Design and synthesis of substituted morpholin/piperidin-1-yl-carbamodithioates as promising vaginal microbicides with spermicidal potential

Veenu Bala; Santosh Jangir; Vikas Kumar; Dhanaraju Mandalapu; Sonal Gupta; Lalit Kumar; Bhavana Kushwaha; Yashpal S Chhonker; Atul Krishna; Jagdamba P Maikhuri; Praveen K Shukla; Rabi S Bhatta; Gopal Gupta; Vishnu L Sharma

doi:10.1016/j.bmcl.2014.10.040

Design and synthesis of substituted morpholin/piperidin-1-yl-carbamodithioates as promising vaginal microbicides with spermicidal potential

Bioorg Med Chem Lett. 2014 Dec 15;24(24):5782-5786. doi: 10.1016/j.bmcl.2014.10.040. Epub 2014 Oct 25.

Authors

Affiliations

¹ Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research, New Delhi, India.
² Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
³ National Institute of Pharmaceutical Education and Research, Raebareli, India.
⁴ Endocrinology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
⁵ Pharmacokinetics and Metabolism Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research, New Delhi, India.
⁶ Microbiology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
⁷ 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.

PMID: 25453819
DOI: 10.1016/j.bmcl.2014.10.040

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.

Keywords: Carbamodithioates; Microbicidal; Nonoxynol-9; Spermicide; Trichomonas vaginalis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antifungal Agents / chemical synthesis*
Antifungal Agents / pharmacology
Antifungal Agents / toxicity
Cell Survival / drug effects
Drug Design*
Female
HeLa Cells
Hexokinase / antagonists & inhibitors
Hexokinase / metabolism
Humans
Lactobacillus / drug effects
Male
Microbial Sensitivity Tests
Morpholines / chemistry
Piperidines / chemical synthesis*
Piperidines / chemistry
Piperidines / pharmacology
Piperidines / toxicity
Spermatocidal Agents / chemical synthesis*
Spermatocidal Agents / pharmacology
Spermatocidal Agents / toxicity
Spermatozoa / drug effects
Spermatozoa / enzymology
Structure-Activity Relationship
Sulfhydryl Compounds / chemistry*
Sulfhydryl Compounds / pharmacology
Sulfhydryl Compounds / toxicity
Thiocarbamates / chemical synthesis*
Thiocarbamates / pharmacology
Thiocarbamates / toxicity
Trichomonas vaginalis / drug effects

Substances

2-(pyrrolidin-1-yl)ethyl piperidin-1-yl-carbamodithioate
Antifungal Agents
Morpholines
Piperidines
Spermatocidal Agents
Sulfhydryl Compounds
Thiocarbamates
piperidine
morpholine
Hexokinase