title: Role of disulfide linkage in action of bis(dialkylaminethiocarbonyl)disulfides as potent double-Edged microbicidal spermicide: Design, synthesis and biology.
abstract: Trichomoniasis and candidiasis are amongst the most common morbidity-causing reproductive tract infections, generally treated by Metronidazole and Fluconazole respectively. Poor vaginal efficacy, drug-resistance and non-spermicidal nature limit their use as topical microbicidal contraceptives. Bis(dialkylaminethiocarbonyl)disulfides (4-38) were designed as dually active, non-surfactant molecules capable of eliminating Trichomonas vaginalis and Candida strains as well as irreversibly immobilizing 100% human sperm instantly, at doses non-cytotoxic to human cervical epithelial cells and vaginal microflora in vitro. Compounds 12, 16, 17 were fifty times more active than nonoxynol-9, OTC vaginal spermicide, and compounds 12 and 17 have shown remarkable in vivo activity in rabbit model. Most promising compound 17 has shown promise for further development as a double-edged vaginal microbicide due to their improved activity and safety along with notable in vivo trichomonicidal activity. Role of disulfide group was established by loss of spermicidal activity on chemical modifications (39-56). These disulfides might be targeting thiol groups present over cell membrane of human sperm and Trichomonas as shown by fluorescence labeling of free thiols.
authors.affiliation: Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India.
authors.forename: Nand
authors.initials: N
authors.lastname: Lal
authors.affiliation: Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India.
authors.forename: Santosh
authors.initials: S
authors.lastname: Jangir
authors.affiliation: Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific & Innovative Research (AcSIR), New Delhi, 110001, India.
authors.forename: Veenu
authors.initials: V
authors.lastname: Bala
authors.affiliation: Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India.
authors.forename: Dhanaraju
authors.initials: D
authors.lastname: Mandalapu
authors.affiliation: Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India.
authors.forename: Amit
authors.initials: A
authors.lastname: Sarswat
authors.affiliation: Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India.
authors.forename: Lalit
authors.initials: L
authors.lastname: Kumar
authors.affiliation: Endocrinology Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India.
authors.forename: Ashish
authors.initials: A
authors.lastname: Jain
authors.affiliation: Endocrinology Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India.
authors.forename: Lokesh
authors.initials: L
authors.lastname: Kumar
authors.affiliation: Endocrinology Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India.
authors.forename: Bhavana
authors.initials: B
authors.lastname: Kushwaha
authors.affiliation: Microbiology Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India.
authors.forename: Atindra K
authors.initials: AK
authors.lastname: Pandey
authors.affiliation: Molecular & Structural Biology Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India.
authors.forename: Shagun
authors.initials: S
authors.lastname: Krishna
authors.affiliation: Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India.
authors.forename: Tara
authors.initials: T
authors.lastname: Rawat
authors.affiliation: Microbiology Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India.
authors.forename: Praveen K
authors.initials: PK
authors.lastname: Shukla
authors.affiliation: Endocrinology Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India.
authors.forename: Jagdamba P
authors.initials: JP
authors.lastname: Maikhuri
authors.affiliation: Molecular & Structural Biology Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India.
authors.forename: Mohammad I
authors.initials: MI
authors.lastname: Siddiqi
authors.affiliation: Endocrinology Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India.
authors.forename: Gopal
authors.initials: G
authors.lastname: Gupta
authors.affiliation: Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific & Innovative Research (AcSIR), New Delhi, 110001, India. Electronic address: vl_sharma@cdri.res.in.
authors.forename: Vishnu L
authors.initials: VL
authors.lastname: Sharma
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002175:Candida / Q000187:drug effects; D004220:Disulfides / Q000737:chemistry*; D008297:Male; D051379:Mice; D011817:Rabbits; D013089:Spermatocidal Agents; D013094:Spermatozoa / Q000187:drug effects; D014246:Trichomonas vaginalis / Q000187:drug effects
chemical_list: D000890:Anti-Infective Agents; D004220:Disulfides; D013089:Spermatocidal Agents
keywords: Contraceptive; Disulfide; Disulfiram; Dithiocarbamate; Spermicide; Sulfhydryl