title: Design and synthesis of substituted morpholin/piperidin-1-yl-carbamodithioates as promising vaginal microbicides with spermicidal potential.
abstract: A series of seventeen morpholin/piperidin-1-yl-carbamodithioate (3-19) were synthesized as topical vaginal microbicidal spermicides. The synthesized compounds were evaluated for their anti-Trichomonas activity against MTZ susceptible and resistant strains along with their spermicidal and antifungal potential. All the synthesized compounds were assessed for their safety through cytotoxic assay against human cervical cell line (HeLa) and compatibility with vaginal flora, Lactobacillus. The study identified eleven dually active compounds with apparent safety. The plausible mode of action of these compounds was through sulfhydryl binding, confirmed via reduction in available free thiols on human sperm. The most promising compound 9 significantly inhibited (P<0.001) thiol-sensitive sperm hexokinase. The stability of compound 9 in simulated vaginal fluid (SVF) was performed via HPLC-PDA method, which supported its utility for vaginal administration.
authors.affiliation: Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research, New Delhi, India.
authors.forename: Veenu
authors.initials: V
authors.lastname: Bala
authors.affiliation: Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Santosh
authors.initials: S
authors.lastname: Jangir
authors.affiliation: National Institute of Pharmaceutical Education and Research, Raebareli, India.
authors.forename: Vikas
authors.initials: V
authors.lastname: Kumar
authors.affiliation: Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Dhanaraju
authors.initials: D
authors.lastname: Mandalapu
authors.affiliation: Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Sonal
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Medicinal and 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: Bhavana
authors.initials: B
authors.lastname: Kushwaha
authors.affiliation: Pharmacokinetics and Metabolism Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research, New Delhi, India.
authors.forename: Yashpal S
authors.initials: YS
authors.lastname: Chhonker
authors.affiliation: Microbiology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Atul
authors.initials: A
authors.lastname: Krishna
authors.affiliation: Endocrinology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Jagdamba P
authors.initials: JP
authors.lastname: Maikhuri
authors.affiliation: Microbiology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Praveen K
authors.initials: PK
authors.lastname: Shukla
authors.affiliation: Pharmacokinetics and Metabolism Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research, New Delhi, India.
authors.forename: Rabi S
authors.initials: RS
authors.lastname: Bhatta
authors.affiliation: Endocrinology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Gopal
authors.initials: G
authors.lastname: Gupta
authors.affiliation: Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research, New Delhi, India. Electronic address: vlscdri@gmail.com.
authors.forename: Vishnu L
authors.initials: VL
authors.lastname: Sharma
mesh_terms: D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D005260:Female; D006367:HeLa Cells; D006593:Hexokinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D007778:Lactobacillus / Q000187:drug effects; D008297:Male; D008826:Microbial Sensitivity Tests; D009025:Morpholines / Q000737:chemistry; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D013089:Spermatocidal Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D013094:Spermatozoa / Q000187:drug effects / Q000201:enzymology; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D013859:Thiocarbamates / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D014246:Trichomonas vaginalis / Q000187:drug effects
chemical_list: C000600081:2-(pyrrolidin-1-yl)ethyl piperidin-1-yl-carbamodithioate; D000935:Antifungal Agents; D009025:Morpholines; D010880:Piperidines; D013089:Spermatocidal Agents; D013438:Sulfhydryl Compounds; D013859:Thiocarbamates; C032727:piperidine; C037574:morpholine; D006593:Hexokinase
keywords: Carbamodithioates; Microbicidal; Nonoxynol-9; Spermicide; Trichomonas vaginalis