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Enhancement of benzothiazoles as Pteridine Reductase-1 (PTR1) inhibitors for the treatment of Trypanosomatidic infections

DOI: 10.1021/acs.jmedchem.8b02021 DOI Help

Authors: Pasquale Linciano (University of Modena and Reggio Emilia) , Cecilia Pozzi (University of Siena) , Lucia Dello Iacono (University of Siena) , Flavio Di Pisa (University of Siena) , Giacomo Landi (University of Siena) , Alessio Bonucci (University of Siena) , Sheraz Gul (Fraunhofer Institute for Molecular Biology and Applied Ecology Screening Port) , Maria Kuzikov (Fraunhofer Institute for Molecular Biology and Applied Ecology Screening Port) , Bernhard Ellinger (Fraunhofer Institute for Molecular Biology and Applied Ecology Screening Port) , Gesa Witt (Fraunhofer Institute for Molecular Biology and Applied Ecology Screening Port) , Nuno Santarem (Universidade do Porto and Institute for Molecular and Cell Biology) , Catarina Baptista (Universidade do Porto and Institute for Molecular and Cell Biology) , Caio Franco (Centro Nacional de Pesquisaem Energia e Materiais (CNPEM)) , Carolina Borsoi Moraes (Centro Nacional de Pesquisaem Energia e Materiais (CNPEM)) , Wolfgang Müller (Heidelberg Institute for Theoretical Studies (HITS)) , Ulrike Wittig (Heidelberg Institute for Theoretical Studies (HITS)) , Rosaria Luciani (University of Modena and Reggio Emilia) , Antony Sesenna (University of Modena and Reggio Emilia) , Antonio Quotadamo (University of Modena and Reggio Emilia) , Stefania Ferrari (University of Modena and Reggio Emilia) , Ina Pöhner (Heidelberg Institute for Theoretical Studies (HITS)) , Anabela Cordeiro-da-silva (Universidade do Porto and Institute for Molecular and Cell Biology) , Stefano Mangani (University of Siena) , Luca Costantino (University of Modena and Reggio Emilia) , Maria Paola Costi (University of Modena and Reggio Emilia)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: March 2019
Diamond Proposal Number(s): 11690 , 15832

Abstract: 2-amino-benzo[d]thiazole has been identified as new core moiety for the development of improved PTR1 inhibitors and anti-Trypanosomatidic agents. Through a molecular docking approach and the crystal structure of 6-(methylsulfonyl)benzo[d]thiazol-2-amine ternary complex with TbPTR1, 42 new compounds were designed, synthesized and evaluated for their ability to inhibit T. brucei and L. major PTR1 enzymes and in-vitro activity against Trypanosoma brucei and amastigote stage of Leishmania infantum. We identified several 2-amino-benzo[d]thiazole derivatives with improved activity against the enzymes (TbPTR1 IC50 = 0.35 µM; LmPTR1 IC50 = 1.9 µM) and anti-parasitic activity against T. brucei in the low µM range. Ten compounds, with low/sub micromolar inhibitor activity against TbPTR1, were able to potentiate the antiparasitic activity of methotrexate (MTX) when evaluated in combination against T. brucei, with a Potentiating Index (PI) ranging between 1.2 and 2.7. The compound library was profile for an early ADME-Toxicity profile and the compounds showing the best in vitro/enzymatic inhibition properties were selected for progression. 2-amino-N-benzylbenzo[d]thiazole-6-carboxamide (4c), was finally identified as a novel potent and selective anti-trypanocydal agent (EC50 = 7.0 µM) with an overall safe early ADME-Toxicity profile. The pharmacokinetic studies of 4c in BALB/c mice using a hydroxypropyl-β-cyclodextrin formulation yielded good oral bioavailability, confirming its suitability for progression to in-vivo anti-parasitic studies.

Subject Areas: Chemistry, Biology and Bio-materials


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography

Other Facilities: ESRF