaria Treatment

Neil Norcross; Caroline Wilson; Beatriz Baragana; Irene Hallyburton; Maria Osuna-Cabello; Suzanne Norval; Jennifer Riley; Daniel Fletcher; Robert Sinden; Michael J. Delves; Andrea Ruecker; Sandra Duffy; Stephan Meister; Yevgeniya Antonova-Koch; Benigno Crespo; Cristina de Cózar; Laura Sanz; Francisco-Javier Gamo; Vicky M. Avery; Julie A. Frearson; David Gray; Alan Fairlamb; Elizabeth A. Winzeler; David Waterson; Simon F. Campbell; Paul Willis; Kevin Read; Ian Gilbert

doi:10.1002/cmdc.201900329

Substituted Aminoacetamides as Novel Leads for Malaria Treatment

Neil Norcross, Caroline Wilson, Beatriz Baragana, Irene Hallyburton, Maria Osuna-Cabello, Suzanne Norval, Jennifer Riley, Daniel Fletcher, Robert Sinden, Michael J. Delves, Andrea Ruecker, Sandra Duffy, Stephan Meister, Yevgeniya Antonova-Koch, Benigno Crespo, Cristina de Cózar, Laura Sanz, Francisco-Javier Gamo, Vicky M. Avery, Julie A. FrearsonDavid Gray, Alan Fairlamb, Elizabeth A. Winzeler, David Waterson, Simon F. Campbell, Paul Willis, Kevin Read (Lead / Corresponding author), Ian Gilbert (Lead / Corresponding author)

Research output: Contribution to journal › Article › peer-review

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Abstract

Herein we describe the optimization of a phenotypic hit against Plasmodium falciparum based on an aminoacetamide scaffold. This led to N-(3-chloro-4-fluorophenyl)-2-methyl-2-{[4-methyl-3-(morpholinosulfonyl)phenyl]amino}propanamide (compound 28) with low-nanomolar activity against the intraerythrocytic stages of the malaria parasite, and which was found to be inactive in a mammalian cell counter-screen up to 25 μm. Inhibition of gametes in the dual gamete activation assay suggests that this family of compounds may also have transmission blocking capabilities. Whilst we were unable to optimize the aqueous solubility and microsomal stability to a point at which the aminoacetamides would be suitable for in vivo pharmacokinetic and efficacy studies, compound 28 displayed excellent antimalarial potency and selectivity; it could therefore serve as a suitable chemical tool for drug target identification.

Original language	English
Pages (from-to)	1329-1335
Number of pages	7
Journal	ChemMedChem
Volume	14
Issue number	14
Early online date	12 Jun 2019
DOIs	https://doi.org/10.1002/cmdc.201900329
Publication status	Published - 17 Jul 2019

Keywords

Plasmodium falciparum
aminoacetamides
antimalarial agents
hit optimization
malaria

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Pharmacology
Drug Discovery
Pharmacology, Toxicology and Pharmaceutics(all)
Organic Chemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/cmdc.201900329Licence: CC BY

Final Published VersionFinal published version, 638 KBLicence: CC BY

Cite this

Norcross, N., Wilson, C., Baragana, B., Hallyburton, I., Osuna-Cabello, M., Norval, S., Riley, J., Fletcher, D., Sinden, R., Delves, M. J., Ruecker, A., Duffy, S., Meister, S., Antonova-Koch, Y., Crespo, B., de Cózar, C., Sanz, L., Gamo, F.-J., Avery, V. M., ... Gilbert, I. (2019). Substituted Aminoacetamides as Novel Leads for Malaria Treatment. ChemMedChem, 14(14), 1329-1335. https://doi.org/10.1002/cmdc.201900329

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title = "Substituted Aminoacetamides as Novel Leads for Malaria Treatment",

abstract = "Herein we describe the optimization of a phenotypic hit against Plasmodium falciparum based on an aminoacetamide scaffold. This led to N-(3-chloro-4-fluorophenyl)-2-methyl-2-{[4-methyl-3-(morpholinosulfonyl)phenyl]amino}propanamide (compound 28) with low-nanomolar activity against the intraerythrocytic stages of the malaria parasite, and which was found to be inactive in a mammalian cell counter-screen up to 25 μm. Inhibition of gametes in the dual gamete activation assay suggests that this family of compounds may also have transmission blocking capabilities. Whilst we were unable to optimize the aqueous solubility and microsomal stability to a point at which the aminoacetamides would be suitable for in vivo pharmacokinetic and efficacy studies, compound 28 displayed excellent antimalarial potency and selectivity; it could therefore serve as a suitable chemical tool for drug target identification.",

keywords = "Plasmodium falciparum, aminoacetamides, antimalarial agents, hit optimization, malaria",

author = "Neil Norcross and Caroline Wilson and Beatriz Baragana and Irene Hallyburton and Maria Osuna-Cabello and Suzanne Norval and Jennifer Riley and Daniel Fletcher and Robert Sinden and Delves, {Michael J.} and Andrea Ruecker and Sandra Duffy and Stephan Meister and Yevgeniya Antonova-Koch and Benigno Crespo and {de C{\'o}zar}, Cristina and Laura Sanz and Francisco-Javier Gamo and Avery, {Vicky M.} and Frearson, {Julie A.} and David Gray and Alan Fairlamb and Winzeler, {Elizabeth A.} and David Waterson and Campbell, {Simon F.} and Paul Willis and Kevin Read and Ian Gilbert",

note = "Funding: Wellcome Trust (Grant 100476 and a Principal Research Fellowship to A.H.F. Grant 079838)",

year = "2019",

month = jul,

day = "17",

doi = "10.1002/cmdc.201900329",

language = "English",

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Norcross, N, Wilson, C , Baragana, B , Hallyburton, I, Osuna-Cabello, M, Norval, S , Riley, J, Fletcher, D, Sinden, R, Delves, MJ, Ruecker, A, Duffy, S, Meister, S, Antonova-Koch, Y, Crespo, B, de Cózar, C, Sanz, L, Gamo, F-J, Avery, VM, Frearson, JA, Gray, D , Fairlamb, A, Winzeler, EA, Waterson, D, Campbell, SF, Willis, P, Read, K & Gilbert, I 2019, 'Substituted Aminoacetamides as Novel Leads for Malaria Treatment', ChemMedChem, vol. 14, no. 14, pp. 1329-1335. https://doi.org/10.1002/cmdc.201900329

TY - JOUR

T1 - Substituted Aminoacetamides as Novel Leads for Malaria Treatment

AU - Norcross, Neil

AU - Wilson, Caroline

AU - Baragana, Beatriz

AU - Hallyburton, Irene

AU - Osuna-Cabello, Maria

AU - Norval, Suzanne

AU - Riley, Jennifer

AU - Fletcher, Daniel

AU - Sinden, Robert

AU - Delves, Michael J.

AU - Ruecker, Andrea

AU - Duffy, Sandra

AU - Meister, Stephan

AU - Antonova-Koch, Yevgeniya

AU - Crespo, Benigno

AU - de Cózar, Cristina

AU - Sanz, Laura

AU - Gamo, Francisco-Javier

AU - Avery, Vicky M.

AU - Frearson, Julie A.

AU - Gray, David

AU - Fairlamb, Alan

AU - Winzeler, Elizabeth A.

AU - Waterson, David

AU - Campbell, Simon F.

AU - Willis, Paul

AU - Read, Kevin

AU - Gilbert, Ian

N1 - Funding: Wellcome Trust (Grant 100476 and a Principal Research Fellowship to A.H.F. Grant 079838)

PY - 2019/7/17

Y1 - 2019/7/17

N2 - Herein we describe the optimization of a phenotypic hit against Plasmodium falciparum based on an aminoacetamide scaffold. This led to N-(3-chloro-4-fluorophenyl)-2-methyl-2-{[4-methyl-3-(morpholinosulfonyl)phenyl]amino}propanamide (compound 28) with low-nanomolar activity against the intraerythrocytic stages of the malaria parasite, and which was found to be inactive in a mammalian cell counter-screen up to 25 μm. Inhibition of gametes in the dual gamete activation assay suggests that this family of compounds may also have transmission blocking capabilities. Whilst we were unable to optimize the aqueous solubility and microsomal stability to a point at which the aminoacetamides would be suitable for in vivo pharmacokinetic and efficacy studies, compound 28 displayed excellent antimalarial potency and selectivity; it could therefore serve as a suitable chemical tool for drug target identification.

AB - Herein we describe the optimization of a phenotypic hit against Plasmodium falciparum based on an aminoacetamide scaffold. This led to N-(3-chloro-4-fluorophenyl)-2-methyl-2-{[4-methyl-3-(morpholinosulfonyl)phenyl]amino}propanamide (compound 28) with low-nanomolar activity against the intraerythrocytic stages of the malaria parasite, and which was found to be inactive in a mammalian cell counter-screen up to 25 μm. Inhibition of gametes in the dual gamete activation assay suggests that this family of compounds may also have transmission blocking capabilities. Whilst we were unable to optimize the aqueous solubility and microsomal stability to a point at which the aminoacetamides would be suitable for in vivo pharmacokinetic and efficacy studies, compound 28 displayed excellent antimalarial potency and selectivity; it could therefore serve as a suitable chemical tool for drug target identification.

KW - Plasmodium falciparum

KW - aminoacetamides

KW - antimalarial agents

KW - hit optimization

KW - malaria

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U2 - 10.1002/cmdc.201900329

DO - 10.1002/cmdc.201900329

M3 - Article

C2 - 31188540

SN - 1860-7179

VL - 14

SP - 1329

EP - 1335

JO - ChemMedChem

JF - ChemMedChem

IS - 14

ER -

Substituted Aminoacetamides as Novel Leads for Malaria Treatment

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

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A Translational Engine for Biomedical Discoveries (Strategic Grant)

Aref#d: 18185. Characterization and validation of drug targets in the Kinetoplastida (Principal Research Fellowship/Programme Grant)

Cite this

Substituted Aminoacetamides as Novel Leads for Malaria Treatment

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Projects

A Translational Engine for Biomedical Discoveries (Strategic Grant)

Aref#d: 18185. Characterization and validation of drug targets in the Kinetoplastida (Principal Research Fellowship/Programme Grant)

Cite this