title: Novel trichomonacidal spermicides.
abstract: 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.
authors.affiliation: Division of Endocrinology, Central Drug Research Institute, Lucknow 226 001, India.
authors.forename: Ashish
authors.initials: A
authors.lastname: Jain
authors.forename: Nand
authors.initials: N
authors.lastname: Lal
authors.forename: Lokesh
authors.initials: L
authors.lastname: Kumar
authors.forename: Vikas
authors.initials: V
authors.lastname: Verma
authors.forename: Rajeev
authors.initials: R
authors.lastname: Kumar
authors.forename: Lalit
authors.initials: L
authors.lastname: Kumar
authors.forename: Vishal
authors.initials: V
authors.lastname: Singh
authors.forename: Raghav K
authors.initials: RK
authors.lastname: Mishra
authors.forename: Amit
authors.initials: A
authors.lastname: Sarswat
authors.forename: S K
authors.initials: SK
authors.lastname: Jain
authors.forename: J P
authors.initials: JP
authors.lastname: Maikhuri
authors.forename: V L
authors.initials: VL
authors.lastname: Sharma
authors.forename: Gopal
authors.initials: G
authors.lastname: Gupta
mesh_terms: D000981:Antiprotozoal Agents / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D006367:HeLa Cells; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008795:Metronidazole / Q000494:pharmacology; D013089:Spermatocidal Agents / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D013094:Spermatozoa / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014246:Trichomonas vaginalis / Q000187:drug effects*
chemical_list: D000981:Antiprotozoal Agents; D013089:Spermatocidal Agents; D008795:Metronidazole