Antitrypanosomal, antileishmanial, and antimalarial activities of quaternary arylalkylammonium 2-amino-4-chlorophenyl phenyl sulfides, a new class of trypanothione reductase inhibitor, and of N-acyl derivatives of 2-amino-4-chlorophenyl phenyl sulfide

Seheli Parveen, Mohammed O F Khan, Susan E. Austin, Simon L. Croft, Vanessa Yardley, Peter Rock, Kenneth T. Douglas

    Research output: Contribution to journalArticlepeer-review

    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-phenylsulfanylphenylamino)-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, K′i = 11.3-42.8 μM). The quaternized analogues of the 2-chlorophenyl phenyl sulfides had strong antitrypanosomal and antileishmanial activity in vitro against T. brucei rhodesiense 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. © 2005 American Chemical Society.
    Original languageEnglish
    Pages (from-to)8087-8097
    Number of pages10
    JournalJournal of Medicinal Chemistry
    Volume48
    Issue number25
    DOIs
    Publication statusPublished - 15 Dec 2005

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