title: Ammonium salts of carbamodithioic acid as potent vaginal trichomonacides and fungicides.
abstract: Chemical attenuation of the reactive oxygen species (ROS)-sensitive anaerobes Trichomonas vaginalis, which is the most prevalent non-viral sexually transmitted infection, and two often coexisting vaginal infections, namely Candida albicans and Staphylococcus aureus, which are opportunistic reproductive tract infections, was attempted with novel ammonium salts of carbamodithioic acid through inhibition of free thiols. In vitro and in vivo efficacies of the designed compounds were evaluated as topical vaginal microbicides. Five compounds showed exceptional activity against drug-resistant and -susceptible strains with negligible toxicity to host (HeLa) cells in vitro in comparison with the standard vaginal microbicide nonoxynol-9 (N-9), without disturbing the normal vaginal flora (i.e. Lactobacillus). The compounds significantly inhibited the cytopathic effects of Trichomonas on HeLa cells in vitro with efficacies comparable with metronidazole (MTZ); however, their efficacy to rescue host cells from co-infection (protozoal and fungal) was greater than that of MTZ. The compounds inhibited β-haemolysis of red blood cells caused by Trichomonas and were found to be active in vivo in the mouse subcutaneous abscess assay. Some compounds rapidly immobilized human sperm. A mechanism involving inhibition of free thiols and consequently the cysteine proteases of T. vaginalis by the new compounds has been proposed. Thus, a unique scaffold of antimicrobial agents has been discovered that warrants further investigation for development as contraceptive vaginal microbicides.
authors.affiliation: Division of Endocrinology, CSIR - Central Drug Research Institute, Lucknow 226 031, India.
authors.forename: Bhavana
authors.initials: B
authors.lastname: Kushwaha
authors.affiliation: Division of Medicinal and Process Chemistry, CSIR - Central Drug Research Institute, Lucknow 226 031, India.
authors.forename: Dhanaraju
authors.initials: D
authors.lastname: Mandalapu
authors.affiliation: Division of Medicinal and Process Chemistry, CSIR - Central Drug Research Institute, Lucknow 226 031, India.
authors.forename: Veenu
authors.initials: V
authors.lastname: Bala
authors.affiliation: Division of Endocrinology, CSIR - Central Drug Research Institute, Lucknow 226 031, India.
authors.forename: Lokesh
authors.initials: L
authors.lastname: Kumar
authors.affiliation: Division of Endocrinology, CSIR - Central Drug Research Institute, Lucknow 226 031, India.
authors.forename: Aastha
authors.initials: A
authors.lastname: Pandey
authors.affiliation: Division of Endocrinology, CSIR - Central Drug Research Institute, Lucknow 226 031, India.
authors.forename: Deepti
authors.initials: D
authors.lastname: Pandey
authors.affiliation: Division of Endocrinology, CSIR - Central Drug Research Institute, Lucknow 226 031, India.
authors.forename: Santosh Kumar
authors.initials: SK
authors.lastname: Yadav
authors.affiliation: Division of Microbiology, CSIR - Central Drug Research Institute, Lucknow 226 031, India.
authors.forename: Pratiksha
authors.initials: P
authors.lastname: Singh
authors.affiliation: Division of Microbiology, CSIR - Central Drug Research Institute, Lucknow 226 031, India.
authors.forename: P K
authors.initials: PK
authors.lastname: Shukla
authors.affiliation: Division of Endocrinology, CSIR - Central Drug Research Institute, Lucknow 226 031, India.
authors.forename: Jagdamba P
authors.initials: JP
authors.lastname: Maikhuri
authors.affiliation: Department of Urology, King George's Medical University, Lucknow 226 003, India.
authors.forename: Satya N
authors.initials: SN
authors.lastname: Sankhwar
authors.affiliation: Division of Medicinal and Process Chemistry, CSIR - Central Drug Research Institute, Lucknow 226 031, India.
authors.forename: Vishnu L
authors.initials: VL
authors.lastname: Sharma
authors.affiliation: Division of Endocrinology, CSIR - Central Drug Research Institute, Lucknow 226 031, India. Electronic address: g_gupta@cdri.res.in.
authors.forename: Gopal
authors.initials: G
authors.lastname: Gupta
mesh_terms: D000282:Administration, Intravaginal; D000818:Animals; D000891:Anti-Infective Agents, Local / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry* / Q000494:pharmacology*; D002175:Candida / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004050:Ditiocarb / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004847:Epithelial Cells / Q000187:drug effects; D005260:Female; D006367:HeLa Cells; D006801:Humans; D007778:Lactobacillus / Q000187:drug effects; D051379:Mice; D008826:Microbial Sensitivity Tests; D013211:Staphylococcus aureus / Q000187:drug effects*; D014246:Trichomonas vaginalis / Q000187:drug effects*
chemical_list: D000891:Anti-Infective Agents, Local; D004050:Ditiocarb
keywords: Candida albicans; HeLa; Lactobacillus; Metronidazole; Staphylococcus aureus; Trichomonas vaginalis