title: Potentiating Metronidazole Scaffold against Resistant Trichomonas: Design, Synthesis, Biology and 3D-QSAR Analysis.
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.
authors.affiliation: Medicinal & Process Chemistry Division, Endocrinology Division, and Molecular & Structural Biology Division, CSIR-Central Drug Research Institute , Lucknow-226001, India.
authors.forename: Lalit
authors.initials: L
authors.lastname: Kumar
authors.affiliation: Medicinal & Process Chemistry Division, Endocrinology Division, and Molecular & Structural Biology Division, CSIR-Central Drug Research Institute , Lucknow-226001, India.
authors.forename: Ashish
authors.initials: A
authors.lastname: Jain
authors.affiliation: Medicinal & Process Chemistry Division, Endocrinology Division, and Molecular & Structural Biology Division, CSIR-Central Drug Research Institute , Lucknow-226001, India.
authors.forename: Nand
authors.initials: N
authors.lastname: Lal
authors.affiliation: Medicinal & Process Chemistry Division, Endocrinology Division, and Molecular & Structural Biology Division, CSIR-Central Drug Research Institute , Lucknow-226001, India.
authors.forename: Amit
authors.initials: A
authors.lastname: Sarswat
authors.affiliation: Medicinal & Process Chemistry Division, Endocrinology Division, and Molecular & Structural Biology Division, CSIR-Central Drug Research Institute , Lucknow-226001, India.
authors.forename: Santosh
authors.initials: S
authors.lastname: Jangir
authors.affiliation: Medicinal & Process Chemistry Division, Endocrinology Division, and Molecular & Structural Biology Division, CSIR-Central Drug Research Institute , Lucknow-226001, India.
authors.forename: Lokesh
authors.initials: L
authors.lastname: Kumar
authors.affiliation: Medicinal & Process Chemistry Division, Endocrinology Division, and Molecular & Structural Biology Division, CSIR-Central Drug Research Institute , Lucknow-226001, India.
authors.forename: Vishal
authors.initials: V
authors.lastname: Singh
authors.affiliation: Medicinal & Process Chemistry Division, Endocrinology Division, and Molecular & Structural Biology Division, CSIR-Central Drug Research Institute , Lucknow-226001, India.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Shah
authors.affiliation: Department of Biotechnology, Jamia Hamdard University , New Delhi-110062, India.
authors.forename: Swatantra K
authors.initials: SK
authors.lastname: Jain
authors.affiliation: Medicinal & Process Chemistry Division, Endocrinology Division, and Molecular & Structural Biology Division, CSIR-Central Drug Research Institute , Lucknow-226001, India.
authors.forename: Jagdamba P
authors.initials: JP
authors.lastname: Maikhuri
authors.affiliation: Medicinal & Process Chemistry Division, Endocrinology Division, and Molecular & Structural Biology Division, CSIR-Central Drug Research Institute , Lucknow-226001, India.
authors.forename: Mohammad I
authors.initials: MI
authors.lastname: Siddiqi
authors.affiliation: Medicinal & Process Chemistry Division, Endocrinology Division, and Molecular & Structural Biology Division, CSIR-Central Drug Research Institute , Lucknow-226001, India.
authors.forename: Gopal
authors.initials: G
authors.lastname: Gupta
authors.affiliation: Medicinal & Process Chemistry Division, Endocrinology Division, and Molecular & Structural Biology Division, CSIR-Central Drug Research Institute , Lucknow-226001, India.
authors.forename: Vishnu L
authors.initials: VL
authors.lastname: Sharma
keywords: antitrichomonas; contraception; dithiocarbamate; metronidazole; microbicidal; piperidine