Discovery of potent pteridine reductase inhibitors to guide antiparasite drug development was written by Cavazzuti, Antonio;Paglietti, Giuseppe;Hunter, William N.;Gamarro, Francisco;Piras, Sandra;Loriga, Mario;Alleca, Sergio;Corona, Paola;McLuskey, Karen;Tulloch, Lindsay;Gibellini, Federica;Ferrari, Stefania;Costi, Maria Paola. And the article was included in Proceedings of the National Academy of Sciences of the United States of America in 2008.Safety of Ethyl 3-chloroquinoxaline-2-carboxylate This article mentions the following:
Pteridine reductase (PTR1) is essential for salvage of pterins by parasitic trypanosomatids and is a target for the development of improved therapies. To identify inhibitors of Leishmania major and Trypanosoma cruzi PTR1, a rapid-screening strategy using a folate-based library was combined with structure-based design. Assays were carried out against folate-dependent enzymes including PTR1, dihydrofolate reductase (DHFR), and thymidylate synthase. Affinity profiling determined selectivity and specificity of a series of quinoxaline and 2,4-diaminopteridine derivatives, and nine compounds showed greater activity against parasite enzymes compared with human enzymes. Compound I [R = H, Me (II)] displayed a Ki of 100 nM toward LmPTR1, and the crystal structure of the LmPTR1:NADPH:I ternary complex revealed a substrate-like binding mode distinct from that previously observed for similar compounds A second round of design, synthesis, and assay produced a compound II with a significantly improved Ki (37 nM) against LmPTR1, and the structure of this complex was also determined Biol. evaluation of selected inhibitors was performed against the extracellular forms of T. cruzi and L. major, both wild-type and overexpressing PTR1 lines, as a model for PTR1-driven antifolate drug resistance and the intracellular form of T. cruzi. An additive profile was observed when PTR1 inhibitors were used in combination with known DHFR inhibitors, and a reduction in toxicity of treatment was observed with respect to administration of a DHFR inhibitor alone. The successful combination of antifolates targeting two enzymes indicates high potential for such an approach in the development of previously undescribed antiparasitic drugs. In the experiment, the researchers used many compounds, for example, Ethyl 3-chloroquinoxaline-2-carboxylate (cas: 49679-45-0Safety of Ethyl 3-chloroquinoxaline-2-carboxylate).
Ethyl 3-chloroquinoxaline-2-carboxylate (cas: 49679-45-0) belongs to quinoxaline derivatives. Condensed heterocycles of quinoxalines have become attractive targets in synthetic and medicinal chemistry due to their significant biological activities. Quinoxalines are used as dyes, pharmaceuticals, and antibiotics such as echinomycin, levomycin exhibiting antitumoral properties. Quinoxalines establish also the basis of anthelmintics and receptor antagonists.Safety of Ethyl 3-chloroquinoxaline-2-carboxylate
Referemce:
Quinoxaline – Wikipedia,
Quinoxaline | C8H6N2 | ChemSpider