P44.01
Background: The growing health and economic burden of STIs, HIV, and population growth in resource-poor countries have led to integrate them and vaginal microbicides have emerged as an option with additional advantage of women control.
Methods: Fifteen N-alkyl/aryl-4-(3-substituted-3-phenylpropyl) piperazine-1-carbothioamide (13-27) derivatives were synthesized as topical vaginal microbicides and evaluated for anti-Trichomonas, spermicidal, antifungal and reverse transcriptase (RT) inhibitory activities. To assist the sulfhydryl (SH) binding molecular mechanism of synthesized compounds, hexokinase and DTNB assays were carried out because -SH group present over sperm and Trichomonas is vital for their survival. All compounds were tested for safety through cytotoxic assay against human cervical cell line (Hela) and compatibility with vaginal flora, Lactobacillus. Docking study of most promising vaginal microbicide (13) was carried out to find out its docking position and orientation in comparison to known RT inhibitor Nevirapine. The preliminary in vivo pharmacokinetics of compound 13 was performed in female NZ-rabbits to evaluate systemic toxicity in comparison to clinically used spermicide Nonoxynol-9.
Results: Compound 13 appeared as most favorable multiple active scaffold, comprising of RT inhibition (72.30%), spermicidal (MEC 0.01%), anti-Trichomonas (MIC 7.78 μg/mL) and antifungal (MIC 3.12-50 μg/mL) actions. The compound's low toxicity to HeLa cells and Lactobacillus growth would eventually favor vaginal administration. Hexokinase and DTNB assays proved the molecular mechanism involving SH binding. Compound 13 docked on RT in a position and orientation similar to the Nevirapine. In vivo pharmacokinetics of 13 suggested minimal side effects in comparison to N-9.
Conclusions: The study resulted into novel compound (13) as women controlled topical vaginal microbicidal spermicide possessing RT inhibitory activity in order to empower women to deal independently with their reproductive health and fertility.
