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Thromboxane A2 (TxA2), a bioactive metabolite of the Arachidonic acid (AA), is a potent mediator of platelet aggregation, vasoconstriction and bronchoconstriction. It plays an important role in major human diseases, such as myocardial infraction, unstable angina, pregnancy-induced hypertension and preeclampsia, thrombosis and thrombotic disorders, pulmonary hypertension, asthma, septic shock, atherosclerosis, lupus nephritis, and Raynauds phenomenon. Thus, TxA2 is a therapeutic target for many research groups. A number of TXA(2) receptor antagonists as well as thromboxane synthase inhibitors have been developed. In this research we review and evaluate new quantitative structure activity relationships of thromboxane synthase inhibitors and thromboxane receptor antagonists, using the C-QSAR program of Biobyte. Lipophicity, as Clog P is a significant physicochemical parameter for this biological response. CMR/MR molar refractivity as well as sterimol parameters seemed to be important as well Molecular Volume. Electronic effects with the exception of σ Hammetts constant are not found to govern the biological activity. The derived equations will be very helpful for the design of new potent molecules.

Chalcones are a group of phenolic compounds which possess a wide variety of cytoprotective and modulatory functions. They have been shown to possess antioxidant, oxygen scavenging and anti-inflammatory properties in a variety of experimental systems and can trigger the intracellular cascade of protective pathways offering a promising stratagem for therapeutic applications. In this research we will review the anti-inflammatory effect of chalcone derivatives and new approaches.

Inflammation is the primary host defense mechanism against all forms of injury. Excessive or inadequate activation of the system can have serious effects, as can the failure of inactivation mechanisms. Coumarins can reduce tissue edema and inflammation and inhibit prostaglandin biosynthesis, which involves fatty acid hydroperoxy intermediates. It is to be expected that coumarins might affect the formation and scavenging of reactive substances derived from oxygen species (ROS) and influence processes involving free radical-mediated injury, as can flavonoids. During these years a small number of (Q)SAR studies concerning coumarins as NSAIDs has been presented and reviewed. In this research we tried to examine the structure-function relationship for coumarins, presenting antiinflammatory activity. Coumarin (1), the prototypical compound presents anti-inflammatory activity. The hydroxylaromatic substituted derivatives (5- or 6- or 7-hydroxy or the vicinal dihydroxy) seems to be potent inhibitors of lipoxygenase. Several synthetic derivatives simple or more complicated were found to be potent antiinflammatories/antioxidant agents.

The synthesis of several coumarin Mannich bases is described. The structures of the synthesized compounds were confirmed by spectral and elemental analysis. Their lipophilicity was determined experimentally by RPTLC method. All compounds were evaluated for their antiinflammatory and antioxidant activity and for their ability to inhibit in vitro lipoxygenase. The derivatives were found to present antioxidant and antiinflammatory activities. The tested derivatives inhibited carraggeenin-induced hind paw edema. They also significantly suppressed the arthritis induced by Freund's adjuvant. Compound 10, the most active in vivo, was found to possess protective properties against adjuvant-induced arthritis in rats. The biological in vitro activities were concentration dependent. Hydrophilicity, the presence of a free 7-OH, and steric requirements for the substituent at position 8 are the most important factors in terms of SAR. An attempt was made to correlate several physicochemical properties of the molecules with their in vivo/in vitro activity.

The matrix metalloproteinases (MMPs) are a family of more than 20 enzymes that are intimately involved in tissue remodelling. These zinc-containing endopeptidases consist of several subsets of enzymes, including collagenase, stromelysins and gelatinases and are involved in the degradation of the extracellullar matrix (ECM) that forms the connective material between cells and around tissues. Disease processes associated with the MMPs are generally related to imbalance between the inhibition and activation of MMPs resulting in excessive degradation of the ECM. These indications include osteoarthritis rheumatoid arthritis, tumour metastasis and congestive heart failure. Inhibitors for these enzymes have been developed for the treatment of a starthingly wide array of disease process where matrix remodelling plays a key role. There are three major components to most MMP inhibitorsthe zinc binding group ZBG, the peptidic backbone and the pocket occupying side chain. Most MMPs inhibitors are classified according to their ZBG. Inhibitors interactions at active-site zinc plays a critical role in defining the binding mode and relative inhibitor potency. The majority of MMP inhibitors reported in the literature contain an effective zinc binding group (e.g. hydroxamic acid, carboxylic acid, sulfhydryl group) that is either generally substituted with a peptide-like structure that mimics the substrates that they cleave or appended to smaller side chains that may interact with specific subsites (e.g., P1, P2, P3) within the active site. Although carboxylates exhibit weaker zinc binding properties than hydroxamates, they are known to show better oral bioavailability and are less prone to metabolic degradation. The expected loss of binding affinity after replacement of hydroxamates against carboxylates is faced by adequate choice of elongated S1 directed substituents. The need for novel selective MMP inhibitors makes them an attractive target for the QSAR and molecular modelling. 3-D QSAR models were derived using CoMFA, CoMSIA and GRID approaches leading to the identification of binding regions where steric, electronic or hydrophobic effects are important for affinity. Some structural requirements essential for achieving high binding affinity and selectivity are: an acidic unit tightly anchored through four contact points, bidentate chelation of Zn2, carbonyl groups for hydrogen bonding, more than two extra units for hydrogen bonds, a hydrophobic moiety.

Following a Claisen—Schmidt condensation between piperidine hydrochloride monohydrate (I) and aryl aldehydes (II) or an aldol condensation between (I) and aryl aldehydes (VI) gives rise to formation of curcumin analogues (III) and (VII).