Elsevier

Bioorganic & Medicinal Chemistry

Volume 16, Issue 17, 1 September 2008, Pages 8127-8135
Bioorganic & Medicinal Chemistry

Synthesis and elastase-inhibiting activity of 2-pyridinyl-isothiazol-3(2H)-one 1,1-dioxides

https://doi.org/10.1016/j.bmc.2008.07.049Get rights and content

Abstract

The synthesis of a series of new isothiazol-3(2H)-one 1,1-dioxides with halogenated (mostly fluorinated) pyridinyl and pentafluorophenyl substituents at 2-position is reported. These compounds (1824) became easily accessible from 2-thiocyanato-1-carboxaldehydes and aminopyridines, pentafluoroaniline, respectively, by an isothiazolium cyclization–oxidation route. Compound 21 exhibited an IC50 value of 3.1 μM toward human leukocyte elastase. The proteases cathepsin G, trypsin, cathepsin L, and angiotensin-converting enzyme, and the serine esterases acetylcholinesterase and cholesterol esterase were not inhibited by 21.

Introduction

With a van der Waals radius of 1.47 Å, covalently bound fluorine occupies a smaller volume than other substituents except of hydrogen (van der Waals radius of 1.20 Å). Thus, the substitution of hydrogen by fluorine in bioactive molecules results in minor steric changes but alters their physico-chemical properties, including lipophilicity as well as basicity or acidity of adjacent functional groups. The difference in electronegativity between carbon and the most electronegative element, fluorine, generates strong dipole moments in the carbon–fluorine bond and may contribute to the ability of the molecule to engage in intermolecular interactions. It was demonstrated that aromatic carbon-bound fluorine can interact with positively charged molecules or positively polarized electrophilic centers.1, 2 Currently, the occurrence of fluorine within hydrogen-bonding distance of N–H, O–H, or C–H groups, respectively, is viewed as an attractive dipolar contact rather than a true hydrogen bond.2, 3, 4, 5

Although it is not common in natural products, covalently bound fluorine has attracted much attention in medicinal chemistry.6, 7In comparison with the non-fluorinated counterparts, a desirable reduction in their rate of metabolism has been shown for several fluorine-containing drugs. Fluorination of aromatic groups can improve the binding of ligands to target proteins, which was attributed either to the direct fluorine–protein interaction or to an altered polarity of other groups. For example, fluorination of phthalimides led to potent inhibitors of angiogenesis and inhibitors of the production of tumor necrosis factor-α.8, 9, 10, 11, 12, 13 Favorable (fluorophilic) and unfavorable (fluorophobic) environments within the target proteins have been determined. Such an approach was explored to develop inhibitors of serine and cysteine proteases.2, 3, 4, 5, 6, 14, 15 An example is the DPP-4 inhibitor sitagliptin, a recently approved antidiabetic, where a trifluorophenyl rest occupies the hydrophobic S1 pocket of the protease.16

Human leukocyte elastase (HLE) is a serine protease with a primary specificity for small aliphatic residues in P1 position of the substrate. The active enzyme is stored within cytoplasmic azurophilic granules for the remaining life of the neutrophils until extruded into phagolysosomes or out of the cell. HLE is capable of degrading a variety of proteins, including elastin, collagens, laminin, fibronectin, and cartilage proteoglycans as well as immunoglobulins and complement components. HLE can indirectly favor the breakdown of matrix proteins by proteolytic activation of matrix metalloproteinases. Under normal conditions, the activity of extracellular HLE is regulated by endogenous inhibitors, but an imbalance between HLE and its endogenous inhibitors may result in several pathological states. Thus, HLE is considered to be the primary source of tissue damage associated with such inflammatory diseases as pulmonary emphysema and adult respiratory distress syndrome.17, 18, 19, 20 Small-molecular weight HLE inhibitors could be therapeutically useful in the treatment of such diseases, and a number of inhibitors are currently in development.21, 22

Herein, we report on the synthesis of a series of new isothiazol-3(2H)-one 1,1-dioxides with halogenated (mostly fluorinated) aromatic substituents at 2-position. The final compounds were evaluated as inhibitors of HLE, and were additionally assessed against a panel of proteases and two serine esterases, acetylcholinesterase (AChE) and cholesterol esterase (CEase). Isothiazol-3(2H)-one 1,1-dioxides have already been reported as inhibitors of HLE. For example, saccharin derivatives with a leaving group within the 2-substituent have been designed as enzyme-activated inhibitors of HLE,23, 24, 25 and Hlasta et al. have designed specific saccharin-based inactivators of HLE showing excellent potency and blood stability.26, 27, 28

Section snippets

Chemistry

The new halopyridinyl-substituted isothiazolium salts 1015, the pentafluoro derivative 16, and the non-halogenated derivative 17 were easily accessible by cyclocondensation reactions of thiocyanates 1329, 30, 31 with the corresponding aromatic amines 49 (Scheme 1). In the second step, the halopyridinyl-isothiazol-3(2H)-one 1,1 dioxides 1823, the pentafluorophenyl compound 24, and 25 were prepared in moderate to good yields by oxidation of the salts 1017 with glacial acetic acid and

Results and discussion

Saccharin derivatives substituted at the N-2 atom can easily be obtained by N-alkylation with alkyl halides. In contrast, the reaction with alcohols under Mitsunobu conditions tended to favor O-alkylation, as recently found.36 N-Arylation of saccharin was successfully achieved with triphenylbismuth and cupric acetate in the presence of pyridine or triethylamine.37 2-Phenylsaccharin was also obtained by N-arylation with ortho-silylphenyl triflate in the presence of cesium fluoride.38 The

General methods and materials

Meting points were determined with a Boetius micro-melting point apparatus and are corrected. UV/vis spectra were recorded on a Beckman DU 650 spectrophotometer. Maximum wavelengths are noted in nanometer and log ε values are given in parentheses. IR spectra were measured on a Genesis FTIR Unicam Analytical System (ATI Mattson). 1H (200 or 300 MHz), 13C (50 or 75 MHz), and 19F (188 MHz) spectra were recorded on Varian Gemini-200 or Varian Gemini-300 spectrometers. Chemical shifts are given as δ

Acknowledgments

The authors are grateful to Stephanie Hautmann, Jing Zhou, and Gisela Kirsten for assistance. The work was supported by the Graduiertenkolleg 677 ‘Struktur und molekulare Interaktion als Basis der Arzneimittelwirkung’.

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