Synthesis and biological evaluation of substituted 2-sulfonyl-phenyl-3-phenyl-indoles: a new series of selective COX-2 inhibitors

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Abstract

A new series of substituted 2-sulfonyphenyl-3-phenyl-indole derivatives were synthesized and evaluated for their ability to inhibit COX-2 and COX-1enzymes. Most of the compounds synthesized were found to be highly potent and selective inhibitors of COX-2. This work led to the discovery of 2-aminosulfonylphenyl-3-phenyl-indole 5a which possesses higher activity and selectivity for COX-2 than Celecoxib both in vitro and in vivo.

Introduction

Nonsteroidal anti-inflammatory drugs (NSAIDs) remain among the most widely prescribed drugs worldwide for the treatment of inflammation that can cause pain and fever among other symptoms. The mechanism of action is through their inhibition of prostaglandin biosynthesis via the enzyme cyclooxygenase-2 (COX-2).1 COX-2 and COX-1 are two similar but distinct isoforms of cyclooxygenase (COX).2, 3, 4, 5 COX-2 is induced in response to inflammatory stimuli and is responsible for the progression of inflammation, whereas COX-1 is a constitutively expressed isoform and is responsible for the maintenance of physiological homestasis, such as gastrointestinal integrity and renal function. Thus selective inhibition of COX-2 over COX-1 is useful for the treatment of inflammation and inflammation-associated disorders with reduced gastrointestinal toxicities when compared with the traditional NSAIDs.

Current research has focused on developing safer NSAIDs—selective COX-2 inhibitors. Several selective COX-2 inhibitors such as Celecoxib,6 Rofecoxib7, 8 and Valdecoxib9 have been marketed as a new generation of NSAIDs. These compounds all have the diarylheterocyclic structural features.10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32 The other two categories of selective COX-2 inhibitors33, 34 are sulfonanilide inhibitors,35, 36, 37 and modifications of classical NSAIDs,38, 39, 40, 41 The pharmacophore of diarylheterocycles inhibitors is characterized by a central carbocyclic or heterocyclic ring system bearing two vicinal aryl moieties and one benzene ring being substituted with methylsulfonyl or aminosulfonyl group at the para position. The major difference in the compounds of this class is the structure of the central ring. Thus, alteration in the central ring will lead to new COX-2 inhibitors. Indole ring constitutes an important template for drug design such as the classical NSAIDs indomethacin and indoxole.42 We herein developed a new series of COX-2 inhibitors of diarylheterocycles using indole as the central ring (I).

Section snippets

Chemistry

All the compounds (I) described here (except compounds Scheme 3, fx2 and Scheme 3, fx2) were synthesized by using the general routes outlined in Scheme 1, Scheme 2. The key step of the routes is to construct an indole skeleton by McMurry coupling reaction. Aromatic acylamido-substituted benzophenones can be cyclized to indole derivatives upon the treatment with the low-valent titanium reagents.43, 44, 45 In this paper the coupling reagent ‘low-valent’ Ti was prepared in situ from TiCl4 and Zn

Results and discussion

We have synthesized three series of the indole analogues (Table 1) with: different substitutents (R2) at the para-position of the 3-phenyl ring such as hydrogen, halogen, methoxy, methyl and others (fx2, Scheme 3); chloro group at different position of the 3-phenyl ring (9a9f) and various substitutent (R3) at 5-position of the indole ring (9g9n). All the compounds except for Scheme 3, fx2 and Scheme 3, fx2 were prepared as both the methyl sulfones and the corresponding sulfonamides.

The

Conclusions

The series of substituted 2-sulfonylphenyl-3-phenyl-indole described in this paper were proved to be potent and highly selective inhibitors of COX-2. The indole ring was proved to be an effective central ring that derives a new diarylheterocycle class of COX-2 inhibitors. The structure–activity relationship of the series of inhibitors was analyzed and the acetylation of sulfonamide compound still retained the activity against COX-2. This work led to the discovery of compound Scheme 3, fx2

1. In vitro test of inhibitory activity for cyclooxygenase-1 and cyclooxygenase-2. Cell culture

Adherent macrophages were harvested from the peritoneal cells of male mice (C57BL-6J, Level 2, from the Experiment Animal Center, Academy of Military Medical Science) after the injection (ip) of brewer thioglycollate medium (5 mL/100 g body weight) for 3 days. Shortly, peritoneal cells obtained from 3–4 mice were mixed and seeded in 48 well cell culture cluster (Costar) at a cell density of 1×109 cell/L in RPMI-1640 supplemented with 5% (v/v) newborn calf serum, 100 ku/L penicillin and 100 g/L

Chemistry

All solvents were dried and freshly distilled. Melting points were determined using Yanaco melting point apparatus and are uncorrected. 1HNMR were recorded on a Bruker AM-300 (300 MHz) spectrometer. Elemental analyses were performed at analytical division of Institute of Material Medica and were within 0.4% of the calculated values.

Acknowledgements

This project was supported by the National Natural Science Foundation of China (No. 20072057). We thank the analytical division of Institute of Material Medica for the spectroscopic data and elementary analyses.

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