In:
ChemMedChem, Wiley, Vol. 10, No. 10 ( 2015-10), p. 1739-1753
Abstract:
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 Trichomonas strains at minimal inhibitory concentration (MIC) ranges of 10.81–377.64 and 10.81–754.14 μ M , respectively, and fungicidal at MIC 7.93–86.50 μ M . These compounds were also found to be non‐cytotoxic to human cervical (HeLa) epithelial cells and vaginal microflora ( Lactobacilli ) in vitro. The most promising compound, 2,2′‐disulfanediylbis(3‐(pyrrolidin‐1‐yl)propane‐2,1‐diyl)dipyrrolidine‐1‐carbodithioate ( 5 ), 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 5 .
Type of Medium:
Online Resource
ISSN:
1860-7179
,
1860-7187
DOI:
10.1002/cmdc.201500291
Language:
English
Publisher:
Wiley
Publication Date:
2015
detail.hit.zdb_id:
2209649-8
SSG:
15,3
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