Discovery and Structure-Activity Relationships of Quinazolinone-2-carboxamide Derivatives as Novel Orally Efficacious Antimalarials

Benoît Laleu; Yuichiro Akao; Atsuko Ochida; Sandra Duffy; Leonardo Lucantoni; David M. Shackleford; Gong Chen; Kasiram Katneni; Francis C.K. Chiu; Karen L. White; Xue Chen; Angelika Sturm; Koen J. Dechering; Benigno Crespo; Laura M. Sanz; Binglin Wang; Sergio Wittlin; Susan A. Charman; Vicky M. Avery; Nobuo Cho; Masahiro Kamaura

doi:10.1021/acs.jmedchem.1c00441

Discovery and Structure-Activity Relationships of Quinazolinone-2-carboxamide Derivatives as Novel Orally Efficacious Antimalarials

Benoît Laleu
, Yuichiro Akao
, Atsuko Ochida
, Sandra Duffy
, Leonardo Lucantoni
, David M. Shackleford
, Gong Chen
, Kasiram Katneni
, Francis C.K. Chiu
, Karen L. White
, Xue Chen
, Angelika Sturm
, Koen J. Dechering
, Benigno Crespo
, Laura M. Sanz
, Binglin Wang
, Sergio Wittlin
, Susan A. Charman
, Vicky M. Avery
, Nobuo Cho

Masahiro Kamaura

Centre for Drug Candidate Optimisation

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

40 Citations (Scopus)

Abstract

A phenotypic high-throughput screen allowed discovery of quinazolinone-2-carboxamide derivatives as a novel antimalarial scaffold. Structure-activity relationship studies led to identification of a potent inhibitor 19f, 95-fold more potent than the original hit compound, active against laboratory-resistant strains of malaria. Profiling of 19f suggested a fast in vitro killing profile. In vivo activity in a murine model of human malaria in a dose-dependent manner constitutes a concomitant benefit.

Original language	English
Pages (from-to)	12582-12602
Number of pages	21
Journal	Journal of Medicinal Chemistry
Volume	64
Issue number	17
DOIs	https://doi.org/10.1021/acs.jmedchem.1c00441
Publication status	Published - 9 Sept 2021

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SDG 3 Good Health and Well-being

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10.1021/acs.jmedchem.1c00441Licence: CC BY-NC-ND

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Laleu, B., Akao, Y., Ochida, A., Duffy, S., Lucantoni, L., Shackleford, D. M., Chen, G., Katneni, K., Chiu, F. C. K., White, K. L., Chen, X., Sturm, A., Dechering, K. J., Crespo, B., Sanz, L. M., Wang, B., Wittlin, S., Charman, S. A., Avery, V. M., ... Kamaura, M. (2021). Discovery and Structure-Activity Relationships of Quinazolinone-2-carboxamide Derivatives as Novel Orally Efficacious Antimalarials. Journal of Medicinal Chemistry, 64(17), 12582-12602. https://doi.org/10.1021/acs.jmedchem.1c00441

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title = "Discovery and Structure-Activity Relationships of Quinazolinone-2-carboxamide Derivatives as Novel Orally Efficacious Antimalarials",

abstract = "A phenotypic high-throughput screen allowed discovery of quinazolinone-2-carboxamide derivatives as a novel antimalarial scaffold. Structure-activity relationship studies led to identification of a potent inhibitor 19f, 95-fold more potent than the original hit compound, active against laboratory-resistant strains of malaria. Profiling of 19f suggested a fast in vitro killing profile. In vivo activity in a murine model of human malaria in a dose-dependent manner constitutes a concomitant benefit.",

author = "Beno{\^i}t Laleu and Yuichiro Akao and Atsuko Ochida and Sandra Duffy and Leonardo Lucantoni and Shackleford, \{David M.\} and Gong Chen and Kasiram Katneni and Chiu, \{Francis C.K.\} and White, \{Karen L.\} and Xue Chen and Angelika Sturm and Dechering, \{Koen J.\} and Benigno Crespo and Sanz, \{Laura M.\} and Binglin Wang and Sergio Wittlin and Charman, \{Susan A.\} and Avery, \{Vicky M.\} and Nobuo Cho and Masahiro Kamaura",

note = "Funding Information: Research reported in this publication was supported by the Global Health Innovative Technology (GHIT) Fund under the project title “New Hit-to-Lead Activity for New Anti-malarials between MMV and Takeda” (Project ID: H2016–205) Publisher Copyright: {\textcopyright} 2021 The Authors. Published by American Chemical Society. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = sep,

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doi = "10.1021/acs.jmedchem.1c00441",

language = "English",

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Laleu, B, Akao, Y, Ochida, A, Duffy, S, Lucantoni, L, Shackleford, DM, Chen, G, Katneni, K, Chiu, FCK, White, KL, Chen, X, Sturm, A, Dechering, KJ, Crespo, B, Sanz, LM, Wang, B, Wittlin, S, Charman, SA, Avery, VM, Cho, N & Kamaura, M 2021, 'Discovery and Structure-Activity Relationships of Quinazolinone-2-carboxamide Derivatives as Novel Orally Efficacious Antimalarials', Journal of Medicinal Chemistry, vol. 64, no. 17, pp. 12582-12602. https://doi.org/10.1021/acs.jmedchem.1c00441

TY - JOUR

T1 - Discovery and Structure-Activity Relationships of Quinazolinone-2-carboxamide Derivatives as Novel Orally Efficacious Antimalarials

AU - Laleu, Benoît

AU - Akao, Yuichiro

AU - Ochida, Atsuko

AU - Duffy, Sandra

AU - Lucantoni, Leonardo

AU - Shackleford, David M.

AU - Chen, Gong

AU - Katneni, Kasiram

AU - Chiu, Francis C.K.

AU - White, Karen L.

AU - Chen, Xue

AU - Sturm, Angelika

AU - Dechering, Koen J.

AU - Crespo, Benigno

AU - Sanz, Laura M.

AU - Wang, Binglin

AU - Wittlin, Sergio

AU - Charman, Susan A.

AU - Avery, Vicky M.

AU - Cho, Nobuo

AU - Kamaura, Masahiro

N1 - Funding Information: Research reported in this publication was supported by the Global Health Innovative Technology (GHIT) Fund under the project title “New Hit-to-Lead Activity for New Anti-malarials between MMV and Takeda” (Project ID: H2016–205) Publisher Copyright: © 2021 The Authors. Published by American Chemical Society. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/9/9

Y1 - 2021/9/9

N2 - A phenotypic high-throughput screen allowed discovery of quinazolinone-2-carboxamide derivatives as a novel antimalarial scaffold. Structure-activity relationship studies led to identification of a potent inhibitor 19f, 95-fold more potent than the original hit compound, active against laboratory-resistant strains of malaria. Profiling of 19f suggested a fast in vitro killing profile. In vivo activity in a murine model of human malaria in a dose-dependent manner constitutes a concomitant benefit.

AB - A phenotypic high-throughput screen allowed discovery of quinazolinone-2-carboxamide derivatives as a novel antimalarial scaffold. Structure-activity relationship studies led to identification of a potent inhibitor 19f, 95-fold more potent than the original hit compound, active against laboratory-resistant strains of malaria. Profiling of 19f suggested a fast in vitro killing profile. In vivo activity in a murine model of human malaria in a dose-dependent manner constitutes a concomitant benefit.

UR - https://www.scopus.com/pages/publications/85114630433

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DO - 10.1021/acs.jmedchem.1c00441

M3 - Article

C2 - 34437804

AN - SCOPUS:85114630433

SN - 0022-2623

VL - 64

SP - 12582

EP - 12602

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 17

ER -

Discovery and Structure-Activity Relationships of Quinazolinone-2-carboxamide Derivatives as Novel Orally Efficacious Antimalarials

Abstract

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