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

• Published in: European journal of medicinal chemistry Vol. 83; pp. 245 - 255
• Main Authors: Barot, Kuldipsinh P., Jain, Shailesh V., Gupta, Nirzari, Kremer, Laurent, Singh, Shubhra, Takale, Vijay B., Joshi, Kruti, Ghate, Manjunath D.
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 18-08-2014
• Subjects: Animals; Antitubercular Agents - chemical synthesis; Antitubercular Agents - metabolism; Antitubercular Agents - pharmacology; Antitubercular Agents - toxicity; Bacterial Proteins - chemistry; Bacterial Proteins - metabolism; Benzimidazole derivatives; Cercopithecus aethiops; Chemistry Techniques, Synthetic; Cytoskeletal Proteins - chemistry; Cytoskeletal Proteins - metabolism; Cytotoxicity assay; Docking study; Drug Design; Imidazoles - chemical synthesis; Imidazoles - metabolism; Imidazoles - pharmacology; Imidazoles - toxicity; In vitro antitubercular activity; Molecular Docking Simulation; Mycobacterium tuberculosis - drug effects; Protein Conformation; Pyridines - chemical synthesis; Pyridines - metabolism; Pyridines - pharmacology; Pyridines - toxicity; Structure-Activity Relationship; Structure–activity relationship (SAR); Tuberculosis; Vero Cells; In vitro antitubercular activity; Cytotoxicity assay; Structure–activity relationship (SAR); Docking study; Tuberculosis; Benzimidazole derivatives
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2014.06.019

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: 1RLU, resolution 2.08 Å). 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, 1H NMR, 13C 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 μg/mL and 4.7 μg/mL whereas compound 7t exhibited in vitro antitubercular activity 6.25 μg/mL and 9.4 μg/mL using GAST/Fe medium after week 1 and week 2 respectively against Mycobacterium tuberculosis H37Rv. 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.
[Display omitted]
•Novel imidazo [1,2-c]pyrimidin-4-ol derivatives are designed.•Molecular docking study was carried out.•Synthetic methodologies leading to targeted molecules have been reported.•X-ray crystallographic study (ORTEP) of compound 7g was carried out.•Compounds are subjected to screening for antitubercular activity and cytotoxicity assay.