Grupo de Química Medicinal, Laboratorio de Química Orgánica, Facultad de Ciencias-Facultad de Química, Uruguay.
Bioorg Med Chem. 2012 Mar 15;20(6):2158-71. doi: 10.1016/j.bmc.2012.01.034. Epub 2012 Feb 2.
We report the design, the synthesis and the biological evaluation of the analgesic and anti-inflammatory activities of furoxanyl N-acylhydrazones (furoxanyl-NAH) by applying molecular hybridization approach. Hybrid compounds with IL-8-release inhibition capabilities were identified. Among them, furoxanyl-NAH, 17, and benzofuroxanyl-derivative, 24, together with furoxanyl-NAH derivative, 31, without IL-8 inhibition displayed both orally analgesic and anti-inflammatory activities. These hybrid derivatives do not have additional LOX- or COX-inhibition activities. For instance, LOX-inhibition by furoxanyl-NAH derivative, 42, emerged as a structural lead to develop new inhibitors. The lack of mutagenicity of the active derivatives 17, 31, and 42, allow us to propose them as candidates for further clinical studies. These results confirmed the success in the exploitation of hybridization strategy for identification of novel N-acylhydrazones (NAH) with optimized activities.
我们报告了通过应用分子杂交方法设计、合成和评估呋喃甲酰基酰肼（呋喃甲酰基-NAH）的镇痛和抗炎活性。鉴定出具有抑制 IL-8 释放能力的杂交化合物。其中，呋喃甲酰基-NAH、17 和苯并呋喃甲酰基衍生物 24 以及呋喃甲酰基-NAH 衍生物 31 没有抑制 IL-8 的作用，但具有口服镇痛和抗炎活性。这些杂合衍生物没有额外的 LOX 或 COX 抑制活性。例如，呋喃甲酰基-NAH 衍生物 42 的 LOX 抑制作用成为开发新型抑制剂的结构先导。活性衍生物 17、31 和 42 没有致突变性，这使我们可以将它们作为进一步临床研究的候选药物。这些结果证实了在开发具有优化活性的新型 N-酰基酰肼（NAH）方面杂交策略的成功。
