Improved Tricyclic Inhibitors of Trypanothione Reductase by Screening and Chemical Synthesis

Abstract

Trypanothione reductase (TryR) is a key validated enzyme in the trypanothione-based redox metabolism of pathogenic trypanosomes and leishmania parasites. This system is absent in humans, being replaced with glutathione and glutathione reductase, and as such offers a target for selective inhibition. As part of a program to discover antiparasitic drugs, the LOPAC1280 library of 1266 compounds was screened against TryR and the top hits evaluated against glutathione reductase and T. brucei parasites. The top hits included a number of known tricyclic neuroleptic drugs along with other new scaffolds for TryR. Three novel druglike hits were identified and SAR studies on one of these using information from the tricyclic neuroleptic agents led to the discovery of a competitive inhibitor (Ki=330 nm) with an improved potency against T. brucei (EC50=775 nm).

Synthesis, Inhibition Potency, Binding Mode, and Antiprotozoal Activities of Fluorescent Inhibitors of Trypanothione Reductase Based on Mepacrine‐Conjugated Diaryl Sulfide Scaffolds

“…Reaction of thiols 7-9 with fluoride 6 yielded diaryl sulfide derivatives 10-12. The CF 3 -substituted compound 13 was obtained by treatment of 4-(trifluoromethyl)bromobenzene (14) with tBuLi followed by addition of sulfur and subsequent S N Ar reaction with 2,6-difluorobenzonitrile (6).…”

“…[13] Nevertheless, a number of TR inhibitors have been identified over the last decade. [8,10,14,15] Often, a protonated…”

Ebsulfur Is a Benzisothiazolone Cytocidal Inhibitor Targeting the Trypanothione Reductase of Trypanosoma brucei

“…DL-␣-Difluoromethylornithine inhibits the biosynthesis of spermidine, a constituent of trypanothione (15), and antimonials form complexes with T(SH) 2 and TryR (16). Several classes of compounds have been shown to inhibit TryR (17)(18)(19)(20)(21)(22).…”

Synthesis, biological profiling and mechanistic studies of 4-aminoquinoline-based heterodimeric compounds with dual trypanocidal–antiplasmodial activity

“…The TryR inhibitory activity of selected compounds of these series, namely heterodimers 3d, 5b and 8b, as well as the parent huprine Y, 1, was determined through a described methodology based on the colorimetric reduction of 5,5'-dithiobis(2-nitrobenzoic) acid (DTNB) by dithiol trypanothione (T[SH] 2 ), the product of the reaction catalyzed by TryR. 53,54 The four tested compounds exhibited submicromolar to low micromolar IC 50 values for TryR inhibition (Table 3). The most potent compound turned out to be 3d (series I) which was 6-8-fold more potent than the parent huprine and the heterodimers of the other series.…”

“…53,54 The assay mixture consisted of: 40 mM HEPES pH 7.4, 1 mM EDTA, 6 µM trypanothione disulfide (T[S] 2 ), 50 µM DTNB, 2 mU mL 1 TryR and 150 µM NADPH. IC 50 values were determined using 11 serial dilutions.…”