David Waterson

Medicines for Malaria Venture

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Sergio Wittlin

University of Basel

Michael J. Witty

Global Alliance for Livestock Veterinary Medicines

Susan A. Charman

Monash University

ÍA

Íñigo Angulo‐Barturen

Euskadiko Parke Teknologikoa

Jeremy N. Burrows

Medicines for Malaria Venture

Karen L. White

Monash University

Marı́a Belén Jiménez-Dı́az

Euskadiko Parke Teknologikoa

Leslie J. Street

University of Cape Town

Diego Gonzàlez Cabrera

University of Cape Town

María Santos Martínez

Consejo Nacional de Investigaciones Científicas y Técnicas

Cooperative Institutions

AstraZeneca (United Kingdom)

135

AstraZeneca (India)

University of York

Cambridge University Press

GlaxoSmithKline (United Kingdom)

University of Cape Town

Medicines for Malaria Venture

University of Dundee

GlaxoSmithKline (Spain)

University of Basel

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Structure–Activity Relationship Studies of Orally Active Antimalarial 3,5-Substituted 2-Aminopyridines

Journal of Medicinal Chemistry (2012)

Diego Gonzàlez Cabrera Frédèric Douelle Yassir Younis Tzu‐Shean Feng Claire Le Manach

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.

hERG

Aminopyridines

Cardiotoxicity

Plasmodium berghei

Structure–activity relationship

Primaquine

10.1021/jm301476b

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Citations (38)

Crystal Structure of Human MMP9 in Complex with a Reverse Hydroxamate Inhibitor

Journal of Molecular Biology (2002)

Siân Rowsell Paul Hawtin Claire A. Minshull Holly Jepson Sarah Brockbank

MMP9

10.1016/s0022-2836(02)00262-0

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Citations (233)

Discovery of a Quinoline-4-carboxamide Derivative with a Novel Mechanism of Action, Multistage Antimalarial Activity, and Potent in Vivo Efficacy

Journal of Medicinal Chemistry (2016)

Beatriz Baragaña Neil R. Norcross Caroline Wilson Achim Porzelle Irene Hallyburton

The antiplasmodial activity, DMPK properties, and efficacy of a series of quinoline-4-carboxamides are described. This series was identified from a phenotypic screen against the blood stage of Plasmodium falciparum (3D7) and displayed moderate potency but with suboptimal physicochemical properties and poor microsomal stability. The screening hit (1, EC50 = 120 nM) was optimized to lead molecules with low nanomolar in vitro potency. Improvement of the pharmacokinetic profile led to several compounds showing excellent oral efficacy in the P. berghei malaria mouse model with ED90 values below 1 mg/kg when dosed orally for 4 days. The favorable potency, selectivity, DMPK properties, and efficacy coupled with a novel mechanism of action, inhibition of translation elongation factor 2 (PfEF2), led to progression of 2 (DDD107498) to preclinical development.

Quinoline

Plasmodium berghei

Mechanism of Action

Carboxamide

10.1021/acs.jmedchem.6b00723

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Citations (77)

Structure–Activity Relationship Studies of Orally Active Antimalarial 2,4-Diamino-thienopyrimidines

Journal of Medicinal Chemistry (2015)

Diego Gonzàlez Cabrera Frédèric Douelle Claire Le Manach Ze Han Tanya Paquet

Based on the initial optimization of orally active antimalarial 2,4-diamino-thienopyrimidines and with the help of metabolite identification studies, a second generation of derivatives involving changes at the 2- and 4-positions of the thienopyrimidine core were synthesized. Improvements in the physiochemical properties resulted in the identification of 15a, 17a, 32, and 40 as lead molecules with improved in vivo exposure. Furthermore, analogue 40 exhibited excellent in vivo antimalarial activity when dosed orally at 50 mg/kg once daily for 4 days in the Plasmodium berghei mouse model, which is superior to the activity seen with previously reported compounds, and with a slightly improved hERG profile.

Plasmodium berghei

hERG

Active metabolite

Structure–activity relationship

10.1021/acs.jmedchem.5b01156

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Citations (16)

An efficient synthesis for a new class antimalarial agent, 7-(2-carboxyethyl)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole

Tetrahedron Letters (2011)

Yong-Kang Zhang Jacob J. Plattner Eric E. Easom David Waterson Min Ge

Antimalarial Agent

10.1016/j.tetlet.2011.05.088

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Citations (30)

Antimalarial Aminothiazoles and Aminopyridines From Phenotypic Whole-Cell Screening Of A SoftFocus ^® Library

Future Medicinal Chemistry (2012)

Tanya Paquet Richard K. Gordon David Waterson Michael J. Witty Kelly Chibale

The current state of antimalarial drug resistance emphasizes the need for new therapies with novel modes of action that will add a significant benefit compared with current standards. In this regard, high throughput phenotypic whole-cell screening aids the discovery of novel antiplasmodial scaffolds that are inherently suited to hit-to-lead and lead-optimization efforts. The aminothiazoles and aminopyridines exemplify two such compound classes stemming from whole-cell screening. Respective structure–activity relationship determinations and subsequent optimization around these scaffolds led to frontrunner compounds in each series, which possess the desired antimalarial efficacy, bioavailability and metabolic stability to further progress medicinal chemistry programs.

Aminopyridines

Phenotypic screening

High-Throughput Screening

10.4155/fmc.12.176

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Citations (27)

ChemInform Abstract: 1,2,4‐Triazolo(4,3‐a)pyrazine Derivatives with Human Renin Inhibitory Activity. Part 2. Synthesis, Biological Properties, and Molecular Modeling of Hydroxyethylene Isostere Derivatives.

ChemInform (1991)

Robert H. Bradbury John S. Major Alec A. Oldham Janet E. Rivett David A. Roberts

Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Pyrazine

Isostere

10.1002/chin.199108220

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Benzoxaborole antimalarial agents. Part 2: Discovery of fluoro-substituted 7-(2-carboxyethyl)-1,3-dihydro-1-hydroxy-2,1-benzoxaboroles

Bioorganic & Medicinal Chemistry Letters (2011)

Yong-Kang Zhang Jacob J. Plattner Yvonne R. Freund Eric E. Easom Yasheen Zhou

Antimalarial Agent

Side chain

Benzene derivatives

Structure–activity relationship

IC50

10.1016/j.bmcl.2011.12.096

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Citations (51)

Exploring a Tetrahydroquinoline Antimalarial Hit from the Medicines for Malaria Pathogen Box and Identification of its Mode of Resistance as PfeEF2

ChemMedChem (2022)

Benoı̂t Laleu Kelly Rubiano Tomas Yeo Irene Hallyburton Mark Anderson

New antimalarial treatments with novel mechanism of action are needed to tackle Plasmodium falciparum infections that are resistant to first-line therapeutics. Here we report the exploration of MMV692140 (2) from the Pathogen Box, a collection of 400 compounds that was made available by Medicines for Malaria Venture (MMV) in 2015. Compound 2 was profiled in in vitro models of malaria and was found to be active against multiple life-cycle stages of Plasmodium parasites. The mode of resistance, and putatively its mode of action, was identified as Plasmodium falciparum translation elongation factor 2 (PfeEF2), which is responsible for the GTP-dependent translocation of the ribosome along mRNA. The compound maintains activity against a series of drug-resistant parasite strains. The structural motif of the tetrahydroquinoline (2) was explored in a chemistry program with its structure-activity relationships examined, resulting in the identification of an analog with 30-fold improvement of antimalarial asexual blood stage potency.

Mode of Action

10.1002/cmdc.202200393

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Citations (7)

4-Methoxy-2-methyltetrahydropyrans: chiral leukotriene biosynthesis inhibitors, related to ICI D2138, which display enantioselectivity

Journal of Medicinal Chemistry (1993)

G. C. CRAWLEY Malcolm T. Briggs Robert I. Dowell Philip N. Edwards Patricia M. Hamilton

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXT4-Methoxy-2-methyltetrahydropyrans: chiral leukotriene biosynthesis inhibitors, related to ICI D2138, which display enantioselectivityGraham C. Crawley, Malcolm T. Briggs, Robert I. Dowell, Philip N. Edwards, Patricia M. Hamilton, John F. Kingston, Keith Oldham, David Waterson, and David P. WhalleyCite this: J. Med. Chem. 1993, 36, 2, 295–296Publication Date (Print):January 1, 1993Publication History Published online1 May 2002Published inissue 1 January 1993https://doi.org/10.1021/jm00054a016Request reuse permissionsArticle Views156Altmetric-Citations14LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (272 KB) Get e-Alertsclose Get e-Alerts

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10.1021/jm00054a016

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Citations (14)