2-Arylidene-1-indandiones as Pleiotropic Agents with Antioxidant and Inhibitory Enzymes Activities

Abstract

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.

Pyrazoles and Pyrazolines as Anti-Inflammatory Agents

“…The novel derivatives were studied for their interaction with the stable 2,2-diphenyl-1-picrylhydrazyl free radical (DPPH) at concentrations 50 µM, 100 µM, 200 µM and after 20 and 60 min ( Table 3 ) [ 42 ]. This assay is based on the reduction of the DPPH by transferring an electron from the antioxidant.…”

“…Closed chromatography tanks saturated with the mobile phase at 24 °C were used for the development of the plates while the spots were detected under UV light. For the determination of R M values, five individual measurements of R f values were recorded, and the R M values were derived from the equation R M = log [(1/R f ) − 1] [ 42 , 43 ] ( Table 2 ).…”

“…A stock solution (10 mM) of the novel derivatives in DMSO was prepared and an equal volume of it was added to a solution of DPPH in absolute ethanol to reach final concentrations 50, 100 µM and 200 µM. The absorbance was recorded at 517 nm, after 20 and 60 min at room temperature ( Table 3 ) [ 42 , 43 ].…”

“…The stock solutions of the compounds were incubated with sodium linoleate (0.1 mM) and 0.2 mL of soybean lipoxygenase solution (1/9 × 10 −4 w / v in saline) at room temperature. In vitro test was performed as previously published [ 42 , 43 , 44 ]. The test follows our previously published methods [ 42 , 43 , 44 ] The production of 13-hydroperoxylinoleic acid was recorded at 234 nm using using NDGA as reference compound ( Table 3 , Table 5 ).…”

5-(4H)-Oxazolones and Their Benzamides as Potential Bioactive Small Molecules

“…Then, 200 µL of albumin (6 mg in 3 mL of distilled water) was added and incubated again at 37 °C for 24 h. After the incubation 1 mL trichloroacetic acid (5% w / w ) was added to terminate the reaction. The mixture is centrifugated, the water layer is collected and monitored at 280 nm [ 61 ].…”