Diaryl sulfide-based inhibitors of trypanothione reductase: inhibition potency, revised binding mode and antiprotozoal activities

Abstract

Trypanothione reductase (TR) is an essential enzyme of trypanosomatids and therefore a promising target for the development of new drugs against African sleeping sickness and Chagas' disease. Diaryl sulfides with a central anilino moiety, decorated with a flexible N-alkyl side chain bearing a terminal ammonium ion, are a known class of inhibitors. Using computer modelling, we revised the binding model for this class of TR inhibitors predicting simultaneous interactions of the ammonium ion-terminated N-alkyl chain with Glu18 as well as Glu465'/Glu466' of the second subunit of the homodimer, whereas the hydrophobic substituent of the aniline ring occupies the "mepacrine binding site" near Trp21 and Met113. Systematic alteration of the carboxylate-binding fragments and the diaryl sulfide core of the inhibitor scaffold provided evidence for the proposed binding mode. In vitro studies showed IC(50) values in the low micromolar to submicromolar range against Trypanosoma brucei rhodesiense as well as the malaria parasite Plasmodium falciparum.

Pentafluorosulfanyl as a Novel Building Block for Enzyme Inhibitors: Trypanothione Reductase Inhibition and Antiprotozoal Activities of Diarylamines

“…[26,27] The same pattern emerged with the series of diphenylamines presented here. The nonquaternary derivatives, with the exception of the trifluoromethyl compound 20, exhibit decent activities with IC 50 values between 1.2 and 2.8 mm.…”

“…Adopting the binding mode proposed for structurally closely related diaryl sulfide inhibitors, [27] the phenylamine moiety bearing a CF 3 , SF 5 , or tBu substituent occupies the hydrophobic "mepacrine binding site" roughly framed by Trp21, Tyr110, and Met113. Furthermore, the 1,2-diaminophenyl motif should act as a ligand for Glu18 whereas the cationic nitrogen may interact electrostatically with Glu465'/Glu466'.…”

“…For the sulfur analog of the CF 3 -substituted diarylamine 4, a K ic of 6 mm was previously reported. [27] Potential inhibitors were manually docked in the empty active site structure of T. cruzi TR cocrystallized with trypanothione (PDB code: 1BZL). [28] The enzyme structure was fixed (except for the Glu18 side chain), and the energy of the system was minimized using the MAB force field as implemented in the computer program Table 1.…”

Improved Inhibitors of Trypanothione Reductase by Combination of Motifs: Synthesis, Inhibitory Potency, Binding Mode, and Antiprotozoal Activities

“…Within this region of the active site, contacts with nonconserved residues between TR and hGR can be established, thereby achieving the necessary selectivity. [22] Interestingly, according to our modeling results presented here, the recently published 1-(1-(benzo[b]thiophen-2-yl)cyclohexyl)piperidine (BTCP) analogues [16] bind to the hydrophobic Z-site, formed by Phe 395', Pro 397', and Leu 398'. This pocket is thought to be utilized by the benzyl moieties of cationic phenothiazineand diaryl sulfide-based derivatives but has been otherwise overlooked with regard to drug design.…”

“…This pocket is thought to be utilized by the benzyl moieties of cationic phenothiazineand diaryl sulfide-based derivatives but has been otherwise overlooked with regard to drug design. [19,22] Herein we report the design, synthesis, and biological activity of novel potent and selective TR inhibitors. In the first series of compounds, a new imidazole platform was introduced into diaryl sulfide-based ligands.…”