Structural Insights into the Development of Cycloguanil Derivatives as Trypanosoma brucei Pteridine-Reductase-1 Inhibitors.


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 developed, resulting in 1 and 2a having IC50 values of 692 and 186 nM, respectively, toward 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 promising new strategy for the treatment of human African trypanosomiasis. For this purpose, 1,6-dihydrotriazines represent new molecular tools to develop potent dual PTR and DHFR inhibitors.


PubMed ID: 31012301

Projects: NMTrypI - New Medicines for Trypanosomatidic Infections

Publication type: Journal

Journal: ACS Infect Dis

Citation: ACS Infect Dis. 2019 Jul 12;5(7):1105-1114. doi: 10.1021/acsinfecdis.8b00358. Epub 2019 May 1.

Date Published: 12th Jul 2019

Registered Mode: by PubMed ID

Authors: G. Landi, P. Linciano, C. Borsari, C. P. Bertolacini, C. B. Moraes, A. Cordeiro-da-Silva, S. Gul, G. Witt, M. Kuzikov, M. P. Costi, C. Pozzi, S. Mangani

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Created: 22nd Jul 2020 at 15:51

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