title: 2-Methyl-4/5-nitroimidazole derivatives potentiated against sexually transmitted Trichomonas: Design, synthesis, biology and 3D-QSAR study.
abstract: Trichomoniasis is the most prevalent, non-viral sexually transmitted diseases (STD) caused by amitochondriate protozoan Trichomonas vaginalis. Increased resistance of T. vaginalis to the marketed drug Metronidazole necessitates the development of newer chemical entities. A library of sixty 2-methyl-4/5-nitroimidazole derivatives was synthesized via nucleophilic ring opening reaction of epoxide and the efficacies against drug-susceptible and -resistant Trichomonas vaginalis were evaluated. All the molecules except two were found to be active against both susceptible and resistant strains with MICs ranging 8.55-336.70 μM and 28.80-1445.08 μM, respectively. Most of the compounds were remarkably more effective than the standard Metronidazole. This study analyzes the in vitro and in vivo activities of the new 5-nitroimidazoles, which were found to be safe against human cervical HeLa cells with good selectivity index. The exploration of SAR by the synthesis of four different prototypes and 3D-QSAR study has shown the importance of prototype 1 over other prototypes.
authors.affiliation: Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow, 226031, India.
authors.forename: Dhanaraju
authors.initials: D
authors.lastname: Mandalapu
authors.affiliation: Endocrinology Division, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow, 226031, India.
authors.forename: Bhavana
authors.initials: B
authors.lastname: Kushwaha
authors.affiliation: Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110001, India.
authors.forename: Sonal
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Molecular and Structural Biology Division, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow, 226031, India.
authors.forename: Nidhi
authors.initials: N
authors.lastname: Singh
authors.affiliation: Pharmacokinetic & Metabolism Division, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow, 226031, India.
authors.forename: Mahendra
authors.initials: M
authors.lastname: Shukla
authors.affiliation: Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Raebareli, 229 010, India.
authors.forename: Jitendra
authors.initials: J
authors.lastname: Kumar
authors.affiliation: Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Raebareli, 229 010, India.
authors.forename: Dilip K
authors.initials: DK
authors.lastname: Tanpula
authors.affiliation: Department of Urology, King George Medical University, Lucknow, 226003, India.
authors.forename: Satya N
authors.initials: SN
authors.lastname: Sankhwar
authors.affiliation: Endocrinology Division, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow, 226031, India.
authors.forename: Jagdamba P
authors.initials: JP
authors.lastname: Maikhuri
authors.affiliation: Molecular and Structural Biology Division, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow, 226031, India.
authors.forename: Mohammad I
authors.initials: MI
authors.lastname: Siddiqi
authors.affiliation: Pharmacokinetic & Metabolism Division, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow, 226031, India.
authors.forename: Jawahar
authors.initials: J
authors.lastname: Lal
authors.affiliation: Endocrinology Division, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110001, India.
authors.forename: Gopal
authors.initials: G
authors.lastname: Gupta
authors.affiliation: Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110001, India. Electronic address: vl_sharma@cdri.res.in.
authors.forename: Vishnu L
authors.initials: VL
authors.lastname: Sharma
mesh_terms: D000818:Animals; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D004351:Drug Resistance / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D008297:Male; D008795:Metronidazole / Q000494:pharmacology; D008958:Models, Molecular; D008968:Molecular Conformation; D009593:Nitroimidazoles / Q000009:adverse effects / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D012449:Safety; D012749:Sexually Transmitted Diseases / Q000517:prevention & control*; D014246:Trichomonas vaginalis / Q000187:drug effects* / Q000502:physiology
chemical_list: D009593:Nitroimidazoles; D008795:Metronidazole; C052587:4-nitroimidazole
keywords: 4/5-Nitroimidazoles; Anti-Trichomonas; Dithiocarbamate; Hybridization; Resistant Trichomonas