Antitrypanosomal, Antileishmanial, and Antimalarial Activities of Quaternary Arylalkylammonium 2-Amino-4-Chlorophenyl Phenyl Sulfides, a New Class of Trypanothione Reductase Inhibitor, and ofN-Acyl Derivatives of 2-Amino-4-Chlorophenyl Phenyl Sulfide

Abstract

Quaternization of the nitrogen atom of 2-amino-4-chlorophenyl phenyl sulfide analogues of chlorpromazine improved inhibition approximately 40-fold (3',4'-dichlorobenzyl-[5-chloro-2-phenylsulfanyl-phenylamino)-propyl]-dimethylammonium chloride inhibited trypanothione reductase from Trypanosoma cruzi with a linear competitive Ki value of 1.7 +/- 0.2 microM). 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, Ki' = 11.3-42.8 microM). 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.

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.…”

“…[24] Noticeably, several of them feature a basic or quaternary nitrogen connected through a flexible alkyl chain to a hydrophobic core. One of the prototypes of this inhibitor class are diaryl sulfide-based compounds, first reported by Sergheraert et al [25] and further explored by Douglas et al [26] In order to explore the eligibility of SF 5 as a building block for TR inhibitors and to compare it with the corresponding CF 3 or CA C H T U N G T R E N N U N G (CH 3 ) 3 analogues, we designed and synthesized diarylamine derivatives 1-6, which are structurally related to the known class of diphenyl sulfide inhibitors (Scheme 1).…”

Trypanothione Reductase High-Throughput Screening Campaign Identifies Novel Classes of Inhibitors with Antiparasitic Activity

“…A focus set of compounds was then chosen by considering inhibitory potency, synthetic accessibility, and compound novelty. The focus set consisted of nine structural classes and 44 compounds, including 12 analogues of one structural class, and had a median IC 50 of 16 M. The biological activity of the focus set was further explored by whole-parasite and cytotoxicity assays conducted at the STI (41), and based on their parasiticidal activities, five chemical classes were chosen for further investigation, which included preliminary ADME profiling and SAR probing. These five classes comprised aryl/ alkyl piperidines (compounds 1 and 2), basic benzhydryls (compound 3), nitrogenous heterocycles (compounds 4 and 5), conjugated indoles (compound 6), and iminobenzimidazoles (compound 7) (Fig.…”

Discovery of 2-iminobenzimidazoles as a new class of trypanothione reductase inhibitor by high-throughput screening

“…12 The biological inhibitory activity of a small selection of 2-iminobenzimidazoles (3, 16, 25) was further explored in whole parasite and cytotoxicity assays (Table 5). 31 The 2-iminobenzimidazoles tested displayed potent trypanocidal activity against Trypanosoma brucei rhodesiense (STB 900) and relatively low cytotoxicity against a human bladder carcinoma cell line (HT-29). It is possible that the cytotoxicity observed, particularly with compound 16, may be due to inhibition of human GR.…”