16,17-N′-(alky/arylsulfonyl)pyrazoline substituted neuroprotective heterosteroids: Synthesis, molecular docking and preclinical efficacy/toxicity studies in rodents

Abstract

The synthesis and neuroprotective efficacy and toxicity studies of a new series of 16,17-N′-(alkyl/arylsulfonyl)pyrazolinyl steroids is presented. Significant suppression of the overexpressed acetylcholinesterase and lipid peroxidation, marked reduction of nitrite, oxidative stress and TNF-α levels and noticeable improvement in cognitive and locomotor functions were observed after treatment with the newly synthesized steroids 2-4a-d in the LPS-treated animal models. Higher neuroprotective effects were produced by some of the pyrazolinyl steroids in comparison to the reference drugs celecoxib and dexamethasone. N′-(4-fluorobenzenesulfonyl) derivative 4c showed the most promising effects on all the analyzed parameters and is the most potent molecule among all compounds of this series. Acute toxicity studies on the most active steroids 2-4c at 50 mg/kg did not reveal any toxic effects on animals, however hepatitis and chronic nephritis were observed in histological examination of liver and kidney of mice after 28 days of treatment. The pyrazolinyl steroids 2-4a-d could be considered as promising candidates for the designing of novel multitarget-directed neuroprotectives for an effective therapy of AD and PD.