Structure-activity relationship studies of orally active antimalarial 3,5-substituted 2-aminopyridines

Diego González Cabrera; Frederic Douelle; Yassir Younis; Tzu Shean Feng; Claire Le Manach; Aloysius T. Nchinda; Leslie J. Street; Christian Scheurer; Jolanda Kamber; Karen L. White; Oliver D. Montagnat; Eileen Ryan; Kasiram Katneni; K. Mohammed Zabiulla; Jayan T. Joseph; Sridevi Bashyam; David Waterson; Michael J. Witty; Susan A. Charman; Sergio Wittlin; Kelly Chibale

doi:10.1021/jm301476b

Structure-activity relationship studies of orally active antimalarial 3,5-substituted 2-aminopyridines

Diego González Cabrera
, Frederic Douelle
, Yassir Younis
, Tzu Shean Feng
, Claire Le Manach
, Aloysius T. Nchinda
, Leslie J. Street
, Christian Scheurer
, Jolanda Kamber
, Karen L. White
, Oliver D. Montagnat
, Eileen Ryan
, Kasiram Katneni
, K. Mohammed Zabiulla
, Jayan T. Joseph
, Sridevi Bashyam
, David Waterson
, Michael J. Witty
, Susan A. Charman
, Sergio Wittlin

Kelly Chibale

University of Cape Town
Swiss Tropical and Public Health Institute
University of Basel
Monash University
Syngene International Ltd.
ICC

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

Abstract

In an effort to address potential cardiotoxicity liabilities identified with earlier frontrunner compounds, a number of new 3,5-diaryl-2-aminopyridine derivatives were synthesized. Several compounds exhibited potent antiplasmodial activity against both the multidrug resistant (K1) and sensitive (NF54) strains in the low nanomolar range. Some compounds displayed a significant reduction in potency in the hERG channel inhibition assay compared to previously reported frontrunner analogues. Several of these new analogues demonstrated promising in vivo efficacy in the Plasmodium berghei mouse model and will be further evaluated as potential clinical candidates. The SAR for in vitro antiplasmodial and hERG activity was delineated.

Original language	English
Pages (from-to)	11022-11030
Number of pages	9
Journal	Journal of Medicinal Chemistry
Volume	55
Issue number	24
DOIs	https://doi.org/10.1021/jm301476b
Publication status	Published - 27 Dec 2012
Externally published	Yes

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

SDG 3 Good Health and Well-being

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10.1021/jm301476b

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González Cabrera, D., Douelle, F., Younis, Y., Feng, T. S., Le Manach, C., Nchinda, A. T., Street, L. J., Scheurer, C., Kamber, J., White, K. L., Montagnat, O. D., Ryan, E., Katneni, K., Zabiulla, K. M., Joseph, J. T., Bashyam, S., Waterson, D., Witty, M. J., Charman, S. A., ... Chibale, K. (2012). Structure-activity relationship studies of orally active antimalarial 3,5-substituted 2-aminopyridines. Journal of Medicinal Chemistry, 55(24), 11022-11030. https://doi.org/10.1021/jm301476b

@article{729d84e1aa23443397e911d688e99260,

title = "Structure-activity relationship studies of orally active antimalarial 3,5-substituted 2-aminopyridines",

abstract = "In an effort to address potential cardiotoxicity liabilities identified with earlier frontrunner compounds, a number of new 3,5-diaryl-2-aminopyridine derivatives were synthesized. Several compounds exhibited potent antiplasmodial activity against both the multidrug resistant (K1) and sensitive (NF54) strains in the low nanomolar range. Some compounds displayed a significant reduction in potency in the hERG channel inhibition assay compared to previously reported frontrunner analogues. Several of these new analogues demonstrated promising in vivo efficacy in the Plasmodium berghei mouse model and will be further evaluated as potential clinical candidates. The SAR for in vitro antiplasmodial and hERG activity was delineated.",

author = "\{Gonz{\'a}lez Cabrera\}, Diego and Frederic Douelle and Yassir Younis and Feng, \{Tzu Shean\} and \{Le Manach\}, Claire and Nchinda, \{Aloysius T.\} and Street, \{Leslie J.\} and Christian Scheurer and Jolanda Kamber and White, \{Karen L.\} and Montagnat, \{Oliver D.\} and Eileen Ryan and Kasiram Katneni and Zabiulla, \{K. Mohammed\} and Joseph, \{Jayan T.\} and Sridevi Bashyam and David Waterson and Witty, \{Michael J.\} and Charman, \{Susan A.\} and Sergio Wittlin and Kelly Chibale",

year = "2012",

month = dec,

day = "27",

doi = "10.1021/jm301476b",

language = "English",

volume = "55",

pages = "11022--11030",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "24",

}

González Cabrera, D, Douelle, F, Younis, Y, Feng, TS, Le Manach, C, Nchinda, AT, Street, LJ, Scheurer, C, Kamber, J, White, KL, Montagnat, OD, Ryan, E, Katneni, K, Zabiulla, KM, Joseph, JT, Bashyam, S, Waterson, D, Witty, MJ, Charman, SA, Wittlin, S & Chibale, K 2012, 'Structure-activity relationship studies of orally active antimalarial 3,5-substituted 2-aminopyridines', Journal of Medicinal Chemistry, vol. 55, no. 24, pp. 11022-11030. https://doi.org/10.1021/jm301476b

TY - JOUR

T1 - Structure-activity relationship studies of orally active antimalarial 3,5-substituted 2-aminopyridines

AU - González Cabrera, Diego

AU - Douelle, Frederic

AU - Younis, Yassir

AU - Feng, Tzu Shean

AU - Le Manach, Claire

AU - Nchinda, Aloysius T.

AU - Street, Leslie J.

AU - Scheurer, Christian

AU - Kamber, Jolanda

AU - White, Karen L.

AU - Montagnat, Oliver D.

AU - Ryan, Eileen

AU - Katneni, Kasiram

AU - Zabiulla, K. Mohammed

AU - Joseph, Jayan T.

AU - Bashyam, Sridevi

AU - Waterson, David

AU - Witty, Michael J.

AU - Charman, Susan A.

AU - Wittlin, Sergio

AU - Chibale, Kelly

PY - 2012/12/27

Y1 - 2012/12/27

N2 - In an effort to address potential cardiotoxicity liabilities identified with earlier frontrunner compounds, a number of new 3,5-diaryl-2-aminopyridine derivatives were synthesized. Several compounds exhibited potent antiplasmodial activity against both the multidrug resistant (K1) and sensitive (NF54) strains in the low nanomolar range. Some compounds displayed a significant reduction in potency in the hERG channel inhibition assay compared to previously reported frontrunner analogues. Several of these new analogues demonstrated promising in vivo efficacy in the Plasmodium berghei mouse model and will be further evaluated as potential clinical candidates. The SAR for in vitro antiplasmodial and hERG activity was delineated.

AB - In an effort to address potential cardiotoxicity liabilities identified with earlier frontrunner compounds, a number of new 3,5-diaryl-2-aminopyridine derivatives were synthesized. Several compounds exhibited potent antiplasmodial activity against both the multidrug resistant (K1) and sensitive (NF54) strains in the low nanomolar range. Some compounds displayed a significant reduction in potency in the hERG channel inhibition assay compared to previously reported frontrunner analogues. Several of these new analogues demonstrated promising in vivo efficacy in the Plasmodium berghei mouse model and will be further evaluated as potential clinical candidates. The SAR for in vitro antiplasmodial and hERG activity was delineated.

UR - https://www.scopus.com/pages/publications/84871642734

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DO - 10.1021/jm301476b

M3 - Article

C2 - 23189922

AN - SCOPUS:84871642734

SN - 0022-2623

VL - 55

SP - 11022

EP - 11030

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 24

ER -

Structure-activity relationship studies of orally active antimalarial 3,5-substituted 2-aminopyridines

Abstract

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