Division of Endocrinology, Central Drug Research Institute, Lucknow 226 001, India.
Antimicrob Agents Chemother. 2011 Sep;55(9):4343-51. doi: 10.1128/AAC.00199-11. Epub 2011 Jun 27.
Metronidazole, the U.S. Food and Drug Administration-approved drug against trichomoniasis, is nonspermicidal and thus cannot offer pregnancy protection when used vaginally. Furthermore, increasing resistance of Trichomonas vaginalis to 5-nitro-imidazoles is a cause for serious concern. On the other hand, the vaginal spermicide nonoxynol-9 (N-9) does not protect against sexually transmitted diseases and HIV in clinical situations but may in fact increase their incidence due to its nonspecific, surfactant action. We therefore designed dually active, nonsurfactant molecules that were capable of killing Trichomonas vaginalis (both metronidazole-susceptible and -resistant strains) and irreversibly inactivating 100% human sperm at doses that were noncytotoxic to human cervical epithelial (HeLa) cells and vaginal microflora (lactobacilli) in vitro. Anaerobic energy metabolism, cell motility, and defense against reactive oxygen species, which are key to survival of both sperm and Trichomonas in the host after intravaginal inoculation, depend crucially on availability of free thiols. Consequently, molecules were designed with carbodithioic acid moiety as the major pharmacophore, and chemical variations were incorporated to provide high excess of reactive thiols for interacting with accessible thiols on sperm and Trichomonas. We report here the in vitro activities, structure-activity relationships, and safety profiles of these spermicidal antitrichomonas agents, the most promising of which was more effective than N-9 (the OTC spermicide) in inactivating human sperm and more efficacious than metronidazole in killing Trichomonas vaginalis (including metronidazole-resistant strain). It also significantly reduced the available free thiols on human sperm and inhibited the cytoadherence of Trichomonas on HeLa cells. Experimentally in vitro, the new compounds appeared to be safer than N-9 for vaginal use.
甲硝唑是美国食品和药物管理局批准用于治疗滴虫病的药物，它没有杀精作用，因此阴道内使用时不能提供妊娠保护。此外，阴道毛滴虫对 5-硝基咪唑类药物的耐药性不断增加是一个令人严重关切的问题。另一方面，阴道杀精剂壬苯醇醚-9（N-9）在临床情况下不能预防性传播疾病和艾滋病毒，但实际上由于其非特异性表面活性剂作用，可能会增加这些疾病的发病率。因此，我们设计了具有双重活性、非表面活性剂的分子，这些分子能够杀死阴道毛滴虫（包括甲硝唑敏感和耐药株），并在体外以非细胞毒性剂量不可逆地失活 100%的人精子。厌氧能量代谢、细胞运动以及对活性氧的防御，这些对于精子和阴道毛滴虫在阴道内接种后在宿主体内的生存都是至关重要的，这取决于游离巯基的可用性。因此，这些分子的设计以碳二硫代酸酯部分作为主要药效团，并进行了化学变异，以提供高过量的反应性硫醇，用于与精子和阴道毛滴虫上可及的巯基相互作用。我们在此报告这些杀精子抗滴虫剂的体外活性、构效关系和安全性概况，其中最有前途的一种比 N-9（非处方杀精剂）更有效地灭活人精子，比甲硝唑更有效地杀死阴道毛滴虫（包括甲硝唑耐药株）。它还显著降低了人精子上可用的游离巯基，并抑制了阴道毛滴虫在 HeLa 细胞上的细胞黏附。在体外实验中，新化合物似乎比 N-9 更安全，可用于阴道。
