Microwave Assisted Synthesis of Antioxidant Dihydro-Pyrazole Hybrids as Possible Lipoxygenase Inhibitors

Free radicals and inflammation have pivotal role in various degenerative diseases like cancer, rheumatoid arthritis, diabetes, cardiovascular and neurodegenerative disorders. Pyrazoles possess a wide range of biological activities such as antifungal, antituberculosis, antimicrobial, antiviral, anti-inflammatory, anti-convulsant, anticancer etc. In this present study a series of dibenzalacetones and the corresponding pyrazole hybrids were designed through bioisosterism, synthesized and biologically evaluated to highlight the importance of the extended conjugated system and substitution to the anti-inflammatory and antioxidant activity. The synthesis of dibenzalacetones was achieved via Claisen-Schmidt reaction. The dihydro-pyrazoles were synthesized from the substituted dibenzacetones and phenylhydrazines, hydrazine and semicarbazide under microwave irradiation optimizing reaction conditions. The synthesized compounds were spectroscopically characterized and evaluated for their anti-lipid peroxidation (AAPH) activity, their interaction with the free radical DPPH and the inhibition of soybean LOX. The novel derivatives were studied in terms of their physicochemical properties. Many of the dihydro-pyrazoles showed potent antioxidant properties and significant inhibition of soybean lipoxygenase as a result of their physicochemical features. Compounds 4a and 4b presented the most potent anti-lipid peroxidation abilities (98% and 97%), whereas compounds 2d and 2e have proved to be the most potent lipoxygenase inhibitors with IC₅₀ values 2.5 μM and 0.35 μM. Moreover, docking studies with soybean lipoxygenase highlight the interactions of the novel derivatives with the enzyme.