Design, Synthesis, and Pharmacological Evaluation of Pyridinic Analogues of Nimesulide as Cyclooxygenase-2 Selective Inhibitors

Abstract

In this study, we report the synthesis and pharmacological evaluation of original pyridinic sulfonamides related to nimesulide, a cyclooxygenase-2 (COX-2) preferential inhibitor widely used as an anti-inflammatory agent. These original pyridinic derivatives were synthesized in three steps starting from the condensation of 3-bromo-4-nitropyridine N-oxide with appropriately substituted phenols, thiophenols, or anilines followed by a reduction of the nitro moiety into the corresponding aminopyridine, which was finally condensed with alkane- or trifluoromethanesulfonyl chloride to obtain the corresponding sulfonamides. The pK(a) determinations demonstrated that the major ionic form present in solution at physiological pH depends on the nature of the sulfonamide moiety subsituent. Indeed, alkanesulfonamides were mainly present as zwitterionic molecules while trifluoromethanesulfonamides, more acidic derivatives, were mainly present as anionic molecules. The in vitro pharmacological evaluation of the synthesized compounds against COX-1 and COX-2 was performed in a human whole blood model. Results obtained demonstrated that most of alkanesulfonamide derivatives displayed a COX-2 preferential inhibition with selectivity ratio values (IC(50)(COX-1)/IC(50)(COX-2)) up to 7.92 (celecoxib displaying a ratio value of 7.46 in the same test). On the other hand, trifluoromethanesulfonamide derivatives displayed weaker selectivity ratios although they exhibited IC(50) values against COX-2 up to 0.09 microM (celecoxib IC(50) against COX-2: 0.35 microM). Finally, in vivo evaluation of selected compounds showed that they exhibited anti-inflammatory properties similar to that of nimesulide when tested in a carrageenan-induced rat paw oedema model.

Crystal structure and electronic properties of two nimesulide derivatives: A combined X-ray powder diffraction and quantum mechanical study

“…In addition to good anti-inflammatory, analgesic, anti-pyretic activities and low gastrointestinal toxicity, 1 is also useful in a wide range of disorders, which include various arthritic conditions, gynaecological and urological problems, post-surgical and cancer pain, and vascular diseases [3]. Several analogues of nimesulide (1) aimed at enhancing the antiinflammatory activity and reducing its toxicity have been reported by changing in 1 the R-group of the -NHSO 2 R moiety, the electron withdrawing group at the C-4 position and the central aryl ring by a pyridine or pyridinium moiety [4][5][6]. The X-ray structure analyses and molecular dynamics simulations of COX-2 complexes with nimesulide analogues indicate a network of hydrogen bonds in the COX-2 active site involving the nitrogen and oxygen atoms of the inhibitor molecule [7,8].…”

Chemical modifications of nimesulide

“…nitro by carboxy, ethoxycarbonyl, aminocarbonyl, cyano, aminosulfonyl or trifluoromethyl group and (iv) the central aryl ring by pyridine and pyridinium moiety. [14][15][16] All the members of this class of COX-2 inhibitors can be represented by a general structure 8 as shown in the Figure 1.…”

“…We therefore, became interested in attaching the EWG one atom away from the C-4 position and to study its subsequent effect on COX inhibition. Additionally, while the replacement of methyl group of NHSO 2 CH 3 of nimesulide by a trifluoromethyl (CF 3 ) moiety has been reported, 16 the role of acidic NH of methane sulfonamide moiety on anti-inflammatory activities, however, has not been studied extensively. Considering all these aspects and in continuation of our research on the development of novel anti-inflammatory agents we have prepared a number of chemically modified derivatives of nimesulide some of which showed interesting COX inhibiting properties.…”

Quantitative structure-activity relationship studies of cyclooxygenase inhibitors: a comprehensive analysis

“…The negative contribution of p para and sr shows that less hydrophobic and electron-donating para substituents at 2-phenyl ring (R1) play a crucial role in governing COX-2 inhibitory activity. Julemont et al [2004] reported a new series of pyridinic analogs of nimesulide (III) as selective COX-2 inhibitors. All the compounds together with the converted biological activity, pIC 50(COX-2) used for the analysis are given in Table 3 QSAR model 6 is a bi-parametric regression equation developed for COX-2 inhibitory activity.…”