2-Methyl-4/5-nitroimidazole derivatives potentiated against sexually transmitted Trichomonas: Design, synthesis, biology and 3D-QSAR study

• Published in: European journal of medicinal chemistry Vol. 124; pp. 820 - 839
• Main Authors: Mandalapu, Dhanaraju, Kushwaha, Bhavana, Gupta, Sonal, Singh, Nidhi, Shukla, Mahendra, Kumar, Jitendra, Tanpula, Dilip K., Sankhwar, Satya N., Maikhuri, Jagdamba P., Siddiqi, Mohammad I., Lal, Jawahar, Gupta, Gopal, Sharma, Vishnu L.
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 29.11.2016; Elsevier
• Subjects: 4/5-Nitroimidazoles; Animals; Anti-Trichomonas; Chemistry Techniques, Synthetic; Chemistry, Medicinal; Dithiocarbamate; Drug Design; Drug Resistance - drug effects; HeLa Cells; Humans; Hybridization; Life Sciences & Biomedicine; Male; Metronidazole - pharmacology; Models, Molecular; Molecular Conformation; Nitroimidazoles - adverse effects; Nitroimidazoles - chemical synthesis; Nitroimidazoles - pharmacokinetics; Nitroimidazoles - pharmacology; Pharmacology & Pharmacy; Quantitative Structure-Activity Relationship; Rats; Resistant Trichomonas; Safety; Science & Technology; Sexually Transmitted Diseases - prevention & control; Trichomonas vaginalis - drug effects; Trichomonas vaginalis - physiology; TV; SAR; MIC; Anti-Trichomonas; 3D-QSAR; TLC; Hybridization; 4/5-Nitroimidazoles; HeLa; Resistant Trichomonas; LDH; DMEM; DTC; MTZ; STDs; PLS; IC50; Dithiocarbamate; NI; CoMFA; DOCKING; MICROBICIDES; DRUG-RESISTANCE; CELL-DEATH; DISULFIRAM; INFECTION; PARTIAL LEAST-SQUARES; METRONIDAZOLE; INHIBITOR; HYBRIDS
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2016.09.006

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. [Display omitted] •Sixty 2-methyl-4/5-nitroimidazoles were synthesized via ring opening of epoxide.•Evaluated for Metronidazole-susceptible and –resistant Trichomonas activity.•Many compounds were found more active than standard, MTZ against both the strains.•Compound 6 showed good in vivo activity and inhibited thiol groups on Trichomonas.•Prototype 1 was most effective over four different prototypes evaluated.