A series of 3,4-diaryloxazolones were prepared and evaluated for their ability to inhibit cyclooxygenase-2 (COX-2). Extensive structure-activity relationship work was carried out within this series, and a number of potent and selective COX-2 inhibitors were identified. The replacement of the methyl sulfone group on the 4-phenyl ring by a sulfonamide moiety resulted in compounds with superior in vivo antiinflammatory properties. In the sulfonamide series, the introduction of a methyl group at the 5-position of the oxazolone ring gave rise to very COX-2-selective compounds but with decreased in vivo activity. Selected 3,4-diaryloxazolones exhibited excellent activities in experimental models of arthritis and hyperalgesia. The in vivo activity of these compounds was confirmed with the evaluation of their antipyretic effectiveness and their ability to inhibit migration of proinflammatory cells. As expected from their COX-2 selectivity, most of the active compounds lacked gastrointestinal toxicity in vivo in rats after a 4-day treatment of 100 mg/kg/day. Within this novel series, sulfonamides 9-11 have been selected for further preclinical evaluation.

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A series of 2-phenylpyran-4-ones were prepared and evaluated for their ability to inhibit cyclooxygenase-2 (COX-2). Extensive structure-activity relationship work was carried out within this series, and a number of potent and selective COX-2 inhibitors were identified. Compounds having a p-methylsulfone group at the 2-phenyl ring showed the best COX-2 inhibitory activity. The introduction of a substituted phenoxy ring at position 3 enhanced both the in vitro and in vivo activity within the series. A selected group of 3-phenoxypyran-4-ones exhibited excellent activity in an experimental model of pyresis. The in vivo antiinflammatory activity of these compounds was confirmed with the evaluation of their antiarthritic and analgesic effectiveness. Moreover, their pharmacokinetic profile in rats is compatible with a once a day administration by oral route in humans. Within this novel series, compounds 21, 31, 34, and 35 have been selected for further preclinical and clinical evaluation.

In the field of brassinosteroids, which are potent plant growth regulators, we have developed a quantitative structure-activity relationship study to develop knowledge from a structural point of view and to find out new requirement definitions. This will help identify other suitable active brassinosteroid derivatives with a good activity/synthetic cost ratio for further application in agriculture. The methodology used to achieve this goal represents a multidisciplinary study involving synthesis, molecular modeling calculations, and bioactivity evaluation. The influence of different molecular properties in the bioactivity of a set of synthetic compounds (i.e., molecular electrostatic potential and the ability to form H bonds) is discussed. The molecular electrostatic potential is expressed in terms of the electrostatic Carbó similarity index (CI) between brassinolide (1) and other brassinosteroids. We have found that the electrostatic charges of the functional groups play an important role in the description of the activity, as evidenced by its good correlation with the CI in most cases. Deviation from this rule could be explained by the H bonding abilities of some of these compounds, which we believe may play an essential role in binding to the natural receptors.