Innovative Disulfide Esters of Dithiocarbamic Acid as Women‐Controlled Contraceptive Microbicides: A Bioisosterism Approach. Issue 10 (4th September 2015)

• Record Type: Journal Article
• Authors: Mandalapu, Dhanaraju; Lal, Nand; Kumar, Lokesh; Kushwaha, Bhavana; Gupta, Sonal; Kumar, Lalit; Bala, Veenu; Yadav, Santosh K.; Singh, Pratiksha; Singh, Nidhi; Maikhuri, Jagdamba P.; Sankhwar, Satya N.; Shukla, Praveen K.; Siddiqi, Imran; Gupta, Gopal; Sharma, Vishnu L.
• Is Part Of: ChemMedChem. Volume 10:Issue 10(2015:Oct.)
• Page Start: 1739
• Page End: 1753
• Publication Date: 2015-09-04
• Subjects: Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201500291
• Languages: English
• ISSNs: 1860-7179

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>In an ongoing effort to discover an effective, topical, dual‐function, non‐surfactant contraceptive vaginal microbicide, a novel series of 2, 2′‐disulfanediylbis(3‐(substituted‐1‐yl)propane‐2, 1‐diyl) disubstituted‐1‐carbodithioates were designed by using a bioisosterism approach. Thirty‐three compounds were synthesized, and interestingly, most demonstrated multiple activities: they were found to be spermicidal at a minimal effective concentration of 1–0.001 %, trichomonacidal against drug‐susceptible and resistant <italic>Trichomonas</italic> strains at minimal inhibitory concentration (MIC) ranges of 10.81–377.64 and 10.81–754.14 μ<sc>M</sc>, respectively, and fungicidal at MIC 7.93–86.50 μ<sc>M</sc>. These compounds were also found to be non‐cytotoxic to human cervical (HeLa) epithelial cells and vaginal microflora (<italic>Lactobacilli</italic>) in vitro. The most promising compound, 2, 2′‐disulfanediylbis(3‐(pyrrolidin‐1‐yl)propane‐2, 1‐diyl)dipyrrolidine‐1‐carbodithioate (<bold>5</bold>), exhibited spermicidal activity 15‐fold higher than that of the marketed spermicide Nonoxynol‐9 (N‐9) and also demonstrated microbicidal potency. To identify common structural features required for spermicidal activity, a 3D‐QSAR analysis was carried out, as well as in vivo efficacy studies and fluorescent labeling studies to determine the biological targets of compound <bold>5</bold>.</p> </abstract>