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Synfacts 2019; 15(11): 1215
DOI: 10.1055/s-0039-1691017
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Nanomolar Inhibitor of Trypanosoma brucei Trypanothione Reductase

Contributor(s):
Philip Kocienski
De Gasparo R, Halgas O, Harangozo D, Kaiser M. * Pai EF. * Krauth-Siegel RL, Diederich F. * ETH Zurich, Switzerland
Targeting a Large Active Site: Structure-Based Design of Nanomolar Inhibitors of Trypanosoma brucei Trypanothione Reductase.

Chem. Eur. J. 2019;
25: 11416-11421
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Further Information

Publication History

Publication Date:
18 October 2019 (online)

 
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Key words

trypanothione reductase inhibitor - benzotriazole - N,N-acetal - tertiary amine - Suzuki–Miyaura coupling - Sonogashira coupling

Significance

The parasitic protozoa responsible for trypanosomiasis, Chagas’ disease, and leishmaniasis require the reduction of trypanothione disulfide to trypanothione, which the parasites use in several essential processes. Target molecule N is the strongest competitive inhibitor in vitro of trypanothione reductase from Trypanosoma cruzi reported to date.


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Comment

Note the construction of highly hindered amine E by nucleophilic substitution of benzotriazole from N,N-acetal B by the organomagnesium reagent D.


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Review

For a Review on properties and synthetic utility of N-substituted benzotriazoles, see A. R. ­Katritzky, X. Lan, J. Z. Yang Chem. Rev. 1998, 98, 409–548.


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