Hemisynthesis of monoterpene-containing pyridin-2-one, pyrano[2,3-c]pyrazole and dicarbamate derivatives: in vitro and in silico anti-inflammatory activity

Abstract

• The essential oils of four medicinal plants cultivated in Algeria were used as raw materials to hemisynthesize monoterpene-containing pyridin-2-one, pyrano[2,3- c ]pyrazole and dicarbamate derivatives. • ( S )-Perillaldehyde is the major component of the A. leucotrichus essential oil and was used as a chiral pool to produce an enantiopure perillic-containing pyridin-2-one. • Pyridin-2-one derived from citronellal (major component of the E. citriodora essential oil) was produced as a racemate. • The structures of all newly hemisynthesized compounds were unveiled using 1D and 2D NMR techniques as well as single crystal X-ray diffraction and chiral HPLC, where applicable. • Dicarbamate bearing a eugenol moiety was the most active compound in preventing protein denaturation, followed by citronellal-based pyridin-2-one, being both more potent than diclofenac (positive control). New monoterpene-containing pyridin-2-one, pyrano[2,3- c ]pyrazole and dicarbamate derivatives were hemisynthetized from the essential oils of four medicinal plants cultivated in Algeria. Perillaldehyde and citronellal are the major constituents of Ammodaucus leucotrichus and Eucalyptus citriodora essential oils, respectively, and were used as starting materials in multicomponent reactions to produce highly functionalized pyridin-2-ones in fair yields (56–67%). A. leucotrichus essential oil was also used as starting material for the synthesis of a pyrano[2,3- c ]pyrazole bearing a perillic moiety, which was obtained as an inseparable mixture of two diastereomers in good yield (73%). Moreover, eugenol- and carvacrol-containing Syzygium aromaticum and Thymus vulgaris essential oils, respectively, were used as starting materials to synthesize symmetrical dicarbamate derivatives through their reaction with hexamethylene diisocyanate in fair to very good yields (54–88%). Chiral pool synthesis was used to produce the enantiopure perillic-containing pyridin-2-one. On the other hand, pyridin-2-one prepared from citronellal was obtained as a racemate. Finally, the anti-inflammatory activity of the hemisynthetized compounds was evaluated using two different in vitro assays, namely the inhibition of egg albumin denaturation and human red blood cell membrane stabilization. Eugenol-derived dicarbamate was the most active compound in preventing protein denaturation, followed by citronellal-based pyridin-2-one, both being more potent than diclofenac used as positive control. Molecular docking studies performed on cyclooxygenases and the nuclear factor NF-κB provided preliminary insights about the binding interactions of the hemisynthesized compounds with the refereed enzymes, showing their anti-inflammatory potential.