In Silico and In Vitro Studies of Benzothiazole-Isothioureas Derivatives as a Multitarget Compound for Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Inhibiting acetylcholinesterase (AChE), amyloid beta (Aß1-42) aggregation and avoiding the oxidative stress could prevent the progression of AD. Benzothiazole groups have shown neuroprotective activity whereas isothioureas groups act as AChE inhibitors and antioxidants. Therefore, 22 benzothiazole-isothiourea derivatives (3a-v) were evaluated by docking simulations as inhibitors of AChE and Aß1-42 aggregation. In silico studies showed that 3f, 3r and 3t had a delta G (ΔG) value better than curcumin and galantamine on Aß1-42 and AChE, respectively. The physicochemical and pharmacokinetics predictions showed that only 3t does not violate Lipinski's rule of five, though it has moderated cytotoxicity activity. Then, 3f, 3r and 3t were synthetized and chemically characterized for their in vitro evaluation including their antioxidant activity and their cytotoxicity in PC12 cells. 3r was able to inhibit AChE, avoid Aß1-42 aggregation and exhibit antioxidant activity; nevertheless, it showed cytotoxic against PC12 cells. Compound 3t showed the best anti-Aß1-42 aggregation and inhibitory AChE activity and, despite that predictor, showed that it could be cytotoxic; in vitro with PC12 cell was negative. Therefore, 3t could be employed as a scaffold to develop new molecules with multitarget activity for AD and, due to physicochemical and pharmacokinetics predictions, it could be administered in vivo using liposomes due to is not able to cross the BBB.

Evaluation of the Antidiabetic and Antihyperlipidemic Activity of Spondias purpurea Seeds in a Diabetic Zebrafish Model.

Diabetes mellitus (DM) is a serious chronic degenerative disease characterized by high levels of glucose in the blood. It is associated with an absolute or relative deficiency in the production and/or action of insulin. Some of the complications associated with DM are heart disease, retinopathy, kidney disease, and neuropathy; therefore, new natural alternatives are being sought to control the disease. In this work, we evaluate the antidiabetic effect of Spondias purpurea seed methanol extract (CSM) in vitro and in a glucose-induced diabetic zebrafish model. CSM is capable of lowering blood glucose and cholesterol levels, as well as forming advanced glycation end-products, while not presenting toxic effects at the concentrations evaluated. These data show that CSM has a promising antidiabetic effect and may be useful in reducing some of the pathologies associated with diabetes mellitus.

Myeloperoxidase Inhibitory and Antioxidant Activities of (E)-2-Hydroxy-α-aminocinnamic Acids Obtained through Microwave-Assisted Synthesis.

Myeloperoxidase (MPO) is an enzyme present in human neutrophils, whose main role is to provide defenses against invading pathogens. However, highly reactive oxygen species (ROS), such as HOCl, are generated from MPO activity, leading to chronic diseases. Herein, we report the microwave-assisted synthesis of a new series of stable (E)-(2-hydroxy)-α-aminocinnamic acids, in good yields, which are structurally analogous to the natural products (Z)-2-hydroxycinnamic acids. The radical scavenging activity (RSA), MPO inhibitory activity and cytotoxicity of the reported compounds were evaluated. The hydroxy derivatives showed the most potent RSA, reducing the presence of DPPH and ABTS radicals by 77% at 0.32 mM and 100% at 0.04 mM, respectively. Their mechanism of action was modeled with BDEOH, IP and ΔEH-L theoretical calculations at the B3LYP/6 - 31 + G(d,p) level. Compounds showed in vitro inhibitory activity of MPO with IC50 values comparable to indomethacin and 5-ASA, but cytotoxicities below 15% at 100-200 µM. Docking calculations revealed that they reach the amino acid residues present in the distal cavity of the MPO active site, where both the amino and carboxylic acid groups of the α-aminopropenoic acid arm are structural requirements for anchoring. (E)-2-hydroxy-α-aminocinnamic acids have been synthesized for the first time with a reliable method and their antioxidant properties demonstrated.