One-pot three-component synthesis of novel heterocyclic steroids as a central antioxidant and anti-inflammatory agents

• Published in: Steroids Vol. 77; no. 13; pp. 1469 - 1476
• Main Authors: Mohamed, Nadia R., Abdelhalim, Mervat M., Khadrawy, Yasser A., Elmegeed, Gamal A., Abdel-Salam, Omar M.E.
• Format: Journal Article
• Language: English
• Published: NEW YORK Elsevier Inc 01.11.2012; Elsevier
• Subjects: Animals; Anti-Inflammatory Agents - chemical synthesis; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - pharmacology; Anti-neuroinflammatory; Antioxidant; Antioxidants - chemical synthesis; Antioxidants - chemistry; Antioxidants - pharmacology; Biochemistry & Molecular Biology; Biological and medical sciences; Brain - cytology; Brain - drug effects; Chemistry Techniques, Synthetic; Endocrinology & Metabolism; Fundamental and applied biological sciences. Psychology; Heterocyclic Compounds - chemistry; Life Sciences & Biomedicine; Neurons - drug effects; Neurons - metabolism; Oxidative Stress - drug effects; Pyridine; Pyridopyrimidine; Rats; Science & Technology; Steroids - chemical synthesis; Steroids - chemistry; Steroids - pharmacology; Vertebrates: endocrinology; Pyridine; Anti-neuroinflammatory; Antioxidant; Pyridopyrimidine; SUSCEPTIBILITY; PYRIMIDINE; RAT-BRAIN; DERIVATIVES; PARKINSONS-DISEASE; Steroid; Antiinflammatory agent; Biosynthesis
• ISSN: 0039-128X; 1878-5867
• DOI: 10.1016/j.steroids.2012.09.001

Using multi-component reactions, we have attempted a straightforward synthesis of novel pyrido- and pyridopyrimidine steroids that would act to reduce neuro-inflammation and oxidative stress in brain. The tested compounds were assayed in the model of neuro-inflammation produced in rats by cerebral lipopolysacharide injection. Results suggest tested compounds are useful candidates in treatment of cerebral inflammation. [Display omitted] ► One-pot three-component synthesis of novel heterocyclic steroids. ► In vivo study against oxidative stress and neuro-inflammation caused by cerebral injection of lipopolysacharide endotoxin. ► Results suggest tested compounds are useful candidates in treatment of cerebral inflammation. Oxidative stress and inflammation have been implicated in several neurodegenerative and developmental brain disorders. The present work was devoted to the design and synthesis of novel steroid derivatives bearing promising heterocyclic moiety that would act to reduce neuro-inflammation and oxidative stress in brain. The novel heterocyclic steroids were synthesized and their chemical structures were confirmed by studying their analytical and spectral data. The tested compounds were assayed in the model of neuro-inflammation produced in rats by cerebral lipopolysacharide injection. The intracerebral administration of bacterial endotoxin resulted in cerebral inflammatory state evidenced by increased malondialdehyde (MDA), decreased reduced glutathione (GSH) level, increased nitric oxide as well as increased acetylcholinesterase (AChE) activity in the brain. Compounds 6, 10, 8b and 13a markedly increased reduced glutathione. Malondialadehyde and nitric oxide levels were reduced to normal values after treatment with all tested compounds. AChE activity was normalized by compound 8b and reduced to below normal values by compounds 10 and 14a. These results are exciting in that these agents might be useful candidates in treatment of cerebral inflammation.