Sreekumari Rahul B, Saraswati Bindu, Chellan Shiju, Gupta Gopal, Lal Nand
Corporate Research & Development Centre, HLL Lifecare Limited, Akkulam, Trivandrum-695017, India.
Endocrinology Division, CSIR-Central Drug Research Institute, Lucknow-226001, India.
Med Chem. 2018;14(8):773-783. doi: 10.2174/1573406414666180524094429.
In our previous work, several piperazine derived bis(dialkylaminethiocarbonyl) disulfides and disulfide esters of dithiocarbamic acid have been synthesized and evaluated for their spermicidal and microbicidal efficacy. These studies have provided some promising compounds for developing a dually active vaginal microbicidal contraceptive which is under pre-clinical stage.
The main objective of this study was the design synthesis and biological evaluation of bis(dialkylaminethiocarbonyl) disulfides (4-15) and 2,2'-disulfanediylbis (3-(substituted-1-yl) propane-2,1-diyl) disubstituted-1-carbodithioates (19-28) as non-surfactant molecules capable of eliminating Trichomonas vaginalis as well as irreversibly immobilizing 100% human sperm promptly.
Spermicidal, anti-trichomonas, cytotoxicity and biocompatibility study of the synthesized compounds was done as per the reported methodologies.
Among bis(dialkylaminethiocarbonyl) disulfides (4-15, Table 1), compound 4 (MEC 0.02 mM) was found to be the most desirable for spermicidal activity as it was 40 times more active than Nonoxynol-9 (N-9), and also active against Trichomonas vaginalis (MIC 0.02 &1.10 mM). 2, 2'-disulfanediylbis (3-(substituted- 1-yl) propane-2, 1-diyl) disubstituted-1-carbodithioates (19-28, Table 2), and compounds (19, 22, 23, and 24 MEC 0.05 mM) were sixteen times more active than N-9 with promising Trichomonacidal activity.
This study suggested that the disulfide linkage alone and dithiocarbamate along with disulfide group within the same chemical entity impart the desired multiple activities of compounds.
在我们之前的工作中，已经合成了几种哌嗪衍生的双（二烷基氨基硫代羰基）二硫化物和二硫代氨基甲酸盐的二硫酯，并对其杀精和杀菌效果进行了评估。这些研究为开发一种处于临床前阶段的具有双重活性的阴道杀微生物避孕药提供了一些有前景的化合物。
本研究的主要目的是设计合成双（二烷基氨基硫代羰基）二硫化物（4 - 15）和2,2'-二硫代二亚基双（3 -（取代-1-基）丙烷-2,1-二基）二取代-1-碳二硫代酯（19 - 28），作为能够迅速消除阴道毛滴虫并使100%人类精子不可逆地失活的非表面活性剂分子。
按照报道的方法对合成的化合物进行杀精、抗滴虫、细胞毒性和生物相容性研究。
在双（二烷基氨基硫代羰基）二硫化物（4 - 15，表1）中，化合物4（最低有效浓度0.02 mM）被发现是杀精活性最理想的，因为它比壬苯醇醚-9（N - 9）活性高40倍，并且对阴道毛滴虫也有活性（最低抑菌浓度0.02和1.10 mM）。2,2'-二硫代二亚基双（3 -（取代-1-基）丙烷-2,1-二基）二取代-1-碳二硫代酯（19 - 28，表2），以及化合物（19、22、23和24，最低有效浓度0.05 mM）比N - 9活性高16倍，具有良好的抗滴虫活性。
本研究表明，在同一化学实体中，单独的二硫键以及二硫代氨基甲酸盐与二硫基团赋予了化合物所需的多种活性。
