Three-Dimensional Quantitative Structure−Activity Relationships of Cyclo-oxygenase-2 (COX-2) Inhibitors: A Comparative Molecular Field Analysis

Abstract

The three-dimensional quantitative structure-activity relationship (3D-QSAR) approach using comparative molecular field analysis (CoMFA) was applied to an extensive series of 305 varied diarylheterocyclic derivatives known as COX-2 selective inhibitors. X-ray crystal structure of COX-2 bound with SC-558, a selective COX-2 inhibitor, was used to derive the putative bioactive conformation of these inhibitors. Five statistically significant models were obtained from the randomly constituted training sets (229 compounds) and subsequently validated with the corresponding test sets (76 compounds). The best predictive model (n = 229, q(2) = 0.714, N = 8, r(2) = 0.905, s = 0.291, F = 261.545) was selected for further comparison of the CoMFA contour maps obtained for steric, electrostatic, and lipophilic fields with the enzyme structure. The high level of compatibility with the COX-2 enzyme topology shows the great accuracy of this model that can predict inhibitory activities for a wide range of compounds and offers important structural insight into designing novel antiinflammatory drugs prior to their synthesis.

Aromatic Schiff bases and 2,3-disubstituted-1,3-thiazolidin-4-one derivatives as antiinflammatory agents

“…The formation of azomethine 6 was very sluggish and was hastened by the addition of a small amount of zinc chloride as already suggested by C. G. and M. Macarovici 11 for the preparation of Schiff bases of sulfanilamide. 2,3-Disubstituted-1,3-thiazolidin-4-ones (8)(9)(10)(11)(12)(13)(14) were obtained by reacting the Schiff bases with α-mercaptoacetic acid in boiling benzene and removing the formed water by means of a Dean-Stark trap. The yields of thiazolidinone derivatives were improved if aldehydes and amines were directly condensed in refluxing benzene solution, followed by addition of α -mercaptoacetic acid and continuing the heating until reaction completion, avoiding the isolation of the Schiff bases (Scheme 1).…”

“…It is worth noting that in a collateral, ongoing research, aimed to discover novel structures endowed with platelet antiaggregating activity, it was observed that three thiazolidinone derivatives (8)(9)(10) at 30 µM concentration failed to inhibit the rabbit platelet aggregation induced by 100 µM arachidonic acid and, therefore, to inhibit the COX-1.…”

“…Suitably substituted cis-stilbene derivatives are characterized by potent inhibitory activity on COX-2, quite similarly with what is observed for a variety of vicinal diarylheterocycles, among which important antiinflammatory drugs, like celecoxib, rofecoxib and valdecoxib, are found. 8 In the last class of drugs the central five membered ring, may be of very different nature, either heterocyclic or carbocyclic, [8][9][10] while the nature of substituents on the two benzene rings is believed to be responsible for COX-2 selectivity by insertion into the secondary pocket of the enzyme, with the p-sulfonamido and p-methylsulfonyl groups playing a key role. Accordingly in order to improve the previously observed antiinflammatory activity we have now prepared some additional Schiff bases (4-7) bearing these peculiar substituents; moreover, through the reaction with α-mercaptoacetic acid, the Schiff bases 1-7 were converted into 2,3-diaryl-1,3-thiazolidin-4-one derivatives, imposing a cis conformation to the aromatic rings so that the molecules resemble very closely the mentioned antiinflammatory agents.…”

2,2″‐Dimethoxy‐1,1′:3′,1″‐terphenyl as a novel protective group for low‐coordinated phosphorus compounds: The case of diphosphenes

“…The so-called "upup" and "up-down" conformers differ by the position of alkoxy groups relative to each other and relative to the aromatic side rings. There are a few calculations describing conformers of terphenyls, resulting from the rotation of aromatic side rings around the central ring [10][11][12]. The methoxy groups that mainly cause the increase in the energy barrier toward coplanar conformation [10].…”

Synthesis, characterization, antimicrobial activity and molecular docking studies of combined pyrazol-barbituric acid pharmacophores

“…Besides providing great biological properties, the nitrogen atoms are able to act as donors and find applications in the construction of supramolecular blocks. In this context, Pyrazole derivatives are of particular interest because of their pharmacological profile [8][9][10] such as cyclooxygenase 2 inhibitors (e.g., celecoxib, SC-558, and tepoxalin) (e.g., Fig 1) [11,12] and reduction in obesity for example cannabinoid-1 inverse agonists (e.g., rimonabant) [13].…”