Synthesis and biological evaluation of boswellic acid-NSAID hybrid molecules as anti-inflammatory and anti-arthritic agents

Hybrid Compounds Strategy in the Synthesis of Oleanolic Acid Skeleton-NSAID Derivatives

“…Our research examined the reactivity of oleanolic acid (1), oleanolic acid methyl ester (2), and their corresponding oxime derivatives (5,6) in the creation of new dual compounds. In order to obtain the starting reactants, the carboxylic group (C-28) of oleanolic acid (1) was converted into the methyl ester group (2) by use of dimethyl sulfate in an ethanolic solution of sodium hydroxide as a methylation agent [15].…”

“…Racemic compounds, such as ibuprofen (7), aspirin (8), naproxen (9), and ketoprofen (10) were applied as non-steroidal anti-inflammatory particles ( Figure 2). Inspired by the latest literature reports [4][5][6] as a key modulator of the activity of other biologically-active compounds (NSAIDs), we decided to use the broadly advantageous structure of naturally-occurring 3β-hydroxyolean-12-en-28-oic acid, commonly known as oleanolic acid (1). From a chemical point of view, it belongs to pentacyclic triterpene from the β-amyrine group with five six-membered cycles in the molecule, which offers great powers both as a bioactive molecule and as a carrier for other external activities.…”

“…The secondary hydroxyl group at the C-3 position of the oleanolic acid skeleton was reacted in the oxidation process with chromic anhydride in sulfuric acid (Jones reagent) to give 3-oxooleanolic derivatives (3,4) [16]. The carbonyl derivatives formed at the C-3 position were reacted with hydroxylamine hydrochloride in the presence of sodium acetate and converted to corresponding oximes (5,6) [17] (Scheme 1).…”

“…These move in two chemical directions (Scheme 2). Compounds 1 and 2 reacted by the esterification method lead to the formation of ester-type hybrid derivatives (11)(12)(13)(14)(15)(16)(17)(18), while the corresponding terpene oximes (5,6) give an ester of oximes called as iminoester-type hybrid derivatives (19)(20)(21)(22)(23)(24)(25)(26).…”

“…DCC is carboxylic acid activating and coupling agent, while strongly-nucleophilic DMAP acts as an acyl transfer reagent in the Steglich esterification reaction [5,6] which is a very useful process in the conversion of sterically-demanding substrates. The water resulting from a DCC mediated reaction reacts immediately with the carboimide applied and forms dicyclohexylurea (DHU), which is insoluble in a reaction medium and precipitates as a white solid.…”