Document Type

Article

Publication Date

Fall 8-17-2005

Abstract

Quaternization of the nitrogen atom of 2-amino-4-chlorophenyl phenyl sulfide analogues of chlorpromazine improved inhibition ∼40-fold (3′,4′-dichlorobenzyl-[5-chloro-2-phenylsulfan- ylphenylamino)-propyl]-dimethylammonium chloride inhibited trypanothione reductase from Trypanosoma cruzi with a linear competitive Ki value of 1.7 ( 0.2 µM). Molecular modelling explained docking orientations and energies by: (i) involvement of the Z-site hydrophobic pocket (roughly bounded by F396′, P398′, and L399′), (ii) ionic interactions for the cationic nitrogen with Glu-466′ or -467′. A series of N-acyl-2-amino-4-chlorophenyl sulfides showed mixed inhibition (Ki, Ki′ ) 11.3-42.8 µM). The quaternized analogues of the 2-chlorophenyl phenylsulfides had strong antitrypanosomal and antileishmanial activity in vitro against T. bruceirhodesiense STIB900, T. cruzi Tulahuan, and Leishmania donovani HU3. The N-acyl-2-amino-4-chlorophenyl sulfides were active against Plasmodium falciparum. The phenothiazine and diaryl sulfide quaternary compounds were also powerful antimalarials, providing a new structural framework for antimalarial design.

Comments

The copy of record is available from the publish at http://pubs.acs.org/doi/abs/10.1021/jm050819t. Copyright © 2005 American Chemical Society. Reprinted with permission.

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