Atherosclerosis is a multifactorial disease with several mechanisms participating in its manifestation. To address this disorder, we applied a strategy involving the design of a single chemical compound able to simultaneously modulate more than one target. We hereby present the development of novel benzoxazine and benzothiazine derivatives that significantly inhibit in vitro microsomal lipid peroxidation and LDL oxidation as well as squalene synthase activity (IC(50) of 5-16 μM). Further, these compounds show antidyslipidemic and antioxidant properties in vivo, decreasing total cholesterol, LDL, triglyceride, and MDA levels of hyperlipidemic rats by 26-74%. Finally, by determination of their in vivo concentration (up to 24 h) in target tissues (blood/liver), it is shown that compounds reach their targets in the low micromolar range. The new compounds seem to be interesting multifunctional molecules for the development of a new pharmacophore for disease-modifying agents useful in the treatment of atherosclerosis.
A quantitative structure-activity relationship (QSAR) study was performed for a series of antihyperlipidemic morpholine derivatives, exhibiting squalene synthase (SQS) inhibitory as well as antioxidant activity (inhibition of lipid peroxidation). Physico/stereo-chemical descriptors of low energy conformations of the compounds were calculated and a number of QSAR models with statistical significance and predictability were produced. The final models include chemical descriptors such as E LUMO , E HOMO -E LUMO gap, cLogP, electrostatic (FNSA 1 and RNCS) as well as geometry (YZ SHADOW /YZ RECTANGLE ) descriptors, indicating that electron affinity, along with molecular shape and electrostatic effects play a significant role in the compound's described activities. These models provide some insight on the molecular mechanism of action of these derivatives and assist in the prediction of action in vitro as well as the design of more potent derivatives in the search for effective antiatherosclerosis agents.
Cyanoacrylate fuming is a forensic technique that uses the anionic polymerization of cyanoacrylate esters present in "super glue" to render latent fingerprints visible. In this classroom activity, students use this technique on fingerprints created on different types of surfaces. They investigate the technique's effectiveness and test the effects of changing the temperature and humidity of the fuming chamber. The activity is aimed towards high school students. The chemical concepts that are reinforced by the activity include: different states of matter, evaporation, chemical reactions, gas adsorption in thin liquid layers, polymerization, and polymers.
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