2. Academic Validation
  3. Potentiating Metronidazole Scaffold against Resistant Trichomonas: Design, Synthesis, Biology and 3D-QSAR Analysis

Potentiating Metronidazole Scaffold against Resistant Trichomonas: Design, Synthesis, Biology and 3D-QSAR Analysis

  • ACS Med Chem Lett. 2011 Dec 16;3(2):83-7. doi: 10.1021/ml200161t.
Lalit Kumar 1,  Ashish Jain 1,  Nand Lal 1,  Amit Sarswat 1,  Santosh Jangir 1,  Lokesh Kumar 1,  Vishal Singh 1,  Priyanka Shah 1,  Swatantra K Jain 2,  Jagdamba P Maikhuri 1,  Mohammad I Siddiqi 1,  Gopal Gupta 1,  Vishnu L Sharma 1
Affiliations

Affiliations

  • 1 Medicinal & Process Chemistry Division, Endocrinology Division, and Molecular & Structural Biology Division, CSIR-Central Drug Research Institute , Lucknow-226001, India.
  • 2 Department of Biotechnology, Jamia Hamdard University , New Delhi-110062, India.
PMID: 24900434 DOI: 10.1021/ml200161t
Abstract

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.

Keywords

antitrichomonas; contraception; dithiocarbamate; metronidazole; microbicidal; piperidine.

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