A review on synthetic strategy, molecular pharmacology of indazole derivatives, and their future perspective.

With different nitrogen-containing heterocyclic moieties, Indazoles earn one of the places among the top investigated molecules in medicinal research. Indazole, an important fused aromatic heterocyclic system containing benzene and pyrazole ring with a chemical formula of C7 H6 N2 , is also called benzopyrazole. Indazoles consist of three tautomeric forms in which 1H-tautomers (indazoles) and 2H-tautomers (isoindazoles) exist in all phases. The tautomerism in indazoles greatly influences synthesis, reactivity, physical and even the biological properties of indazoles. The thermodynamic internal energy calculation of these tautomers points view 1H-indazole as the predominant and stable form over 2H-indazole. The natural source of indazole is limited and exists in alkaloidal nature (i.e., nigellidine, nigeglanine, nigellicine, etc.) found from Nigella plants. Some of the FDA-approved drugs like Axitinib, Entrectinib, Niraparib, Benzydamine, and Granisetron are being used to treat renal cell cancer, non-small cell lung cancer (NSCLC), epithelial ovarian cancer, chronic inflammation, chemotherapy-induced nausea, vomiting, and many more uses. Besides all these advantages regarding its biological activity, the main issue about indazoles is the less abundance in plant sources, and their synthetic derivatives also often face problems with low yield. In this review article, we discuss its chemistry, tautomerism along with their effects, different schematics for the synthesis of indazole derivatives, and their different biological activities.

Insight γ-Secretase: Structure, Function, and Role in Alzheimer's Disease.

In neurodegenerative disorders, there is a progressive degeneration of the body, leading to the death of nerve cells. In this state, a patient gets affected day by day with mental weakness, dementia, and ataxia. Alzheimer's disease (AD) is the most common irreversible neurodegenerative brain disorder mainly affecting people over the age of 65. Many types of research suggest that the main culprit for AD is the aggregated form of a (39-43) amino acid peptide called amyloid beta. Amyloid beta (Aß) is generated by the action of beta-secretase and gamma-secretase on the larger glycoprotein. Gamma (γ) secretase is an intra-membrane protease complex that cleaves the single-- pass transmembrane protein, the amyloid precursor protein, and Notch. The γ-secretase complex contains presenilin, presenilin enhancer-2, anterior pharynx defective-1, and nicastrin. Any mutation in presenilin-1 or the cleavage of amyloid precursor protein by γ-secretase directly or indirectly is associated with AD. Therefore, the prevention of this enzyme is one of the solutions for AD. In this article, we discuss the γ-secretase complex and its inhibitors that can contribute to the prevention of AD.