Enhancement of the Anti-Inflammatory Activity of NSAIDs by Their Conjugation with 3,4,5-Trimethoxybenzyl Alcohol.

The synthesis of derivatives of three nonspecific COX-1 and COX-2 inhibitors, ibuprofen, ketoprofen, naproxen is presented. These acids were connected via an amide bond with an amino acid (L-proline, L-tyrosine, and beta-alanine) used as a linker. The amino acid carboxylic group was esterified with 3,4,5 trimethoxybenzyl alcohol. The activity of the novel derivatives was examined in vivo on carrageenan-induced inflammation, and in vitro, as cyclooxygenase and lipoxygenase inhibitors. It was found that the new compounds were more potent anti-inflammatory agents than the parent drugs. Thus, the ibuprofen (21) and ketoprofen (16) derivatives reduced rat paw edema by 67 and 91% (the reduction by the relevant NSAIDs was 36 and 47%, respectively). They inhibited COX-2 more than the starting drugs (21 by 67%, ibuprofen 46%, 19 by 94%, ketoprofen 49%). Docking of compounds on the active sites of COX-1 and COX-2 reflects their in vitro activity. Thus, 19 adopts an unfavorable orientation for COX-1 inhibition, but it binds effectively in the binding pocket of COX-2, in agreement with the absence of activity for COX-1 and the high inhibition of COX-2. In conclusion, the performed structural modifications result in the enhancement of the anti-inflammatory activity, compared with the parent NSAIDs.

Lipoic acid. Kinetics and pluripotent biological properties and derivatives.

Lipoic acid (LA) is globally known and its supplements are widely used. Despite its importance for the organism it is not considered a vitamin any more. The multiple metabolic forms and the differences in kinetics (absorption, distribution and excretion), as well as the actions of its enantiomers are analysed in the present article together with its biosynthetic path. The proteins involved in the transfer, biotransformation and activity of LA are mentioned. Furthermore, the safety and the toxicological profile of the compound are commented, together with its stability issues. Mechanisms of lipoic acid intervention in the human body are analysed considering the antioxidant and non-antioxidant characteristics of the compound. The chelating properties, the regenerative ability of other antioxidants, the co-enzyme activity and the signal transduction by the implication in various pathways will be discussed in order to be elucidated the pleiotropic effects of LA. Finally, lipoic acid integrating analogues are mentioned under the scope of the multiple pharmacological actions they acquire towards degenerative conditions.

Antioxidant Serine-(NSAID) Hybrids with Anti-Inflammatory and Hypolipidemic Potency.

A series of L-serine amides of antioxidant acids, such as Trolox, (E)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)acrylic acid (phenolic derivative of cinnamic acid) and 3,5-di-tert-butyl-4-hydroxybenzoic acid (structurally similar to butylated hydroxytoluene), was synthesized. The hydroxy group of serine was esterified with two classical NSAIDs, ibuprofen and ketoprofen. The Trolox derivatives with ibuprofen (7) and ketoprofen (10) were the most potent inhibitors of lipid peroxidation (IC50 3.4 µΜ and 2.8 µΜ), several times more potent than the reference Trolox (IC50 25 µΜ). Most of the compounds decreased carrageenan-induced rat paw edema (37-67% at 150 µmol/kg). They were moderate inhibitors of soybean lipoxygenase, with the exception of ibuprofen derivative 8 (IC50 13 µΜ). The most active anti-inflammatory compounds exhibited a significant decrease in lipidemic indices in the plasma of Triton-induced hyperlipidemic rats, e.g., the most active compound 9 decreased triglycerides, total cholesterol and low-density lipoprotein cholesterol by 52%, 61% and 70%, respectively, at 150 µmol/kg (i.p.), similar to that of simvastatin, a well-known hypocholesterolemic drug. Since the designed compounds seem to exhibit multiple pharmacological actions, they may be of use for the development of agents against inflammatory and degenerative conditions.

Medicinal Chemistry Approaches of Controlling Gastrointestinal Side Effects of Non-Steroidal Anti-Inflammatory Drugs. Endogenous Protective Mechanisms and Drug Design.

BACKGROUND: Non-steroidal anti-inflammatory drugs are the oldest and most widely used medicines. However, their untoward effects, especially gastrointestinal toxicity, remain the main obstacle to their application. Because of their mechanism of action, cycloxygenase (COX) inhibition, in combination with the weekly acidic character of most of them, major protective mechanisms of the gastrointestinal system are suppressed and deregulated. OBJECTIVE: In this review, several compounds designed to retain anti-inflammatory activity, but devoid of gastrointestinal side effects, are presented. Thus, gastro-protective drugs, selective COX-2 inhibitors, nitric monoxide- and hydrogen sulphide-releasing agents, prodrugs, lipoxygenase (LOX) inhibitors and dual COX/LOX inhibitors are presented. Their mechanism of action, as well as their advantages and disadvantages are discussed. CONCLUSION: Efforts, aiming to the development of safe non-steroidal anti-inflammatory agents, are evolving, however there are still several problems concerning gastro-protection to be efficiently solved, thus, design of effective and safe agents for the treatment of inflammatory conditions still remains a major challenge.

Esters of some non-steroidal anti-inflammatory drugs with cinnamyl alcohol are potent lipoxygenase inhibitors with enhanced anti-inflammatory activity.

Novel esters of non steroidal anti-inflammatory drugs, α-lipoic acid and indol-3-acetic acid with cinnamyl alcohol were synthesised by a straightforward method and at high yields (60-98%). They reduced acute inflammation more than the parent acids and are potent inhibitors of soybean lipoxygenase. Selected structures decreased plasma lipidemic indices in Triton-induced hyperlipidemia to rats. Therefore, the synthesised compounds may add to the current knowledge about agents acting against various inflammatory disorders.