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[摘要]：Metronidazole (MTZ), the FDA-approved drug against Trichomonas vaginalis (TV), is being challenged seriously by drug resistance, while its inertness to sperm makes it ineffective as a vaginal contraceptive. Thirteen piperidine dithiocarbamate hybrids of 2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethane (8-20) were designed to potentiate the MTZ framework against drug resistance and sperm. New compounds were 1.2-12.1 times more effective against MTZ-susceptible and -resistant strains of TV. All of the compounds exhibited high safety toward cervical (HeLa) cells and Lactobacillus. Thirty-eight compounds were scrutinized by CoMFA and CoMSIA techniques of 3D quantitative structure activity relationship. Good predictive r(pred)(2) values for CoMFA and CoMSIA models reflected the robustness of the predictive ability. This was validated by designing five new analogues (46-50), which were potently microbicidal (3-10 and 10-20 times against MTZ-susceptible and -resistant TV, respectively) and spermicidal. This in vitro study may have significant clinical relevance, which could become evident in due course. |
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