N, N'-disubstituted Ureas as Novel Antiplatelet Agents: Synthesis, Pharmacological Evaluation and In Silico Studies.

INTRODUCTION: Thrombotic disorders are among the leading causes of morbidity and mortality worldwide. Drugs used in the prevention and treatment of atherothrombosis have pharmacokinetic limitations and adverse effects such as hemorrhagic conditions, highlighting the importance of developing more effective antiplatelet agents. ethod: In this work, we synthesized N,N'-disubstituted ureas 3a-3j and evaluated their antiplatelet profiles through in vitro, ex vivo, and in silico studies. The synthesized derivatives exhibited a selective inhibitory profile against platelet aggregation induced by arachidonic acid (AA) in vitro, without significantly affecting other aspects of primary hemostasis and blood coagulation. The compounds that showed inhibition greater than 85% were submitted to the analysis of their potency by calculating the concentration required to inhibit 50% of platelet aggregation induced by AA (IC50). Urea derivative 3a was the most potent with IC50 of 1.45 µM. Interestingly, this derivative inhibited more than 90% of platelet aggregation induced by AA ex vivo, with a similar effect to acetylsalicylic acid. In the hemolysis assay, most of the urea derivatives presented values below 10% suggesting good hemocompatibility. Additionally, the compounds tested at 100 µM also showed no cytotoxic effects in HepG2 and Vero cells. RESULT: The in silico results suggested that compound 3a may bind to the key residue of COX-1 similar to AA and known COX-1 inhibitors, and the results are also in agreement with our SAR, which suggests that the inhibition of this enzyme is the most likely mechanism of antiplatelet activity. CONCLUSION: Therefore, these results demonstrated that N,N'-disubstituted ureas are promising candidates for the development of novel antiplatelet agents.

Enzymatic synthesis of ascorbyl oleate and evaluation of biological activities.

Compounds that reduce or neutralize free radicals have been evaluated for use as nutraceutical or antioxidant additives in processed foods. This study aimed to enzymatically produce ascorbyl oleate and assess its biological properties. The synthesis was performed under previously maximized conditions (L-ascorbic acid/oleic acid 1:9 molar ratio, 70 °C, 1 h reaction). Immobilized commercial lipase from Candida antarctica (NS 88011) was used as biocatalyst. The reaction product was isolated, and its structure was confirmed by High-Performance Liquid Chromatography and Nuclear Magnetic Resonance. Ascorbyl oleate showed antioxidant and antimicrobial activity, besides no toxicity, did not influencing blood coagulation and also not presenting hemolytic profile. Better storage stability was achieved under refrigerated conditions, and the oxidative stability demonstrated free radicals fighting efficiency, increasing olive oil's shelf life. In vitro gastrointestinal simulation showed that ascorbyl oleate maintained antioxidant potential up to the duodenum stage during the digestive process. Therefore, the synthesized natural compound presented a high potential to be applied in the food and pharmaceutical industries.