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

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

doi:10.1021/acsinfecdis.8b00358

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.

Structural Insights into the Development of Cycloguanil Derivatives as Trypanosoma brucei Pteridine-Reductase-1 Inhibitors / Landi, G.; Linciano, P.; Borsari, C.; Bertolacini, C. P.; Moraes, C. B.; Cordeiro-Da-Silva, A.; Gul, S.; Witt, G.; Kuzikov, M.; Costi, M. P.; Pozzi, C.; Mangani, S.. - In: ACS INFECTIOUS DISEASES. - ISSN 2373-8227. - 5:7(2019), pp. 1105-1114.

Data di pubblicazione:	2019
Data di prima pubblicazione:	1-mag-2019
Titolo:	Structural Insights into the Development of Cycloguanil Derivatives as Trypanosoma brucei Pteridine-Reductase-1 Inhibitors
Autore/i:	Landi, G.; Linciano, P.; Borsari, C.; Bertolacini, C. P.; Moraes, C. B.; Cordeiro-Da-Silva, A.; Gul, S.; Witt, G.; Kuzikov, M.; Costi, M. P.; Pozzi, C.; Mangani, S.
Autore/i UNIMORE:	Landi, Giulia LINCIANO, PASQUALE Borsari C. Bertolacini C. P. Moraes C. B. Cordeiro-Da-Silva A. Gul S. Witt G. Kuzikov M. COSTI, Maria Paola Pozzi C. Mangani S. mostra contributor esterni nascondi contributor esterni
Digital Object Identifier (DOI):	http://dx.doi.org/10.1021/acsinfecdis.8b00358
Rivista:	ACS INFECTIOUS DISEASES
Volume:	5
Fascicolo:	7
Pagina iniziale:	1105
Pagina finale:	1114
Codice identificativo ISI:	WOS:000475825800007
Codice identificativo Scopus:	2-s2.0-85065803830
Codice identificativo Pubmed:	31012301
Citazione:	Structural Insights into the Development of Cycloguanil Derivatives as Trypanosoma brucei Pteridine-Reductase-1 Inhibitors / Landi, G.; Linciano, P.; Borsari, C.; Bertolacini, C. P.; Moraes, C. B.; Cordeiro-Da-Silva, A.; Gul, S.; Witt, G.; Kuzikov, M.; Costi, M. P.; Pozzi, C.; Mangani, S.. - In: ACS INFECTIOUS DISEASES. - ISSN 2373-8227. - 5:7(2019), pp. 1105-1114.
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