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Structure–property studies of an imidazoquinoline chemotype with antitrypanosomal activity
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2020-07-10 , DOI: 10.1039/d0md00103a Dana M Klug 1 , Rosario Diaz-Gonzalez 2 , Travis J DeLano 1 , Eftychia M Mavrogiannaki 1 , Melissa J Buskes 1 , Raeann M Dalton 1 , John K Fisher 1 , Katherine M Schneider 1 , Vivian Hilborne 1 , Melanie G Fritsche 1 , Quillon J Simpson 1 , Westley F Tear 1 , William G Devine 1 , Guiomar Pérez-Moreno 2 , Gloria Ceballos-Pérez 2 , Raquel García-Hernández 2 , Cristina Bosch-Navarrete 2 , Luis Miguel Ruiz-Pérez 2 , Francisco Gamarro 2 , Dolores González-Pacanowska 2 , Maria Santos Martinez-Martinez 3 , Pilar Manzano-Chinchon 3 , Miguel Navarro 2 , Michael P Pollastri 1 , Lori Ferrins 1
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2020-07-10 , DOI: 10.1039/d0md00103a Dana M Klug 1 , Rosario Diaz-Gonzalez 2 , Travis J DeLano 1 , Eftychia M Mavrogiannaki 1 , Melissa J Buskes 1 , Raeann M Dalton 1 , John K Fisher 1 , Katherine M Schneider 1 , Vivian Hilborne 1 , Melanie G Fritsche 1 , Quillon J Simpson 1 , Westley F Tear 1 , William G Devine 1 , Guiomar Pérez-Moreno 2 , Gloria Ceballos-Pérez 2 , Raquel García-Hernández 2 , Cristina Bosch-Navarrete 2 , Luis Miguel Ruiz-Pérez 2 , Francisco Gamarro 2 , Dolores González-Pacanowska 2 , Maria Santos Martinez-Martinez 3 , Pilar Manzano-Chinchon 3 , Miguel Navarro 2 , Michael P Pollastri 1 , Lori Ferrins 1
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Human African trypanosomiasis is a neglected tropical disease (NTD) that is fatal if left untreated. Although approximately 13 million people live in moderate- to high-risk areas for infection, current treatments are plagued by problems with safety, efficacy, and emerging resistance. In an effort to fill the drug development pipeline for HAT, we have expanded previous work exploring the chemotype represented by the compound NEU-1090, with a particular focus on improvement of absorption, distribution, metabolism and elimination (ADME) properties. These efforts resulted in several compounds with substantially improved aqueous solubility, although these modifications typically resulted in a loss of trypanosomal activity. We herein report the results of our investigation into the antiparasitic activity, toxicity, and ADME properties of this class of compounds in the interest of informing the NTD drug discovery community and avoiding duplication of effort.
中文翻译：
具有抗锥虫活性的咪唑喹啉化学型的结构-性质研究
非洲人类锥虫病是一种被忽视的热带病 (NTD)，如果不及时治疗，将会致命。尽管大约有 1300 万人生活在感染中高风险地区，但目前的治疗方法受到安全性、有效性和新出现的耐药性问题的困扰。为了填补 HAT 的药物开发渠道，我们扩展了之前探索以化合物NEU-1090为代表的化学型的工作，特别关注吸收、分布、代谢和消除 (ADME) 特性的改善。这些努力导致几种化合物的水溶性显着改善，尽管这些修饰通常会导致锥虫活性的丧失。我们在此报告我们对此类化合物的抗寄生虫活性、毒性和 ADME 特性的研究结果，以便为 NTD 药物发现界提供信息并避免重复工作。
更新日期：2020-08-20
中文翻译：
具有抗锥虫活性的咪唑喹啉化学型的结构-性质研究
非洲人类锥虫病是一种被忽视的热带病 (NTD)，如果不及时治疗，将会致命。尽管大约有 1300 万人生活在感染中高风险地区，但目前的治疗方法受到安全性、有效性和新出现的耐药性问题的困扰。为了填补 HAT 的药物开发渠道，我们扩展了之前探索以化合物NEU-1090为代表的化学型的工作，特别关注吸收、分布、代谢和消除 (ADME) 特性的改善。这些努力导致几种化合物的水溶性显着改善，尽管这些修饰通常会导致锥虫活性的丧失。我们在此报告我们对此类化合物的抗寄生虫活性、毒性和 ADME 特性的研究结果，以便为 NTD 药物发现界提供信息并避免重复工作。
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