The structural simplification of lysergic acid as a natural lead for synthesizing novel anti-Alzheimer agents.

Alzheimer's disease (AD) is a neurodegenerative disorder, projected to be the second leading cause of mortality by 2040. AD is characterized by a progressive impairment of memory leading to dementia and loss of ability to carry out daily functions. In addition to the deficiency of acetylcholine release in synapse, there are other mechanisms explaining the etiology of the disease. The most disputing ones are associated with the accumulation of damaged proteins ß-amyloid (Aß) and hyperphosphorylated tau outside and inside neurons, respectively. Lysergic acid derivatives have been shown to possess promising anti-Alzheimer effect. Moreover, lysergic acid structure encompasses the general structural requirements for acetylcholinesterase inhibition. In this study, sixteen analogues, derived from lysergic acid structure, were synthesized. Heck and Mannich reactions were carried out to 4-bromo indole nucleus to generate potentially active analogues. Some of them were subsequently cyclized by nitromethane and zinc reduction procedures. Some of these compounds showed neuroprotective and anti-inflammatory effects stronger than the currently used anti-Alzheimer drug; donepezil. Some of the synthesized com-pounds showed a noticeable acetylcholinesterase inhibition. Twelve molecular targets attributed with AD etiology were tested versus the synthesized compounds by in silico modeling. Docking scores of modeling were plotted against in vitro activity of the compounds. The one afforded the strongest positive correlation was ULK-1 which has a significant role in autophagy.

The iron chelating activity of Gundelia tournefortii in iron overloaded experimental rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Gundelia tournefortii is a member of the Asteraceae (Compositae) family which is widely consumed as edible plant in the Eastern Mediterranean. In folkloric medicine, it is used for the treatment of various diseases and conditions, including pain, liver diseases, kidney stones and inflammations. AIM OF THE STUDY: Recently, many commoners use this plant as adjuvant therapy for treating symptoms associated with liver diseases and thalassemia. Thus, the present study was conducted to evaluate, biochemically, the iron chelating activity of G. tournefortii methanolic extract in iron overloaded rats. MATERIALS AND METHODS: Fifty Wister male rats were divided into five groups: one group was a healthy control, while iron overload was induced in the other four groups by 100 mg/kg iron-dextran. Of these, one group was left untreated as a control, while the other three groups were treated with 50 mg/kg deferoxamine, 100 mg/kg and 200 mg/kg of G. tournefortii methanolic extract, respectively. The total flavonoid and phenolic contents of the methanolic extract were estimated. The biochemical assessment was performed by measuring blood levels of iron, ferritin, liver biomarkers (ALT, ALP and AST), cardiac biomarkers (CPK and LDH) and lipid profile. RESULTS: Not only the blood levels of iron, ferritin, liver biomarkers and cardiac biomarkers were reduced significantly by G. tournefortii methanolic extract, but also the lipid profile was improved. This clearly supports the chelating activity of G. tournefortii and its hepatoprotective and cardioprotective effects in iron overloaded rats. CONCLUSIONS: This highlights the value of medicinal plants as alternative therapies for iron overload conditions such as thalassemia.