1,2-NAPHTHOQUINONE DERIVATIVES IN TRICHOMONAS THERAPY

1,2-萘醌衍生物在毛滴虫治疗中的应用

• 批准号: 6014528
• 负责人: Venudhar K Reddy
• 金额: $ 10万
• 依托单位: SLIL BIOMEDICAL CORPORATION
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-01 至 2000-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6014528
• 关键词: Trichomonas vaginalis; analog; antiprotozoal agents; arginine; disease /disorder model; drug design /synthesis /production; drug screening /evaluation; female; glutamine; laboratory mouse; laboratory rat; lysine; naphthoquinones; protozoal infection; vagina

Trichomonas vaginalis is a frequently encountered sexually transmitted parasite with worldwide distribution. The parasite is a major emerging concern in the amplification of HIV transmission, and may also be involved in increased susceptibility to cervical cancer. The disease is presently treated with metronidazole which has a 10% failure rate. In addition, due to mutagenic concerns, metronidazole is not prescribed during early pregnancy. Therefore a need for safe alternative therapy for this disease exists. The object of this proposal is to examine 1,2- naphthoquinone analogs as potential trichomonacides. Our initial findings show that several 1,2-naphthoquinone derivatives are extremely effective growth inhibitors of T. vaginalis. One of these was found to be better than 100-fold more active toward a metronidazole-refractive isolate CDC-085. SL-11051 was also found to be active at 100 mg/kg in a mouse subcutaneous assay. We propose to extend our initial findings by synthesizing new naphthoquinone analogs, some of them with short peptide sequences, such as arginine or methionine, which the parasite has a high demand for. These compounds will be tested for antitrichomonad activity in our in vitro growth assay, and those showing high activity (<0.02 mM) will be tested in vivo using the mouse subcutaneous and rate intravaginal model systems. PROPOSED COMMERCIAL APPLICATIONS: 1,2-Naphthoquinone derivatives have shown to be effective both in vitro and in vivo against T.vaginalis. This parasite causes the most prevalent non-viral, sexually transmitted disease in females. The only drug available for this disease since 1955 is F1agyl(R), and it created resistance. New effective and safe drugs are needed as alternatives.

阴道毛滴虫是一种常见的性传播寄生虫，分布于世界各地。这种寄生虫是艾滋病毒传播扩大的一个主要新问题，也可能与宫颈癌易感性增加有关。目前该疾病采用甲硝唑治疗，失败率为 10%。此外，由于考虑到致突变性，孕早期不宜使用甲硝唑。因此，需要针对这种疾病的安全替代疗法。该提案的目的是检查 1,2-萘醌类似物作为潜在的毛滴虫酸。我们的初步研究结果表明，几种 1,2-萘醌衍生物是极其有效的阴道毛滴虫生长抑制剂。其中一种被发现对甲硝唑折射分离物 CDC-085 的活性高出 100 倍以上。在小鼠皮下试验中还发现 SL-11051 在 100 mg/kg 时具有活性。我们建议通过合成新的萘醌类似物来扩展我们的初步发现，其中一些具有短肽序列，例如寄生虫对其有很高需求的精氨酸或蛋氨酸。这些化合物将在我们的体外生长测定中测试抗滴虫活性，而那些表现出高活性（<0.02 mM）的化合物将使用小鼠皮下和速率阴道内模型系统进行体内测试。拟议的商业应用：1,2-萘醌衍生物已被证明在体外和体内均能有效对抗阴道毛滴虫。这种寄生虫会导致女性中最流行的非病毒性传播疾病。自 1955 年以来，唯一可用于治疗这种疾病的药物是 F1agyl(R)，它产生了耐药性。需要新的有效且安全的药物作为替代品。