Design, Synthesis, and Biological Evaluation of 6-Substituted-3-(4-methanesulfonylphenyl)-4-phenylpyran-2-ones:  A Novel Class of Diarylheterocyclic Selective Cyclooxygenase-2 Inhibitors

Abstract

A group of 6-alkyl (alkoxy or alkylthio)-4-aryl-3-(4-methanesulfonylphenyl)pyran-2-ones (14a-v), possessing either a H or F substituent at the para-position of the C-4 phenyl ring, were designed for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors with in vivo antiinflammatory-analgesic activities. Although 6-ethylthio-3-(4-methanesulfonylphenyl)-4-phenylpyran-2-one (14s) exhibited a very high in vitro COX-2 inhibitory potency (IC(50) = 0.0032 muM) and COX-2 selectivity (SI > 120 000), 14s exhibited moderate antiinflammatory activity compared to celecoxib in a carrageenan-induced rat paw edema assay. In contrast, the less potent (IC(50) = 0.10 muM), and less selective (SI = 2880) COX-2 inhibitor 6-ethoxy-3-(4-methanesulfonylphenyl)-4-phenylpyran-2-one (14i) exhibited good antiinflammatory activity where a 1 mg/kg oral dose reduced inflammation 32 and 67% at 3 and 5 h postdrug administration relative to the reference drug celecoxib where a 50 mg/kg oral dose reduced inflammation by 79 and 58% at the respective 3 and 5 h time periods. Molecular modeling studies, where 14i was docked in the active site of both COX-1 and COX-2, reveals that the C-6 ethoxy substituent orients the pyran-2-one ring to position the SO(2)Me pharmacophore in the vicinity of the secondary pocket in COX-2. The absence of this COX-2 secondary pocket in the COX-1 binding site is due to the presence of the bulky Ile(523) in COX-1 such that access to the amino acid residues (Ile(517), Phe(518), Gln(192), and His(90)), which line the COX-2 secondary pocket with which the SO(2)Me pharmacophore could interact, is hindered. The six-membered pyran-2-one ring system is a suitable central template to design selective COX-2 inhibitors.

Biosynthesis of α-pyrones

“…Several derivatives of 6-alkyl (alkoxy or alkylthio)-4-aryl-3-(4-methanesulfonylphenyl)pyrones 49 had been synthesized to get insights into structure activity relationships, whereby 6-methyl-3-(4-methanesulfonylphenyl)-4-phenylpyran-2-one ( 50 ) showed the best combination of inhibitory concentration and selectivity (IC 50 = 0.68 µM, SI = 904; Fig. 11 ) [ 56 ].…”

A novel and widespread class of ketosynthase is responsible for the head-to-head condensation of two acyl moieties in bacterial pyrone biosynthesis

“…Chemical compounds containing an α-pyrone moiety are widespread in nature [ 1 – 2 ] and show a high diversity in their biological activity. Members of this class of compounds have been identified with antimicrobial, cytotoxic [ 3 ] and antitumor activities [ 4 ], as HIV protease inhibitors [ 5 ] and selective COX-2 inhibitors [ 6 ]. Recently, it was shown that photopyrones ( Fig.…”

Design, Synthesis, and Biological Evaluation of Some Novel Pyrrolizine Derivatives as COX Inhibitors with Anti-Inflammatory/Analgesic Activities and Low Ulcerogenic Liability

“…Both COX-1 and COX-2 inhibitory activities were evaluated using a COX colorimetric inhibitor screening assay kit (Catalog No. 701050, Cayman Chemical Inc., Ann Arbor, MI, USA) according to the previous reports [26][27][28]. The pyrrolizines 12-18 were tested against indomethacin (as a nonselective COX inhibitor) and celecoxib (as a selective COX-2 inhibitor).…”

“…701050). The assay was carried out according to the manufacturer's instructions and as described before [26][27][28].…”