Discovery and structure-activity relationships of pyrrolone antimalarials

Dinakaran Murugesan; Alka Mital; Marcel Kaiser; David M. Shackleford; Julia Morizzi; Kasiram Katneni; Michael Campbell; Alan Hudson; Susan A. Charman; Clive Yeates; Ian H. Gilbert

doi:10.1021/jm400009c

Discovery and structure-activity relationships of pyrrolone antimalarials

Dinakaran Murugesan
, Alka Mital
, Marcel Kaiser
, David M. Shackleford
, Julia Morizzi
, Kasiram Katneni
, Michael Campbell
, Alan Hudson
, Susan A. Charman
, Clive Yeates
, Ian H. Gilbert (Lead / Corresponding author)

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

74 Citations (Scopus)

Abstract

In the pursuit of new antimalarial leads, a phenotypic screening of various commercially sourced compound libraries was undertaken by the World Health Organisation Programme for Research and Training in Tropical Diseases (WHO-TDR). We report here the detailed characterization of one of the hits from this process, TDR32750 (8a), which showed potent activity against Plasmodium falciparum K1 (EC50 similar to 9 nM), good selectivity (>2000-fold) compared to a mammalian cell line (L6), and significant activity against a rodent model of malaria when administered intraperitoneally. Structure-activity relationship studies have indicated ways in which the molecule could be optimized. This compound represents an exciting start point for a drug discovery program for the development of a novel antimalarial.

Original language	English
Pages (from-to)	2975-2990
Number of pages	16
Journal	Journal of Medicinal Chemistry
Volume	56
Issue number	7
DOIs	https://doi.org/10.1021/jm400009c
Publication status	Published - 2013

UN SDGs

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

SDG 3 Good Health and Well-being

Keywords

DRUG
CONDENSED RING-SYSTEMS
DERIVATIVES
REACTIVITY

Access to Document

10.1021/jm400009c

Aref#d: 19815. Wellcome Trust Centre for Drug Discovery (Strategic Award)
Fairlamb, A. (Investigator), Ferguson, M. (Investigator) & Frearson, J. (Investigator)
1/01/08 → 31/12/12
Project: Research

Cite this

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title = "Discovery and structure-activity relationships of pyrrolone antimalarials",

abstract = "In the pursuit of new antimalarial leads, a phenotypic screening of various commercially sourced compound libraries was undertaken by the World Health Organisation Programme for Research and Training in Tropical Diseases (WHO-TDR). We report here the detailed characterization of one of the hits from this process, TDR32750 (8a), which showed potent activity against Plasmodium falciparum K1 (EC50 similar to 9 nM), good selectivity (>2000-fold) compared to a mammalian cell line (L6), and significant activity against a rodent model of malaria when administered intraperitoneally. Structure-activity relationship studies have indicated ways in which the molecule could be optimized. This compound represents an exciting start point for a drug discovery program for the development of a novel antimalarial.",

keywords = "DRUG, CONDENSED RING-SYSTEMS, DERIVATIVES, REACTIVITY",

author = "Dinakaran Murugesan and Alka Mital and Marcel Kaiser and Shackleford, \{David M.\} and Julia Morizzi and Kasiram Katneni and Michael Campbell and Alan Hudson and Charman, \{Susan A.\} and Clive Yeates and Gilbert, \{Ian H.\}",

year = "2013",

doi = "10.1021/jm400009c",

language = "English",

volume = "56",

pages = "2975--2990",

journal = "Journal of Medicinal Chemistry",

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publisher = "American Chemical Society",

number = "7",

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TY - JOUR

T1 - Discovery and structure-activity relationships of pyrrolone antimalarials

AU - Murugesan, Dinakaran

AU - Mital, Alka

AU - Kaiser, Marcel

AU - Shackleford, David M.

AU - Morizzi, Julia

AU - Katneni, Kasiram

AU - Campbell, Michael

AU - Hudson, Alan

AU - Charman, Susan A.

AU - Yeates, Clive

AU - Gilbert, Ian H.

PY - 2013

Y1 - 2013

N2 - In the pursuit of new antimalarial leads, a phenotypic screening of various commercially sourced compound libraries was undertaken by the World Health Organisation Programme for Research and Training in Tropical Diseases (WHO-TDR). We report here the detailed characterization of one of the hits from this process, TDR32750 (8a), which showed potent activity against Plasmodium falciparum K1 (EC50 similar to 9 nM), good selectivity (>2000-fold) compared to a mammalian cell line (L6), and significant activity against a rodent model of malaria when administered intraperitoneally. Structure-activity relationship studies have indicated ways in which the molecule could be optimized. This compound represents an exciting start point for a drug discovery program for the development of a novel antimalarial.

AB - In the pursuit of new antimalarial leads, a phenotypic screening of various commercially sourced compound libraries was undertaken by the World Health Organisation Programme for Research and Training in Tropical Diseases (WHO-TDR). We report here the detailed characterization of one of the hits from this process, TDR32750 (8a), which showed potent activity against Plasmodium falciparum K1 (EC50 similar to 9 nM), good selectivity (>2000-fold) compared to a mammalian cell line (L6), and significant activity against a rodent model of malaria when administered intraperitoneally. Structure-activity relationship studies have indicated ways in which the molecule could be optimized. This compound represents an exciting start point for a drug discovery program for the development of a novel antimalarial.

KW - DRUG

KW - CONDENSED RING-SYSTEMS

KW - DERIVATIVES

KW - REACTIVITY

U2 - 10.1021/jm400009c

DO - 10.1021/jm400009c

M3 - Article

C2 - 23517371

SN - 0022-2623

VL - 56

SP - 2975

EP - 2990

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 7

ER -

Discovery and structure-activity relationships of pyrrolone antimalarials

Abstract

UN SDGs

Keywords

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Projects

Aref#d: 19815. Wellcome Trust Centre for Drug Discovery (Strategic Award)

Cite this