title: Dibenzosuberyl substituted polyamines and analogs of clomipramine as effective inhibitors of trypanothione reductase; molecular docking, and assessment of trypanocidal activities.
abstract: Trypanothione reductase (TR) is an enzyme critical to the maintenance of the thiol redox balance in trypanosomatids, including the genera Trypanosoma and Leishmania that are parasites responsible for several serious diseases. Analogs of clomipramine were prepared since clomipramine is reported to inhibit TR and cure mice infected with trypanosomes, however its psychotropic activity precludes its use as an anti-trypanosomal therapeutic. The clomipramine analogs contained a tricyclic dibenzosuberyl moiety. Additionally a series of polyamines with N-dibenzosuberyl substituents were prepared. All compounds studied were competitive inhibitors of TR and showed trypanocidal activities against Trypanosoma brucei in vitro. The analogs of clomipramine were poor inhibitors of TR, whereas the polyamine derivatives were effective TR inhibitors with the most potent compound, N(4),N(8)-bis(dibenzosuberyl)spermine (7), having a Ki value of 0.26μM. However, compound (7) did not prolong the lives of mice infected with trypanosomes. Analysis of docking studies indicated: the tricyclic groups of inhibitors bind at four distinct hydrophobic regions in the active site of TR; the importance of the chlorine substituent of clomipramine in binding to TR; and binding of the dibenzosuberyl groups of (7) occur at separate and distinct hydrophobic regions within the active site of TR.
authors: Department of Chemistry and Biochemistry, Canisius College, 2001 Main Street, Buffalo, NY 14208, USA. Electronic address: osulliv1@canisius.edu.
authors: Mary C
authors: MC
authors: O'Sullivan
authors: Department of Chemistry, Indiana State University, Terre Haute, IN 47809, USA.
authors: Timothy B
authors: TB
authors: Durham
authors: Department of Chemistry and Biochemistry, Canisius College, 2001 Main Street, Buffalo, NY 14208, USA.
authors: Hannah E
authors: HE
authors: Valdes
authors: Department of Chemistry and Biochemistry, Canisius College, 2001 Main Street, Buffalo, NY 14208, USA.
authors: Kelly L
authors: KL
authors: Dauer
authors: Department of Chemistry and Biochemistry, Canisius College, 2001 Main Street, Buffalo, NY 14208, USA.
authors: Nicholas J
authors: NJ
authors: Karney
authors: Department of Chemistry and Biochemistry, Canisius College, 2001 Main Street, Buffalo, NY 14208, USA.
authors: Andrew C
authors: AC
authors: Forrestel
authors: Haskins Laboratories and Department of Biology, Pace University, New York, NY 10038, USA.
authors: Cyrus J
authors: CJ
authors: Bacchi
authors: Department of Chemistry and Biochemistry, Canisius College, 2001 Main Street, Buffalo, NY 14208, USA.
authors: Jerome F
authors: JF
authors: Baker
mesh_terms: D000818:Animals; D002997:Clomipramine / Q000031:analogs & derivatives* / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D062105:Molecular Docking Simulation; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors*; D011073:Polyamines / Q000737:chemistry / Q000494:pharmacology*; D014344:Trypanocidal Agents / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000201:enzymology
chemical_list: D004791:Enzyme Inhibitors; D011073:Polyamines; D014344:Trypanocidal Agents; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase; D002997:Clomipramine
keywords: Clomipramine; Dibenzosuberyl substituted polyamine; Polyamine; Spermidine; Spermine; Trypanosoma cruzi; Trypanosome; Trypanothione; Trypanothione reductase