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Substituted carbamothioic amine-1-carbothioic thioanhydrides as novel trichomonicidal fungicides: Design, synthesis, and biology
European Journal of Medicinal Chemistry ( IF 6.7 ) Pub Date : 2017-11-23 , DOI: 10.1016/j.ejmech.2017.11.060
Dhanaraju Mandalapu , Bhavana Kushwaha , Sonal Gupta , Shagun Krishna , Nidhi Srivastava , Mahendra Shukla , Pratiksha Singh , Bhavana S. Chauhan , Ravi Goyani , Jagdamba P. Maikhuri , Koneni V. Sashidhara , Brijesh Kumar , Renu Tripathi , Praveen K. Shukla , Mohammad I. Siddiqi , Jawahar Lal , Gopal Gupta , Vishnu L. Sharma

Sexually transmitted diseases like trichomoniasis along with opportunistic fungal infections like candidiasis are major global health burden in female reproductive health. In this context a novel non-nitroimidazole class of substituted carbamothioic amine-1-carbothioic thioanhydride series was designed, synthesized, evaluated for trichomonacidal and fungicidal activities, and was found to be more active than the standard drug Metronidazole (MTZ). Compounds were trichomonicidal in the MIC ranges of 4.77–294.1 μM and 32.46–735.20 μM against MTZ-susceptible and -resistant strains, respectively. Further, compounds inhibited the growth of at least two out of ten fungal strains tested at MIC of 7.50–240.38 μM. The most active compound (20) of this series was 3.8 and 9.5 fold more active than the MTZ against the two Trichomonas strains tested. Compound 20 also significantly inhibited the sulfhydryl groups present over Trichomonas vaginalis and was found to be more active than the MTZ in vivo. Further, a docking analysis carried out with cysteine proteases supported their thiol inhibiting ability and preliminary pharmacokinetic study has shown good distribution and systemic clearance.



中文翻译:

取代的氨基甲硫基胺-1-碳硫基硫代酸酐作为新型滴虫杀菌剂:设计,合成和生物学

性传播疾病(如滴虫病)以及机会性真菌感染(如念珠菌病)是女性生殖健康的主要全球健康负担。在这种情况下,设计,合成了一种新型的非硝基咪唑类的取代的氨基甲硫基胺-1-碳硫基硫代酸酐,评估了其对滴虫酸和杀真菌活性的活性,发现其比标准药物甲硝唑(MTZ)更具活性。化合物对于MTZ易感菌株和耐药菌株的MIC范围分别为4.77–294.1μM和32.46–735.20μM。此外,在MIC为7.50–240.38μM的情况下,化合物抑制了十个真菌菌株中至少两个的生长。该系列中活性最高的化合物(20)的活性比MTZ分别高出3.8和9.5倍测试了滴虫菌株。化合物20还显着抑制了阴道毛滴虫上存在的巯基,并被发现比体内的MTZ更具活性。此外,用半胱氨酸蛋白酶进行的对接分析支持了它们的硫醇抑制能力,并且初步的药代动力学研究表明良好的分布和全身清除率。

更新日期:2017-11-23
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