Structural Requirements for Dihydrobenzoxazepinone Anthelmintics: Actions against Medically Important and Model Parasites: Trichuris muris, Brugia malayi, Heligmosomoides polygyrus, and Schistosoma mansoni.
Structural Requirements for Dihydrobenzoxazepinone Anthelmintics: Actions against Medically Important and Model Parasites: Trichuris muris, Brugia malayi, Heligmosomoides polygyrus, and Schistosoma mansoni.
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DOI：
10.1021/acsinfecdis.1c00025
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发表时间：
2021-05-14
影响因子：
5.3
通讯作者：
Sattelle DB
中科院分区：
文献类型：
--
作者：
Partridge FA;Bataille CJR;Forman R;Marriott AE;Forde-Thomas J;Häberli C;Dinsdale RL;O'Sullivan JDB;Willis NJ;Wynne GM;Whiteland H;Archer J;Steven A;Keiser J;Turner JD;Hoffmann KF;Taylor MJ;Else KJ;Russell AJ;Sattelle DB
九亿人感染了土壤传播的蠕虫蛔虫（蛔虫）、钩虫和鞭虫。然而，苯并咪唑类药物（鞭虫预防性化疗的主要药物）的单次剂量治愈率较低，加上寄生虫的耐药性，意味着目前的方法可能无法消除鞭虫的发病率。我们正在寻求开发新的驱虫药物，特别是对鞭虫的活性作为优先事项，以前确定了一系列的二氢苯并氧氮杂卓酮（DHB）化合物，阻止离体鞭虫的运动。在这里，我们报告了一个系统的调查的构效关系的驱虫活性的DHB化合物。我们合成了47个类似物，这使我们能够定义的驱虫作用所必需的分子的功能，以及通过确定具有驱虫活性的二氢苯并喹啉酮（DBQs）来拓宽化学型。我们研究了这些化合物对其他寄生线虫的活性，鉴定了DHB化合物对马来丝虫和多脑Heligmosomoides polygyrus的活性。我们还证明了DHB化合物对曼氏血吸虫（一种引起血吸虫病的寄生虫）的活性。这些结果表明DHB和DBQ化合物作为广谱驱虫剂进一步开发的潜力。
Nine hundred million people are infected with the soil-transmitted helminths Ascaris lumbricoides (roundworm), hookworm, and Trichuris trichiura (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 ex vivo Trichuris muris. 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 Brugia malayi and Heligmosomoides polygyrus. We also demonstrated activity of DHB compounds against the trematode Schistosoma mansoni, a parasite that causes schistosomiasis. These results demonstrate the potential of DHB and DBQ compounds for further development as broad-spectrum anthelmintics.
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DOI：
10.1056/nejmoa1706854
发表时间：
2018-11-08
期刊：
The New England journal of medicine
影响因子：
--
作者：
King CL;Suamani J;Sanuku N;Cheng YC;Satofan S;Mancuso B;Goss CW;Robinson LJ;Siba PM;Weil GJ;Kazura JW
通讯作者：
Kazura JW
影响因子：
3.2
作者：
Keiser J;Panic G;Adelfio R;Cowan N;Vargas M;Scandale I
通讯作者：
Scandale I
影响因子：
3.8
作者：
Diawara A;Halpenny CM;Churcher TS;Mwandawiro C;Kihara J;Kaplan RM;Streit TG;Idaghdour Y;Scott ME;Basáñez MG;Prichard RK
通讯作者：
Prichard RK
类视钉X受体的拮抗剂可在体外降低毛尿症的生存能力。
影响因子：
3.7
作者：
Hurst RJ;Hopwood T;Gallagher AL;Partridge FA;Burgis T;Sattelle DB;Else KJ
通讯作者：
Else KJ
DOI：
10.1016/j.ijpddr.2016.04.002
发表时间：
2016-12
影响因子：
4
作者：
Kuesel, Annette C.
通讯作者：
Kuesel, Annette C.