690631-97-1Relevant articles and documents
Targeting a Large Active Site: Structure-Based Design of Nanomolar Inhibitors of Trypanosoma brucei Trypanothione Reductase
De Gasparo, Raoul,Diederich, Fran?ois,Halgas, Ondrej,Harangozo, Dora,Kaiser, Marcel,Krauth-Siegel, R. Luise,Pai, Emil F.
, (2019)
Trypanothione reductase (TR) plays a key role in the unique redox metabolism of trypanosomatids, the causative agents of human African trypanosomiasis (HAT), Chagas’ disease, and leishmaniases. Introduction of a new, lean propargylic vector to a known class of TR inhibitors resulted in the strongest reported competitive inhibitor of Trypanosoma (T.) brucei TR, with an inhibition constant Ki of 73 nm, which is fully selective against human glutathione reductase (hGR). The best ligands exhibited in vitro IC50 values (half-maximal inhibitory concentration) against the HAT pathogen, T. brucei rhodesiense, in the mid-nanomolar range, reaching down to 50 nm. X-Ray co-crystal structures confirmed the binding mode of the ligands and revealed the presence of a HEPES buffer molecule in the large active site. Extension of the propargylic vector, guided by structure-based design, to replace the HEPES buffer molecule should give inhibitors with low nanomolar Ki and IC50 values for in vivo studies.
Convenient synthesis of 1H-indol-1-yl boronates via palladium(0)-catalyzed borylation of bromo-1H-indoles with 'pinacolborane'
Stadlwieser, Josef F.,Dambaur, Markus E.
, p. 936 - 946 (2007/10/03)
An atom-economic Pd0-catalyzed synthesis of a series of pinacol-type indolylboronates 3 from the corresponding bromoindole substrates 2 and pinacolborane (pinBH) as borylating agent was elaborated. The optimal catalyst system consisted of a 1:2 mixture of [Pd(OAc)2] and the ortho-substituted biphenylphosphine ligand L-3 (Scheme 4, Table). Our synthetic protocol was applied to the fast, preparative-scale synthesis of 1-substituted indolylboronates 3a-h in the presence of different functional groups, and at a catalyst load of only 1 mol-% of Pd.
