2-Arylidene-1-indandiones as Pleiotropic Agents with Antioxidant and Inhibitory Enzymes Activities.
Indandiones are a relatively new group of compounds presenting a wide range of biological activities. The synthesis of these compounds was performed via a Knoevenagel reaction between an aldehyde and 1,3-indandione and were obtained with a yield up to 54%. IR, 1H-Nucleic Magnetic Resonance (NMR), 13C-NMR, LC/MS ESI+ and elemental analysis were used for the confirmation of the structures of the novel derivatives. Lipophilicity values of compounds were calculated theoretically and experimentally by reversed chromatography method as values RM. The novel derivatives were studied through in vitro and in vivo experiments for their activity as anti-inflammatory and antioxidant agents and as inhibitors of lipoxygenase, trypsin, and thrombin. The inhibition of the carrageenin-induced paw edema (CPE) was also determined for representative structures. In the above series of experiments, we find that all the compounds showed moderate to satisfying interaction with the stable DPPH free radical in relation to the concentration and the time 2-arylidene-1-indandione (10) was the strongest. We observed moderate or very low antioxidant activities for selected compounds in the decolorization assay with ABTS+•. Most of the compounds showed high anti-lipid peroxidation of linoleic acid induced by AAPH.2-arylidene-1-indandione (7) showed a strongly inhibited soybean LOX. Only 2-arylidene-1-indandione (3) showed moderate scavenging activity of superoxide anion, whereas 2-arylidene-1-indandione (8) and 2-arylidene-1-indandione (9) showed very strong inhibition on proteolysis. 2-arylidene-1-indandione (8) highly inhibited serine protease thrombin. 2-arylidene-1-indandiones (7, 8 and 9) can be used as lead multifunctional molecules. The compounds were active for the inhibition of the CPE (30-57%) with 2-arylidene-1-indandione (1) being the most potent (57%). According to the predicted results a great number of the derivatives can cross the Blood-Brain Barrier (BBB), act in CNS and easily transported, diffused, and absorbed. Efforts are conducted a) to correlate quantitatively the in vitro/in vivo results with the most important physicochemical properties of the structural components of the molecules and b) to clarify the correlation of actions among them to propose a possible mechanism of action. Hydration energy as EHYDR and highest occupied molecular orbital (HOMO) better describe their antioxidant profile whereas the lipophilicity as RM values governs the in vivo anti-inflammatory activity. Docking studies are performed and showed that soybean LOX oxidation was prevented by blocking into the hydrophobic domain the substrates to the active site.
['Kouzi|Olympia|O|', 'Pontiki|Eleni|E|', 'Hadjipavlou-Litina|Dimitra|D|0000-0002-1844-350X']
D000818:Animals D000893:Anti-Inflammatory Agents D000975:Antioxidants D001812:Blood-Brain Barrier D002351:Carrageenan D004487:Edema D005260:Female D007189:Indans D015227:Lipid Peroxidation D008297:Male D008958:Models, Molecular D062105:Molecular Docking Simulation D010940:Plant Proteins D008249:Protein-Lysine 6-Oxidase D051381:Rats D013025:Soybeans
antioxidants 2-arylidene-1,3-indandiones Lipinski “Rule of five” lipoxygenase inhibitors