title: 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.
abstract: 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, (1)H NMR, (13)C 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.
authors: Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad 382481, Gujarat, India.
authors: Kuldipsinh P
authors: KP
authors: Barot
authors: Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad 382481, Gujarat, India.
authors: Shailesh V
authors: SV
authors: Jain
authors: Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad 382481, Gujarat, India.
authors: Nirzari
authors: N
authors: Gupta
authors: Laboratoire de Dynamique des Interactions Normales et Pathologiques, CNRS UMR 5235, Université Montpellier 2, Eugène Bataillon, 34 095 Montpellier Cedex 5, France; INSERM, DIMNP, Place Eugène Bataillon, 34 095 Montpellier Cedex 05, France.
authors: Laurent
authors: L
authors: Kremer
authors: Laboratoire de Dynamique des Interactions Normales et Pathologiques, CNRS UMR 5235, Université Montpellier 2, Eugène Bataillon, 34 095 Montpellier Cedex 5, France; IFTM University, Lodhipur Rajput, Delhi Road, Moradabad 244102, Uttar Pradesh, India; CSIR, Central Drug Research Institute (CDRI), Sector-10, Sitapur Road, Lucknow 226031, India.
authors: Shubhra
authors: S
authors: Singh
authors: Research & Development Department, Piramal Discovery Solution Ltd, Ahmedabad 382213, Gujarat, India.
authors: Vijay B
authors: VB
authors: Takale
authors: Research & Development Department, Piramal Discovery Solution Ltd, Ahmedabad 382213, Gujarat, India.
authors: Kruti
authors: K
authors: Joshi
authors: Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad 382481, Gujarat, India. Electronic address: barotkuldip@gmail.com.
authors: Manjunath D
authors: MD
authors: Ghate
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism; D060326:Chemistry Techniques, Synthetic; D002522:Chlorocebus aethiops; D003598:Cytoskeletal Proteins / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D007093:Imidazoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D062105:Molecular Docking Simulation; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D011487:Protein Conformation; D011725:Pyridines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D013329:Structure-Activity Relationship; D014709:Vero Cells
chemical_list: C000596334:2-(4'-chlorophenyl)-3-(4'-nitrophenyl)-1,2,3,5-tetrahydrobenzo(4,5)imidazo(1,2-c)pyrimidin-4-ol; D000995:Antitubercular Agents; D001426:Bacterial Proteins; D003598:Cytoskeletal Proteins; C071525:FtsZ protein, Bacteria; D007093:Imidazoles; D011725:Pyridines
keywords: Benzimidazole derivatives; Cytotoxicity assay; Docking study; In vitro antitubercular activity; Structure–activity relationship (SAR); Tuberculosis