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

The pentafluorosulfanyl (SF5) group is a perfectly stable building block under physiological conditions. Pioneering work on the synthesis and properties of SF5-containing aromatic compounds was carried out by Sheppard half a century ago. Thereafter, this novel substituent had been largely ignored by the chemical community for several decades. Due to the ACHTUNGTRENNUNGincreased availability of SF5-substituted derivatives, the organic chemistry of SF5-containing derivatives has come recently under more widespread investigation and has lead to multiple applications in material sciences. Fueled by the knowledge of the pronounced influence of fluorine on the physical and chemical properties 15] and therefore on the bioactivity of molecules, the interest of the life science industry in novel fluorine containing substituents is nowadays prevalent. Accordingly, the SF5 group has gained the attraction of crop ACHTUNGTRENNUNGscience in the recent years, as underlined by the growing number of patents and research articles 17, 18] for mainly agrochemicals containing this functional group. The SF5 group bears much similarity to the CF3 substituent, but it is even more electronegative (Hammett substituent constants: SF5 : sp =+0.68; CF3: sp =+0.54) [3] and has a higher lipophilicity (Hansch hydrophobicity constants: SF5 : p= 1.51, CF3 : p= 1.09). In addition, the SF5 group is distinguished by a higher thermal and chemical stability than its carbon relative 2] and has been characterized as a “super-trifluoromethyl” group in the literature. Its strong polarity in combination with high lipophilicity and thermal stability renders the SF5 group a highly interesting structural motif in medicinal chemistry. To the best of our knowledge, no structure–activity relationship (SAR) data on the target level have been reported for SF5containing derivatives to date. We selected the flavoenzyme trypanothione reductase (TR, EC 1.6.4.8), found in parasites of the trypanosomatid family, as a target for the design of SF5bearing inhibitors. Trypanosomatid parasites possess trypanothione [N,N-bis(glutathionyl)spermidine] and the enzyme TR instead of the nearly ubiquitous glutathione system composed of glutathione and the flavoenzyme glutathione reductase (GR, EC 1.6.4.2). TR, which is the key enzyme of the trypanothione-based antioxidant defence systems of parasitic trypanosomes and Leishmania, has been shown to be essential ; this renders the enzyme a promising target for the development of new drugs against antiparasitic drugs. Trypanosoma brucei is the causative agent of human African trypanosomiasis (African sleeping sickness), which threatens millions of people in ~36 countries of sub-Saharan Africa with an estimated number of current cases between 50 000 and 70 000. Trypanosoma cruzi is the pathogen of Chagas’ disease (American trypanosomiasis), an infection widespread in central and southern America and is responsible for 14 000 deaths each year. Another trypanosomatid-caused disease, leishmaniasis, is provoked by various species of Leishmania. The different forms of the disease range from cutaneous to visceral infections with millions of people infected. Around 50 000 deaths per year are quoted mainly due to L. donovani. New and improved drugs to fight these diseases are urgently needed, as current therapy for all forms of trypanosomiases and leishmaniases is problematic due to the severe adverse effects of the drugs in use, the long duration and high costs of treatment, and an increasing number of drug resistant pathogens. 24] In the search for new drugs against trypanosomatid-induced diseases, TR has become an increasingly popular target. Various compounds have been discovered over the last decade that moderately inhibit TR. 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. and further explored by Douglas et al. In order to explore the eligibility of SF5 as a building block for TR inhibitors and to compare it with the corresponding CF3 or C ACHTUNGTRENNUNG(CH3)3 analogues, we designed and synthesized diarylamine derivatives 1–6, which are structurally related to the known class of diphenyl sulfide inhibitors (Scheme 1). In order to synthesize the diphenylamine core of the inhibitor scaffold, para-CF3-substituted aniline 7 was reacted with 2,5-dichloronitrobenzene, which delivered the desired diphenylamine 8 together with a considerable amount of triphenylACHTUNGTRENNUNGamine 9. This twofold coupled side product of the nucleophilic [a] Dr. B. Stump, C. Eberle, Dr. W. B. Schweizer, Prof. Dr. F. Diederich Laboratorium f r Organische Chemie, ETH Z rich, Hçnggerberg, HCI 8093 Z rich (Switzerland) Fax: (+ 41) 44-632-1109 E-mail : diederich@org.chem.ethz.ch [b] M. Kaiser, Prof. Dr. R. Brun Swiss Tropical Institute Socinstrasse 57, 4002 Basel (Switzerland) [c] Prof. Dr. R. L. Krauth-Siegel Universit t Heidelberg, Biochemie-Zentrum (BZH) Im Neuenheimer Feld 504, 69120 Heidelberg (Germany) [d] Prof. Dr. D. Lentz Institut f r Chemie und Biochemie, Anorganische Chemie Freie Universit t Berlin Fabeckstrasse 34/36, 14195 Berlin (Germany) Supporting information for this article is available on the WWW under http ://www.chembiochem.org or from the author.