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J Med Chem. 2013 Apr 11;56(7):2850-60. doi: 10.1021/jm301687p. Epub 2013 Mar 26.

Optimization of chloronitrobenzamides (CNBs) as therapeutic leads for human African trypanosomiasis (HAT).

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1
Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105-3678, United States.

Abstract

We previously reported the discovery of the activity of chloronitrobenzamides (CNBs) against bloodstream forms of Trypanosoma brucei . Herein we disclose extensive structure-activity relationship and structure-property relationship studies aimed at identification of tractable early leads for clinical development. These studies revealed a promising lead compound, 17b, that exhibited nanomolar potency against T. brucei (EC50 = 27 nM for T. b. brucei, 7 nM for T. b. rhodesiense, and 2 nM for T. b. gambiense ) with excellent selectivity for parasite cells relative to mammalian cell lines (EC50 > 25 μM). In addition compound 17b displayed suitable physiochemical characteristics and microsomal stability (t1/2 > 4 h for human and mouse) to justify pursuing in vivo studies.

PMID:
23484493
DOI:
10.1021/jm301687p
[Indexed for MEDLINE]
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