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Structural insights into the development of cycloguanil derivatives as Trypanosoma brucei pteridine reductase 1 inhibitors

DOI: 10.1021/acsinfecdis.8b00358 DOI Help

Authors: Giacomo Landi (University of Siena) , Pasquale Linciano (University of Modena and Reggio Emilia) , Chiara Borsari (University of Modena and Reggio Emilia) , Claudia P. Bertolacini (National Center for Research in Energy and Materials) , Carolina Borsoi Moraes (National Center for Research in Energy and Materials) , Anabela Cordeiro-Da-Silva (Universidade do Porto and Institute for Molecular and Cell Biology) , Sheraz Gul (Fraunhofer Institute for Molecular Biology & Applied Ecology) , Gesa Witt (Fraunhofer Institute for Molecular Biology & Applied Ecology) , Maria Kuzikov (Fraunhofer Institute for Molecular Biology & Applied Ecology) , Maria Paola Costi (University of Modena and Reggio Emilia) , Cecilia Pozzi (University of Siena) , Stefano Mangani (University of Siena)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acs Infectious Diseases

State: Published (Approved)
Published: April 2019
Diamond Proposal Number(s): 11690

Abstract: Cycloguanil is a known dihydrofolate reductase (DHFR) inhibitor, but there is no evidence of its activity on pteridine reductase (PTR), the main metabolic bypass to DHFR inhibition in trypanosomatid parasites. Here, we provide experimental evidence of cycloguanil as an inhibitor of Trypanosoma brucei PTR1 (TbPTR1). A small library of cycloguanil derivatives was develop, resulting in 1 and 2a having IC50 of 692 and 186 nM, respectively, towards TbPTR1. Structural analysis revealed that the increased potency of 1 and 2a is due to the combined contributions of hydrophobic interactions, H-bonds and halogen bonds. Moreover, in vitro cell growth inhibition tests indicated that 2a is also effective on T. brucei. The simultaneous inhibition of DHFR and PTR1 activity in T. brucei is a new promising strategy for the treatment of human African Trypanosomiasis. On this purpose, 1,6-dihydrotriazines represent new molecular tools to develop potent dual PTR and DHFR inhibitors.

Journal Keywords: Cycloguanil; triazine derivatives; Trypanosoma brucei; anti-parasite drugs; pteridine reductase; folate pathway

Diamond Keywords: Sleeping Sickness

Subject Areas: Biology and Bio-materials, Medicine, Chemistry


Instruments: I02-Macromolecular Crystallography

Other Facilities: ESRF

Added On: 29/04/2019 14:10

Discipline Tags:

Organic Chemistry Life Sciences & Biotech Health & Wellbeing Disease in the Developing World Drug Discovery Infectious Diseases Structural biology Chemistry Biochemistry Parasitology

Technical Tags:

Diffraction Macromolecular Crystallography (MX)