Synthesis and Evaluation of 1‐(1‐(Benzo[b]thiophen‐2‐yl)cyclohexyl)piperidine (BTCP) Analogues as Inhibitors of Trypanothione Reductase

Abstract

Thirty two analogues of phencyclidine were synthesised and tested as inhibitors of trypanothione reductase (TryR), a potential drug target in trypanosome and leishmania parasites. The lead compound BTCP (1, 1-(1-benzo[b]thiophen-2-yl-cyclohexyl) piperidine) was found to be a competitive inhibitor of the enzyme (Ki=1 μm) and biologically active against bloodstream T. brucei (EC50=10 μm), but with poor selectivity against mammalian MRC5 cells (EC50=29 μm). Analogues with improved enzymatic and biological activity were obtained. The structure–activity relationships of this novel series are discussed.

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.…”

“…Conversely, we analyzed the binding mode of BTCP-based TR inhibitors [16] by computer modeling using MOLOC. [23] The implemented MAB force field was applied in order to minimize the energy of the complex, holding the enzyme structure fixed except for the Glu 18 side chain.…”

“…[15] Nevertheless, various compounds have been identified as inhibitors of TR over the past two decades. [9,10,16] Under physiological conditions, most of these compounds feature a protonated ammonium or a quaternary nitrogen center, which Trypanothione reductase (TR) is an essential enzyme in the trypanothione-based redox metabolism of trypanosomatid parasites. This system is absent in humans and, therefore, offers a promising target for the development of selective new drugs against African sleeping sickness and Chagas' disease.…”

Structure- and ligand-based drug design approaches for neglected tropical diseases

“…SBDD approaches applied for the development of TR inhibitors have proven challenging owing to the difficulty of determining the binding modes of several ligands. Nonetheless, molecular modeling strategies have been employed to provide useful structural information for inhibitor drug design [16][17][18]. An important example is the design of a series of diaryl sulfidebased derivatives as new TR inhibitors [19].…”

“…An important example is the design of a series of diaryl sulfidebased derivatives as new TR inhibitors [19]. In this work, molecular docking strategies were employed for the previously reported lead compound BTCP (K i = 1 μM) [18], suggesting the binding of the ligand to the hydrophobic Z-site of the TR enzyme (Fig. 1A).…”