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DISCOVERY OF PYRAZOLOPYRROLIDINONES AS POTENT, BROAD-SPECTRUM INHIBITORS OF LEISHMANIA INFECTION
Heterociclos
Pirazolopirrolidinona
Terapêutica
Parasitologia
Química medicinal
Doença tropical
Leishmania donovani
Leishmania major
Heterocycles
Pyrazolopyrrolidinone
Therapeutics
Parasitology
Medicinal chemistry
Tropical disease
Leishmania donovani
Leishmania major
Terapêutica
Parasitologia
Química Farmacêutica
Medicina Tropical
Leishmania donovani
Leishmania major
Author
Affilliation
Department of Chemistry and Center for Molecular Discovery. Boston University. Boston, Massachusetts, United States of America.
Center for Discovery and Innovation in Parasitic Diseases. Skaggs School of Pharmacy and Pharmaceutical Sciences. University of California San Diego. La Jolla, California, United States of America.
Center for Discovery and Innovation in Parasitic Diseases. Skaggs School of Pharmacy and Pharmaceutical Sciences. University of California San Diego. La Jolla, California, United States of America.
Department of Pathology. Sandler Center for Drug Discovery. University of California San Francisco. San Francisco, California, United States of America.
Center for Discovery and Innovation in Parasitic Diseases. Skaggs School of Pharmacy and Pharmaceutical Sciences. University of California San Diego. La Jolla, California, United States of America.
Global Health Medicines R&D. GlaxoSmithKline. Tres Cantos, Madrid, Spain.
Global Health Medicines R&D. GlaxoSmithKline. Tres Cantos, Madrid, Spain.
Global Health Medicines R&D. GlaxoSmithKline. Tres Cantos, Madrid, Spain.
Global Health Medicines R&D. GlaxoSmithKline. Tres Cantos, Madrid, Spain.
Center for Discovery and Innovation in Parasitic Diseases. Skaggs School of Pharmacy and Pharmaceutical Sciences. University of California San Diego. La Jolla, California, United States of America / Department of Pathology. Sandler Center for Drug Discovery. University of California San Francisco. San Francisco, California, United States of America.
Fundação Oswaldo Cruz. Instituto Gonçalo Muniz. Salvador, BA, Brasil / Instituto Nacional de Ciência e Tecnologia em Doenças Tropicais. Salvador, BA, Brasil / Instituto de Investigação em Imunologia, São Paulo, SP, Brasil.
Center for Discovery and Innovation in Parasitic Diseases. Skaggs School of Pharmacy and Pharmaceutical Sciences. University of California San Diego. La Jolla, California, United States of America / Department of Pathology. Sandler Center for Drug Discovery. University of California San Francisco. San Francisco, California, United States of America.
Global Health Medicines R&D. GlaxoSmithKline. Tres Cantos, Madrid, Spain.
Department of Chemistry and Center for Molecular Discovery. Boston University. Boston, Massachusetts, United States of America.
Department of Chemistry and Center for Molecular Discovery. Boston University. Boston, Massachusetts, United States of America.
Center for Discovery and Innovation in Parasitic Diseases. Skaggs School of Pharmacy and Pharmaceutical Sciences. University of California San Diego. La Jolla, California, United States of America.
Center for Discovery and Innovation in Parasitic Diseases. Skaggs School of Pharmacy and Pharmaceutical Sciences. University of California San Diego. La Jolla, California, United States of America.
Department of Pathology. Sandler Center for Drug Discovery. University of California San Francisco. San Francisco, California, United States of America.
Center for Discovery and Innovation in Parasitic Diseases. Skaggs School of Pharmacy and Pharmaceutical Sciences. University of California San Diego. La Jolla, California, United States of America.
Global Health Medicines R&D. GlaxoSmithKline. Tres Cantos, Madrid, Spain.
Global Health Medicines R&D. GlaxoSmithKline. Tres Cantos, Madrid, Spain.
Global Health Medicines R&D. GlaxoSmithKline. Tres Cantos, Madrid, Spain.
Global Health Medicines R&D. GlaxoSmithKline. Tres Cantos, Madrid, Spain.
Center for Discovery and Innovation in Parasitic Diseases. Skaggs School of Pharmacy and Pharmaceutical Sciences. University of California San Diego. La Jolla, California, United States of America / Department of Pathology. Sandler Center for Drug Discovery. University of California San Francisco. San Francisco, California, United States of America.
Fundação Oswaldo Cruz. Instituto Gonçalo Muniz. Salvador, BA, Brasil / Instituto Nacional de Ciência e Tecnologia em Doenças Tropicais. Salvador, BA, Brasil / Instituto de Investigação em Imunologia, São Paulo, SP, Brasil.
Center for Discovery and Innovation in Parasitic Diseases. Skaggs School of Pharmacy and Pharmaceutical Sciences. University of California San Diego. La Jolla, California, United States of America / Department of Pathology. Sandler Center for Drug Discovery. University of California San Francisco. San Francisco, California, United States of America.
Global Health Medicines R&D. GlaxoSmithKline. Tres Cantos, Madrid, Spain.
Department of Chemistry and Center for Molecular Discovery. Boston University. Boston, Massachusetts, United States of America.
Department of Chemistry and Center for Molecular Discovery. Boston University. Boston, Massachusetts, United States of America.
Abstract
Introduction: Leishmaniasis is a parasitic disease that affects more than 1 million people worldwide annually, predominantly in resource-limited settings. The challenge in compound development is to exhibit potent activity against the intracellular stage of the parasite (the stage present in the mammalian host) without harming the infected host cells. We have identified a compound series (pyrazolopyrrolidinones) active against the intracellular parasites of Leishmania donovani and L. major; the causative agents of visceral and cutaneous leishmaniasis in the Old World, respectively. Methods: In this study, we performed medicinal chemistry on a newly discovered antileishmanial chemotype, with over 100 analogs tested. Studies included assessments of antileishmanial potency, toxicity towards host cells, and in vitro ADME screening of key drug properties. Results and discussion: Members of the series showed high potency against the deadliest form, visceral leishmaniasis (approximate EC50 ≥ 0.01 μM without harming the host macrophage up to 10.0 μM). In comparison, the most efficient monotherapy treatment for visceral leishmaniasis is amphotericin B, which presents similar activity in the same assay (EC50 = 0.2 μM) while being cytotoxic to the host cell at 5.0 μM. Continued development of this compound series with the Discovery Partnership with Academia (DPAc) program at the GlaxoSmithKline Diseases of the Developing World (GSK DDW) laboratories found that the compounds passed all of GSK's criteria to be defined as a potential lead drug series for leishmaniasis. Conclusion: Here, we describe preliminary structure-activity relationships for antileishmanial pyrazolopyrrolidinones, and our progress towards the identification of candidates for future in vivo assays in models of visceral and cutaneous leishmaniasis.
Keywords in Portuguese
LeishmanioseHeterociclos
Pirazolopirrolidinona
Terapêutica
Parasitologia
Química medicinal
Doença tropical
Leishmania donovani
Leishmania major
Keywords
LeishmaniasisHeterocycles
Pyrazolopyrrolidinone
Therapeutics
Parasitology
Medicinal chemistry
Tropical disease
Leishmania donovani
Leishmania major
DeCS
LeishmanioseTerapêutica
Parasitologia
Química Farmacêutica
Medicina Tropical
Leishmania donovani
Leishmania major
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