Partridge Frederick A, Bataille Carole J R, Forman Ruth, Marriott Amy E, Forde-Thomas Josephine, Häberli Cécile, Dinsdale Ria L, O'Sullivan James D B, Willis Nicky J, Wynne Graham M, Whiteland Helen, Archer John, Steven Andrew, Keiser Jennifer, Turner Joseph D, Hoffmann Karl F, Taylor Mark J, Else Kathryn J, Russell Angela J, Sattelle David B
Centre for Respiratory Biology, UCL Respiratory, Division of Medicine, University College London, London WC1E 6JF, United Kingdom.
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford OX1 3TA, United Kingdom.
ACS Infect Dis. 2021 May 14;7(5):1260-1274. doi: 10.1021/acsinfecdis.1c00025. Epub 2021 Apr 2.
Nine hundred million people are infected with the soil-transmitted helminths (roundworm), hookworm, and (whipworm). However, low single-dose cure rates of the benzimidazole drugs, the mainstay of preventative chemotherapy for whipworm, together with parasite drug resistance, mean that current approaches may not be able to eliminate morbidity from trichuriasis. We are seeking to develop new anthelmintic drugs specifically with activity against whipworm as a priority and previously identified a hit series of dihydrobenzoxazepinone (DHB) compounds that block motility of Here, we report a systematic investigation of the structure-activity relationship of the anthelmintic activity of DHB compounds. We synthesized 47 analogues, which allowed us to define features of the molecules essential for anthelmintic action as well as broadening the chemotype by identification of dihydrobenzoquinolinones (DBQs) with anthelmintic activity. We investigated the activity of these compounds against other parasitic nematodes, identifying DHB compounds with activity against and . We also demonstrated activity of DHB compounds against the trematode a parasite that causes schistosomiasis. These results demonstrate the potential of DHB and DBQ compounds for further development as broad-spectrum anthelmintics.
9亿人感染了土壤传播的蠕虫（蛔虫）、钩虫和鞭虫。然而，作为鞭虫预防性化疗主要药物的苯并咪唑类药物单剂量治愈率较低，再加上寄生虫产生抗药性，这意味着目前的方法可能无法消除鞭虫病导致的发病情况。我们正致力于研发新的驱虫药物，将针对鞭虫的活性作为优先目标，此前已鉴定出一系列能阻断鞭虫运动的二氢苯并恶唑酮（DHB）化合物。在此，我们报告对DHB化合物驱虫活性的构效关系进行的系统研究。我们合成了47种类似物，这使我们能够确定分子中对驱虫作用至关重要的特征，同时通过鉴定具有驱虫活性的二氢苯并喹啉酮（DBQ）来拓宽化学类型。我们研究了这些化合物对其他寄生线虫的活性，鉴定出对其他线虫有活性的DHB化合物。我们还证明了DHB化合物对吸虫曼氏血吸虫（一种导致血吸虫病的寄生虫）有活性。这些结果表明DHB和DBQ化合物作为广谱驱虫药进一步开发的潜力。
