ABSTRACT
Aß1-42 and acetylcholinesterase (AChE) are two key therapeutic targets for Alzheimer's disease (AD). The purpose of this study is to develop a dual-target inhibitor that inhibits both of these targets by fusing the chemical structure of baicalein and donepezil. Among them, we modified the structure of baicalein to arylcoumarin, synthesized three kinds of structural compounds, and evaluated their biological activities. The results showed that compound 3b had the strongest inhibitory effect on AChE (IC50 = 0.05 ± 0.02 µM), which was better than those of donepezil and baicalein. In addition, compound 3b has a strong ability to inhibit the aggregation of Aß1-42 and protect nerve cells, and it can also penetrate the blood-brain barrier well. Using a zebrafish behavioral analyzer test, it was found that compound 3b can alleviate the behavioral effects of AlCl3-induced zebrafish larval movement retardation, which has a certain guiding significance for simulating the movement disorders of AD patients. In summary, compound 3b is expected to become a multifunctional agent for treating and alleviating the symptoms of AD patients.
Subject(s)
Acetylcholinesterase , Alzheimer Disease , Amyloid beta-Peptides , Cholinesterase Inhibitors , Drug Design , Zebrafish , Alzheimer Disease/drug therapy , Animals , Cholinesterase Inhibitors/pharmacology , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/metabolism , Structure-Activity Relationship , Acetylcholinesterase/metabolism , Humans , Peptide Fragments/antagonists & inhibitors , Peptide Fragments/pharmacology , Donepezil/pharmacology , Donepezil/chemical synthesis , Donepezil/chemistry , Blood-Brain Barrier/metabolism , Molecular Structure , Flavanones/pharmacology , Flavanones/chemical synthesis , Flavanones/chemistry , Dose-Response Relationship, Drug , Behavior, Animal/drug effectsABSTRACT
In the literature, daidzein has been reported to exhibit cardiovascular protective effects and hypoglycemic activity in mice. We sought to design and synthesize a novel compound, SJ-6, an analog of daidzein, with improved hypoglycemic properties. Although SJ-6 demonstrated favorable hypoglycemic effects, its pharmacokinetic limitations prompted us to design and synthesize prodrugs of SJ-6. We conducted a comprehensive evaluation of the prodrugs, including in vitro and in vivo studies, such as cytotoxicity, absorption, distribution, metabolism, excretion, and toxicity (ADMET) simulation analysis, in vitro blood-brain barrier (BBB) permeability evaluation, compound effect on insulin resistance, oral glucose tolerance test (OGTT), in vivo plasma concentration testing, acute toxicity test in rats, and long-term gavage administration experiment. Furthermore, we examined the antidiabetic nephropathy activity of our lead compound, compound 10, which demonstrated superior efficacy compared with the positive control drug, metformin hydrochloride. Our findings suggest that compound 10 represents a promising lead compound for the prevention and treatment of diabetic nephropathy.
Subject(s)
Diabetes Mellitus , Diabetic Nephropathies , Prodrugs , Animals , Mice , Rats , Diabetic Nephropathies/drug therapy , Structure-Activity Relationship , Hypoglycemic Agents/pharmacology , Blood-Brain BarrierABSTRACT
Flavonoids are ubiquitous compounds in nature and are found in many Chinese herbal medicines. Due to their biological activity, flavonoids show potential for decreasing insulin resistance (IR), thereby delaying the progression of diabetes and accompanying metabolic syndromes. This review focuses on the mechanisms of flavonoids decreasing IR: (1) the interaction between flavonoids and target proteins of the insulin signalling pathway; (2) bioactivities of flavonoids, such as anti-inflammatory, lipid-lowering and antioxidant. Meanwhile, we summarise the structural characteristics, structure activity relationships and biological activity of flavonoids, providing evidence for their potential in the treatment of IR. Here, we also analyse the potential and limitations of their therapeutic use.
Subject(s)
Diabetes Mellitus , Insulin Resistance , Metabolic Syndrome , Humans , Flavonoids/pharmacology , Flavonoids/chemistry , Diabetes Mellitus/drug therapy , Metabolic Syndrome/drug therapy , Anti-Inflammatory Agents/pharmacology , InsulinABSTRACT
Aging is the subject of many studies, facilitating the discovery of many interventions. Epigenetic influences numerous life processes by regulating gene expression and also plays a crucial role in aging regulation. Increasing data suggests that dietary changes can alter epigenetic marks associated with aging. Caloric restriction (CR)is considered an intervention to regulate aging and prolong life span. At present, CR has made some progress by regulating signaling pathways associated with aging as well as the mechanism of action of intercellular signaling molecules against aging. In this review, we will focus on autophagy and epigenetic modifications to elaborate the molecular mechanisms by which CR delays aging by triggering autophagy, epigenetic modifications, and the interaction between the two in caloric restriction. In order to provide new ideas for the study of the mechanism of aging and delaying aging.
