Design, synthesis and docking studies of some novel (R)-2-(4 '-chlorophenyl)-3-(4 '-nitrophenyl)-1,2,3,5-tetrahydrobenzo[4,5] imidazo [1,2-c]pyrimidin-4-ol derivatives as antitubercular agents

作者：Barot Kuldipsinh P; Jain Shailesh V; Gupta Nirzari; Kremer Laurent; Singh Shubhra; Takale Vijay B; Joshi Kruti; Ghate Manjunath D^*

来源：European Journal of Medicinal Chemistry, 2014, 83: 245-255.

DOI：10.1016/j.ejmech.2014.06.019

• Tuberculosis
• Docking study
• Benzimidazole derivatives
• In vitro antitubercular activity
• Cytotoxicity assay
• Structure-activity relationship (SAR)

Filamenting temperature-sensitive mutant (FtsZ) is a novel target for the treatment of tuberculosis. A series of (R)-2-(4'-chlorophenyl)-3-(4'-nitrophenyl)-1,2,3,5-tetrahydrobenzo[4,5] imidazo[1,2-c]pyrimidin-4-ol derivatives were designed and docked on the FtsZ protein crystal structure (PDB Id: I RLU, resolution 2.08 angstrom). Compound 7t showed the highest docking score and H-bond interaction with Arg140 and Gly19. Our strategy for synthesis of (R)-2-(4'-chlorophenyl)-3-(4'-nitrophenyl)-1,2,3,5-tetrahydrobenzo[4,5]imidazo[1,2-c]pyrimidin-4-ol derivatives from o-phenylenediamine as illustrated in scheme. All the synthesized compounds were characterized by FTIR, Mass spectra, H-1 NMR, C-13 NMR, elemental analysis and purity was confirmed by HPLC and LCMS. Compound 7g was also confirmed by single crystal X-ray analysis. The in silico results are also validated with in vitro antitubercular activity of compound 7t. Compound 7b exhibited in vitro antitubercular activity 3.13 mu g/mL and 4.7 mu g/mL whereas compound 7t exhibited in vitro antitubercular activity 6.25 mu g/mL and 9.4 mu g/mL using GAST/Fe medium after week 1 and week 2 respectively against Mycobacterium tuberculosis H(37)Rv. Medium 7H9/ADC/Tween was found to be very less effective for in vitro antitubercular activity of all the benzimidazole derivatives. Assays for in vitro cytotoxicity against VERO cells of all the synthesized compounds was found to be very less cytotoxic.

• 出版日期2014-8-18