Brienne M J, Varech D, Leclercq M, Jacques J, Radembino N, Dessalles M C, Mahuzier G, Gueyouche C, Bories C, Loiseau P
Chimie des Interactions Moléculaires, ER 285 CNRS, Collège de France, Paris.
J Med Chem. 1987 Dec;30(12):2232-9. doi: 10.1021/jm00395a010.
Two series of 2-substituted 1,2-epoxyethanesulfonamides 2 and ethynesulfonamides 5 were synthesized and evaluated for their antifilarial activity. The trans epoxides 2T were stereospecifically prepared by a Darzens reaction between aldehydes and halomethanesulfonamides. The cis isomers 2c were obtained from ethynesulfonamides 5 by semihydrogenation followed by KOCl epoxidation. 2-Substituted ethynesulfonamides 5 were synthesized from appropriate trans-ethenesulfonamides by a bromination/dehydrobromination sequence. These products, as well as several synthetic intermediates, were evaluated for antifilarial activity against Molinema dessetae either in vivo in its natural host, the rodent Proechimys oris, or in vitro by a new test using cultures of the infective larvae. Most of the epoxides 2T and acetylenic derivatives 5 bearing a 2-aryl substituent were active in vitro. Among these compounds, four epoxides 2T and one acetylenic derivative 5 showed marked macrofilaricidal activity in vivo without any microfilaricidal activity. The differences between the in vivo and in vitro results may be due, in part, to the low chemical stability of the epoxy sulfonamides 2T. Despite this limitation, the activities observed in this reliable animal model suggest further development and testing of both series 2T and 5 as macrofilaricides.
合成了两个系列的2-取代的1,2-环氧乙烷磺酰胺2和乙炔磺酰胺5，并对其抗丝虫活性进行了评估。反式环氧化物2T通过醛与卤代甲烷磺酰胺之间的达参反应立体定向制备。顺式异构体2c通过乙炔磺酰胺5半氢化后用KOCl环氧化得到。2-取代的乙炔磺酰胺5由合适的反式乙烯磺酰胺通过溴化/脱溴化氢序列合成。这些产物以及几种合成中间体，通过在其天然宿主啮齿动物奥氏原鼠体内或通过使用感染性幼虫培养物的新试验在体外对德氏莫利线虫进行抗丝虫活性评估。大多数带有2-芳基取代基的环氧化物2T和炔属衍生物5在体外具有活性。在这些化合物中，四种环氧化物2T和一种炔属衍生物5在体内表现出显著的杀成虫活性，而没有任何杀微丝蚴活性。体内和体外结果之间的差异可能部分归因于环氧磺酰胺2T的化学稳定性低。尽管有此限制，但在这个可靠的动物模型中观察到的活性表明，2T和5这两个系列作为杀成虫剂都需要进一步开发和测试。
