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
Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute (CSIR-CDRI), Jankipuram Extension, Sitapur Road, Lucknow 226031 (India).
Endocrinology Division, CSIR-Central Drug Research Institute (CSIR-CDRI), Jankipuram Extension, Sitapur Road, Lucknow 226031 (India).
ChemMedChem. 2015 Oct;10(10):1739-53. doi: 10.1002/cmdc.201500291. Epub 2015 Sep 4.
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 μM, respectively, and fungicidal at MIC 7.93-86.50 μM. 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.
