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Article

Evidence of Pyrimethamine and Cycloguanil Analogues as Dual Inhibitors of Trypanosoma brucei Pteridine Reductase and Dihydrofolate Reductase

1
Department of Biotechnology, Chemistry and Pharmacy, Department of Excellence 2018–2022, University of Siena, via Aldo Moro 2, 53100 Siena, Italy
2
Department of Life Science, University of Modena and Reggio Emilia, via Campi 103, 41125 Modena, Italy
3
Department of Pharmacy, University of Genoa, Viale Benedetto XV n.3, 16132 Genoa, Italy
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editor: Christophe Dardonville
Pharmaceuticals 2021, 14(7), 636; https://doi.org/10.3390/ph14070636
Received: 31 May 2021 / Revised: 24 June 2021 / Accepted: 25 June 2021 / Published: 30 June 2021
(This article belongs to the Special Issue Drug Discovery and Development for Tropical Diseases (TDs))
Trypanosoma and Leishmania parasites are the etiological agents of various threatening neglected tropical diseases (NTDs), including human African trypanosomiasis (HAT), Chagas disease, and various types of leishmaniasis. Recently, meaningful progresses in the treatment of HAT, due to Trypanosoma brucei (Tb), have been achieved by the introduction of fexinidazole and the combination therapy eflornithine–nifurtimox. Nevertheless, due to drug resistance issues and the exitance of animal reservoirs, the development of new NTD treatments is still required. For this purpose, we explored the combined targeting of two key folate enzymes, dihydrofolate reductase (DHFR) and pteridine reductase 1 (PTR1). We formerly showed that the TbDHFR inhibitor cycloguanil (CYC) also targets TbPTR1, although with reduced affinity. Here, we explored a small library of CYC analogues to understand how their substitution pattern affects the inhibition of both TbPTR1 and TbDHFR. Some novel structural features responsible for an improved, but preferential, ability of CYC analogues to target TbPTR1 were disclosed. Furthermore, we showed that the known drug pyrimethamine (PYR) effectively targets both enzymes, also unveiling its binding mode to TbPTR1. The structural comparison between PYR and CYC binding modes to TbPTR1 and TbDHFR provided key insights for the future design of dual inhibitors for HAT therapy. View Full-Text
Keywords: pyrimethamine; cycloguanil; derivatives; Trypanosoma brucei; pteridine reductase; dihydrofolate reductase; antifolate drug; dual inhibitor; X-ray crystallography; structure–activity relationship pyrimethamine; cycloguanil; derivatives; Trypanosoma brucei; pteridine reductase; dihydrofolate reductase; antifolate drug; dual inhibitor; X-ray crystallography; structure–activity relationship
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MDPI and ACS Style

Tassone, G.; Landi, G.; Linciano, P.; Francesconi, V.; Tonelli, M.; Tagliazucchi, L.; Costi, M.P.; Mangani, S.; Pozzi, C. Evidence of Pyrimethamine and Cycloguanil Analogues as Dual Inhibitors of Trypanosoma brucei Pteridine Reductase and Dihydrofolate Reductase. Pharmaceuticals 2021, 14, 636. https://doi.org/10.3390/ph14070636

AMA Style

Tassone G, Landi G, Linciano P, Francesconi V, Tonelli M, Tagliazucchi L, Costi MP, Mangani S, Pozzi C. Evidence of Pyrimethamine and Cycloguanil Analogues as Dual Inhibitors of Trypanosoma brucei Pteridine Reductase and Dihydrofolate Reductase. Pharmaceuticals. 2021; 14(7):636. https://doi.org/10.3390/ph14070636

Chicago/Turabian Style

Tassone, Giusy, Giacomo Landi, Pasquale Linciano, Valeria Francesconi, Michele Tonelli, Lorenzo Tagliazucchi, Maria P. Costi, Stefano Mangani, and Cecilia Pozzi. 2021. "Evidence of Pyrimethamine and Cycloguanil Analogues as Dual Inhibitors of Trypanosoma brucei Pteridine Reductase and Dihydrofolate Reductase" Pharmaceuticals 14, no. 7: 636. https://doi.org/10.3390/ph14070636

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