Innovative Disulfide Esters of Dithiocarbamic Acid as Women-Controlled Contraceptive Microbicides: A Bioisosterism Approach.
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.
Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute (CSIR-CDRI), Jankipuram Extension, Sitapur Road, Lucknow 226031 (India).
Dhanaraju
D
Mandalapu
Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute (CSIR-CDRI), Jankipuram Extension, Sitapur Road, Lucknow 226031 (India).
Nand
N
Lal
Endocrinology Division, CSIR-Central Drug Research Institute (CSIR-CDRI), Jankipuram Extension, Sitapur Road, Lucknow 226031 (India).
Lokesh
L
Kumar
Endocrinology Division, CSIR-Central Drug Research Institute (CSIR-CDRI), Jankipuram Extension, Sitapur Road, Lucknow 226031 (India).
Bhavana
B
Kushwaha
Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute (CSIR-CDRI), Jankipuram Extension, Sitapur Road, Lucknow 226031 (India).
Sonal
S
Gupta
Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute (CSIR-CDRI), Jankipuram Extension, Sitapur Road, Lucknow 226031 (India).
Lalit
L
Kumar
Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute (CSIR-CDRI), Jankipuram Extension, Sitapur Road, Lucknow 226031 (India).|Academy of Scientific and Innovative Research, New Delhi 110001 (India).
Veenu
V
Bala
Endocrinology Division, CSIR-Central Drug Research Institute (CSIR-CDRI), Jankipuram Extension, Sitapur Road, Lucknow 226031 (India).
Santosh K
SK
Yadav
Microbiology Division, CSIR-Central Drug Research Institute (CSIR-CDRI), Jankipuram Extension, Sitapur Road, Lucknow 226031 (India).
Pratiksha
P
Singh
Molecular and Structural Biology Division, CSIR-Central Drug Research Institute (CSIR-CDRI), Jankipuram Extension, Sitapur Road, Lucknow 226031 (India).
Nidhi
N
Singh
Endocrinology Division, CSIR-Central Drug Research Institute (CSIR-CDRI), Jankipuram Extension, Sitapur Road, Lucknow 226031 (India).
Jagdamba P
JP
Maikhuri
Department of Urology, King George Medical University, Lucknow 226003 (India).
Satya N
SN
Sankhwar
Microbiology Division, CSIR-Central Drug Research Institute (CSIR-CDRI), Jankipuram Extension, Sitapur Road, Lucknow 226031 (India).
Praveen K
PK
Shukla
Molecular and Structural Biology Division, CSIR-Central Drug Research Institute (CSIR-CDRI), Jankipuram Extension, Sitapur Road, Lucknow 226031 (India).
Imran
I
Siddiqi
Endocrinology Division, CSIR-Central Drug Research Institute (CSIR-CDRI), Jankipuram Extension, Sitapur Road, Lucknow 226031 (India).
Gopal
G
Gupta
Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute (CSIR-CDRI), Jankipuram Extension, Sitapur Road, Lucknow 226031 (India). vl_sharma@cdri.res.in, vlscdri@gmail.com.|Academy of Scientific and Innovative Research, New Delhi 110001 (India). vl_sharma@cdri.res.in, vlscdri@gmail.com.
Vishnu L
VL
Sharma
D000890:Anti-Infective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003270:Contraceptive Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004220:Disulfides / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004952:Esters / Q000737:chemistry / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D007778:Lactobacillus; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D021281:Quantitative Structure-Activity Relationship; D013859:Thiocarbamates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014244:Trichomonas / Q000187:drug effects*
D000890:Anti-Infective Agents; D003270:Contraceptive Agents; D004220:Disulfides; D004952:Esters; D013859:Thiocarbamates
disulfide esters; dithiocarbamates; drug design; immobilization; spermicides; sulfhydryl groups