Discovery of a Biologically Active Bromodomain Inhibitor by Target-Directed Dynamic Combinatorial Chemistry

• Published in: ACS medicinal chemistry letters Vol. 9; no. 10; pp. 1002 - 1006
• Main Authors: García, Paula, Alonso, Victoria L, Serra, Esteban, Escalante, Andrea M, Furlan, Ricardo L. E
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 11-10-2018
• Subjects: Letter; target-directed chemistry; bromodomain inhibitor; Dynamic combinatorial libraries; Trypanosoma cruzi
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/acsmedchemlett.8b00247

Target-directed dynamic combinatorial chemistry (DCC) has emerged as a strategy for the identification of inhibitors of relevant therapeutic targets. In this contribution, we use this strategy for the identification of a high-affinity binder of a parasite target, the Trypanosoma cruzi bromodomain-containing protein TcBDF3. This protein is essential for viability of T. cruzi, the protozoan parasite that causes Chagas disease. A small dynamic library of acylhydrazones was prepared from aldehydes and acylhydrazides at neutral pH in the presence of aniline. The most amplified library member shows (a) high affinity for the template, (b) interesting antiparasitic activity against different parasite forms, and (c) low toxicity against Vero cells. In addition, parasites are rescued from the compound toxicity by TcBDF3 overexpression, suggesting that the toxicity of this compound is due to the TcBDF3 inhibition, i.e., the binding event that initially drives the molecular amplification is reproduced in the parasite, leading to selective toxicity.