Diversity-Oriented Synthesis-Facilitated Medicinal Chemistry: Toward the Development of Novel Antimalarial Agents

Here, we describe medicinal chemistry that was accelerated by a diversity-oriented synthesis (DOS) pathway, and in vivo studies of our previously reported macrocyclic antimalarial agent that derived from the synthetic pathway. Structure–activity relationships that focused on both appendage and skeletal features yielded a nanomolar inhibitor of P. falciparum asexual blood-stage growth with improved solubility and microsomal stability and reduced hERG binding. The build/couple/pair (B/C/P) synthetic strategy, used in the preparation of the original screening library, facilitated medicinal chemistry optimization of the antimalarial lead.

• Publication year

  2014

• Venue

  Journal of Medicinal Chemistry

• Publication date

  2014-09-11

• Fields of study

  Medicine, Chemistry

• Identifiers
  DOI 10.1021/jm500994nPMID 25211597PMCID 4207553
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Diversity-Oriented Synthesis Probe Targets Plasmodium falciparum Cytochrome b Ubiquinone Reduction Site and Synergizes With Oxidation Site Inhibitors

  2014cited by this paper
• Quinolone-3-Diarylethers: A New Class of Antimalarial Drug

  2013cited by this paper
• Diversity‐Oriented Synthesis and Drug Development: Facilitating the Discovery of Novel Probes and Therapeutics

  2013cited by this paper
• Multiple populations of artemisinin-resistant Plasmodium falciparum in Cambodia

  2013cited by this paper
• Four-year efficacy of RTS,S/AS01E and its interaction with malaria exposure.

  2013cited by this paper
• Synthesis and profiling of a diverse collection of azetidine-based scaffolds for the development of CNS-focused lead-like libraries.

  2012cited by this paper
• Diversity-Oriented Synthesis Yields a Novel Lead for the Treatment of Malaria

  2011cited by this paper
• Improvement in aqueous solubility in small molecule drug discovery programs by disruption of molecular planarity and symmetry.

  2011cited by this paper
• Recent clinical and molecular insights into emerging artemisinin resistance in Plasmodium falciparum

  2011cited by this paper
• An aldol-based build/couple/pair strategy for the synthesis of medium- and large-sized rings: discovery of macrocyclic histone deacetylase inhibitors.

  2010cited by this paper
• Grand challenge commentary: Accessing new chemical space for 'undruggable' targets.

  2010cited by this paper
• New medicines to improve control and contribute to the eradication of malaria

  2010cited by this paper
• New medicines to improve control and contribute to the eradication of malaria

  2009cited by this paper
• The Global Portfolio of New Antimalarial Medicines Under Development

  2009cited by this paper
• In vitro evaluations of antimalarial drugs and their relevance to clinical outcomes.

  2008cited by this paper
• Towards the optimal screening collection: a synthesis strategy.

  2008cited by this paper
• Malaria

  2006cited by this paper
• World malaria report

  2005cited by this paper

• In vitro Antiplasmodial and Molecular Docking Studies of Chemical Constituent Isolated from the Bark of Diospyros lanceifolia (Ebenaceae)

  2025cites this paper
• Repurposing sulfonamide-scaffolds for enhanced and sustainable malaria therapy.

  2025cites this paper
• Innovations in Antimalarial Drug Discovery: New Targets and Leads.

  2025cites this paper
• Study of antiplasmodial activity, toxicity, pharmacokinetic profiles of n-methyl-isatin (CH3ISACN) derivative.

  2025cites this paper
• Mass spectrometry-based metabolomics uncovers distinct metabolic signatures and potential therapeutic targets in Plasmodium knowlesi

  2025cites this paper
• Recent approaches in the drug research and development of novel antimalarial drugs with new targets

  2023cites this paper
• A Diversity‐Oriented Approach to Large Libraries of Artificial Macrocycles

  2021cites this paper
• Back to the Medicinal Chemistry Future.

  2021cites this paper
• Pseudo Natural Products—Chemical Evolution of Natural Product Structure

  2021cites this paper
• Ring Distortion of Vincamine Leads to the Identification of Re-Engineered Antiplasmodial Agents

  2021cites this paper
• Antimalarial Drug Resistance and Novel Targets for Antimalarial Drug Discovery

  2020cites this paper
• Macrolactam Synthesis via Ring-Closing Alkene-Alkene Cross-Coupling Reactions.

  2020cites this paper
• Recent Progress in the Development of New Antimalarial Drugs with Novel Targets

  2020cites this paper
• Recent Progress in the Development of New Antimalarial Drugs with Novel Targets

  2020cites this paper
• Recent Progress in the Development of New Antimalarial Drugs with Novel Targets

  2020cites this paper
• Re-engineering of Yohimbine's Biological Activity through Ring Distortion: Identification and Structure-Activity Relationships of a New Class of Antiplasmodial Agents.

  2020cites this paper
• New dimensions in the field of antimalarial research against malaria resurgence.

  2019cites this paper
• Overview of Recent Strategic Advances in Medicinal Chemistry.

  2019cites this paper
• Strategies for the Diversity-Oriented Synthesis of Macrocycles.

  2019cites this paper
• A Domino 10-Step Total Synthesis of FR252921 and Its Analogues, Complex Macrocyclic Immunosuppressants

  2019cites this paper
• Targeting Channels and Transporters in Protozoan Parasite Infections

  2018cites this paper
• Chemical probes and drug leads from advances in synthetic planning and methodology

  2018cites this paper
• Ring-Closing Metathesis-Based Methods in Chemical Biology: Building a Natural Product-Inspired Macrocyclic Toolbox to Tackle Protein-Protein Interactions

  2017cites this paper
• Design, Properties and Recent Application of Macrocycles in Medicinal Chemistry.

  2017cites this paper
• Sustainable Practices in Medicinal Chemistry Part 2: Green by Design.

  2017cites this paper
• Benzoisoxazolone-based scaffolds for development of diversity driven small molecule libraries : an effective tool to identify novel molecules targeting key therapeutic applications

  2017cites this paper
• Skeletal Diversity in Combinatorial Fashion: A New Format for the Castagnoli-Cushman Reaction.

  2017cites this paper
• Modular Synthesis of Diverse Natural Product‐Like Macrocycles: Discovery of Hits with Antimycobacterial Activity

  2017cites this paper
• Use of big data in drug development for precision medicine

  2016cites this paper
• Highlights from the 51st EUCHEM conference on stereochemistry, Bürgenstock, Switzerland, May 2016.

  2016cites this paper
• Scaffold Diversity Synthesis and Its Application in Probe and Drug Discovery.

  2016cites this paper
• Gerüstdiversitätsbasierte Synthese und ihre Anwendung bei der Sonden‐ und Wirkstoffsuche

  2016cites this paper
• Diversity-oriented synthesis yields novel multistage antimalarial inhibitors

  2016cites this paper
• Macrolactam analogues of macrolide natural products.

  2016cites this paper
• Modular, One-Pot, Sequential Aziridine Ring Opening–SNAr Strategy to 7-, 10-, and 11-Membered Benzo-Fused Sultams

  2015cites this paper
• Refining the chemical toolbox to be fit for educational and practical purpose for drug discovery in the 21st Century.

  2015cites this paper
• Diversity-Oriented Synthesis Probe Targets Plasmodium falciparum Cytochrome b Ubiquinone Reduction Site and Synergizes With Oxidation Site Inhibitors

  2014cites this paper