title: Chroman-4-One Derivatives Targeting Pteridine Reductase 1 and Showing Anti-Parasitic Activity.
abstract: Flavonoids have previously been identified as antiparasitic agents and pteridine reductase 1 (PTR1) inhibitors. Herein, we focus our attention on the chroman-4-one scaffold. Three chroman-4-one analogues (1-3) of previously published chromen-4-one derivatives were synthesized and biologically evaluated against parasitic enzymes (Trypanosoma bruceiPTR1-TbPTR1 andLeishmania major-LmPTR1) and parasites (Trypanosoma bruceiandLeishmania infantum). A crystal structure ofTbPTR1 in complex with compound1and the first crystal structures ofLmPTR1-flavanone complexes (compounds1and3) were solved. The inhibitory activity of the chroman-4-one and chromen-4-one derivatives was explained by comparison of observed and predicted binding modes of the compounds. Compound1showed activity both against the targeted enzymes and the parasites with a selectivity index greater than 7 and a low toxicity. Our results provide a basis for further scaffold optimization and structure-based drug design aimed at the identification of potent anti-trypanosomatidic compounds targeting multiple PTR1 variants.
authors.affiliation: Department of Biotechnology, Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy. dipisa2@unisi.it.
authors.forename: Flavio
authors.initials: F
authors.lastname: Di Pisa
authors.affiliation: Department of Biotechnology, Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy. landi31@unisi.it.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Landi
authors.affiliation: Department of Biotechnology, Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy. delloiacono3@unisi.it.
authors.forename: Lucia
authors.initials: L
authors.lastname: Dello Iacono
authors.affiliation: Department of Biotechnology, Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy. pozzi4@unisi.it.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Pozzi
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 103, 41125 Modena, Italy. chiara.borsari@unimore.it.
authors.forename: Chiara
authors.initials: C
authors.lastname: Borsari
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 103, 41125 Modena, Italy. stefania.ferrari@unimore.it.
authors.forename: Stefania
authors.initials: S
authors.lastname: Ferrari
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 103, 41125 Modena, Italy. matteo.santucci@unimore.it.
authors.forename: Matteo
authors.initials: M
authors.lastname: Santucci
authors.affiliation: Institute for Molecular and Cell Biology, 4150-180 Porto, Portugal and Instituto de Investigação e Inovação em Saúde, Universidade do Porto and Institute for Molecular and Cell Biology, 4150-180 Porto, Portugal. santarem@ibmc.up.pt.
authors.forename: Nuno
authors.initials: N
authors.lastname: Santarem
authors.affiliation: Institute for Molecular and Cell Biology, 4150-180 Porto, Portugal and Instituto de Investigação e Inovação em Saúde, Universidade do Porto and Institute for Molecular and Cell Biology, 4150-180 Porto, Portugal. cordeiro@ibmc.up.pt.
authors.forename: Anabela
authors.initials: A
authors.lastname: Cordeiro-da-Silva
authors.affiliation: Laboratório Nacional de Biociências (LNBio), Centro Nacional de Pesquisa em Energia e Materiais (CNPEM), Campinas SP13083-100, Brazil. carolinaborsoi@gmail.com.
authors.forename: Carolina B
authors.initials: CB
authors.lastname: Moraes
authors.affiliation: Laboratório Nacional de Biociências (LNBio), Centro Nacional de Pesquisa em Energia e Materiais (CNPEM), Campinas SP13083-100, Brazil. laura.alcantara@lnbio.cnpem.br.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Alcantara
authors.affiliation: Laboratório Nacional de Biociências (LNBio), Centro Nacional de Pesquisa em Energia e Materiais (CNPEM), Campinas SP13083-100, Brazil. fontana_vanessa@yahoo.com.br.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Fontana
authors.affiliation: Laboratório Nacional de Biociências (LNBio), Centro Nacional de Pesquisa em Energia e Materiais (CNPEM), Campinas SP13083-100, Brazil. lucio.freitas@butantan.gov.br.|GARDE, Instituto Butantan, São Paulo SP05503-900, Brazil. lucio.freitas@butantan.gov.br.
authors.forename: Lucio H
authors.initials: LH
authors.lastname: Freitas-Junior
authors.affiliation: Fraunhofer Institute for Molecular Biology and Applied Ecology Screening Port, D-22525 Hamburg, Germany. Sheraz.Gul@ime.fraunhofer.de.
authors.forename: Sheraz
authors.initials: S
authors.lastname: Gul
authors.affiliation: Fraunhofer Institute for Molecular Biology and Applied Ecology Screening Port, D-22525 Hamburg, Germany. Maria.Kuzikov@ime.fraunhofer.de.
authors.forename: Maria
authors.initials: M
authors.lastname: Kuzikov
authors.affiliation: Fraunhofer Institute for Molecular Biology and Applied Ecology Screening Port, D-22525 Hamburg, Germany. Birte.Behrens@ime.fraunhofer.de.
authors.forename: Birte
authors.initials: B
authors.lastname: Behrens
authors.affiliation: Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies, 69118 Heidelberg, Germany. ina.poehner@h-its.org.
authors.forename: Ina
authors.initials: I
authors.lastname: Pöhner
authors.affiliation: Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies, 69118 Heidelberg, Germany. rebecca.wade@h-its.org.|Center for Molecular Biology (ZMBH), DKFZ-ZMBH Alliance, Heidelberg University, 69120 Heidelberg, Germany. rebecca.wade@h-its.org.|Interdisciplinary Center for Scientific Computing (IWR), Heidelberg University, 69120 Heidelberg, Germany. rebecca.wade@h-its.org.
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Wade
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 103, 41125 Modena, Italy. mariapaola.costi@unimore.it.
authors.forename: Maria Paola
authors.initials: MP
authors.lastname: Costi
authors.affiliation: Department of Biotechnology, Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy. stefano.mangani@unisi.it.|Magnetic Resonance Center CERM, University of Florence, 50019 Sesto Fiorentino (FI), Italy. stefano.mangani@unisi.it.
authors.forename: Stefano
authors.initials: S
authors.lastname: Mangani
mesh_terms: D000977:Antiparasitic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites; D002839:Chromans / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D020128:Inhibitory Concentration 50; D018320:Leishmania major / Q000187:drug effects / Q000201:enzymology; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011485:Protein Binding; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000201:enzymology
chemical_list: D000977:Antiparasitic Agents; D002839:Chromans; D010088:Oxidoreductases; C085592:pteridine reductase
keywords: Leishmania spp.; Trypanosoma brucei; chroman-4-one; chromen-4-one; crystallographic studies; pteridine reductase 1