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In-silico docking based design and synthesis of [1H,3H] imidazo[4,5-b] pyridines as lumazine synthase inhibitors for their effective antimicrobial activity.

Harer SL, Bhatia MS - J Pharm Bioallied Sci (2014)

Bottom Line: In-silico docking suggests H-bonding, hydrophobic interaction, charge interaction, aromatic interaction, and Vanderwaal forces responsible for stabilizing enzyme-inhibitor complex.Disc diffusion assay method was used for in vitro antimicrobial screening.The superiority of 1H imidazo [4,5-b] pyridine compounds having R' = Cl >No2 > NH2 at the phenyl/aliphatic moiety resident on the imidazopyridine, whereas leading 3H imidazo[4,5-b] pyridine compounds containing R/Ar = Cl > No2 > NH2> OCH3 substituents on the 2(nd) position of imidazole.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Chemistry, Bharati Vidyapeeth College of Pharmacy, Kolhapur, Maharashtra, India.

ABSTRACT

Purpose: The imidazopyridine moiety is important pharmacophore that has proven to be useful for a number of biologically relevant targets, also reported to display antibacterial, antifungal, antiviral properties. Riboflavin biosynthesis involving catalytic step of Lumazine synthase is absent in animals and human, but present in microorganism, one of marked advantage of this study. Still, this path is not exploited as antiinfective target. Here, we proposed different interactions between [1H,3H] imidazo[4,5-b] pyridine test ligands and target protein Lumazine synthase (protein Data Bank 2C92), one-step synthesis of title compounds and further evaluation of them for in vitro antimicrobial activity.

Materials and methods: Active pocket of the target protein involved in the interaction with the test ligands molecules was found using Biopredicta tools in VLifeMDS 4.3 Suite. In-silico docking suggests H-bonding, hydrophobic interaction, charge interaction, aromatic interaction, and Vanderwaal forces responsible for stabilizing enzyme-inhibitor complex. Disc diffusion assay method was used for in vitro antimicrobial screening.

Results and discussion: Investigation of possible interaction between test ligands and target lumazine synthase of Mycobacterium tuberculosis suggested 1i and 2f as best fit candidates showing hydrogen bonding, hydrophobic, aromatic and Vanderwaal's forces. Among all derivatives 1g, 1j, 1k, 1l, 2a, 2c, 2d, 2e, 2h, and 2j exhibited potent activities against bacteria and fungi compared to the standard Ciprofloxacin and Fluconazole, respectively. The superiority of 1H imidazo [4,5-b] pyridine compounds having R' = Cl >No2 > NH2 at the phenyl/aliphatic moiety resident on the imidazopyridine, whereas leading 3H imidazo[4,5-b] pyridine compounds containing R/Ar = Cl > No2 > NH2> OCH3 substituents on the 2(nd) position of imidazole.

No MeSH data available.


Related in: MedlinePlus

Hydrogen bond Interaction of 2-(2-nitrophenyl)-3H-imidazo[4,5-b]pyridine(1i) with GLU122C (2.348 A°, 2.528 A°)
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Figure 4: Hydrogen bond Interaction of 2-(2-nitrophenyl)-3H-imidazo[4,5-b]pyridine(1i) with GLU122C (2.348 A°, 2.528 A°)

Mentions: The crystal structures of the target protein was obtained from PDB and saved in standard three-dimensional coordinate format. The PDB is a repository for three-dimensional structural data of proteins and nucleic acids. This database provides the three-dimensional structure of all the proteins by NMR or by X-ray crystallography. After conducting adequate literature review lumazine synthase of M. tuberculosis (PDB entry code 2C92) was selected as the target for the present study. Preparation of ligands was done by drawing the structures using ChemSketch 12 (ACD) Advanced Chemistry Development (USA) and Chem Draw Ultra 7 Cambridge Soft Chem Draw Ultra in two-dimensional and saved as MDL Molfile format. Further conversion of ligands to three-dimensional format using VLife Engine tools of VlifeMDS 4.3 VLifesciences, A Division of NovaLead Pharma Pvt Ltd, Pune. Protein visualization was done by loading the structure in SWISS PDB viewer. Further the Energy Minimization was performed by VlifeMDS 4.3 docking suite. Docking simulations were performed with Biopredicta tool using grip docking mode. The number of docking runs was set to 10. Different types of binding interactions were studied between docked three-dimensional test ligands and three-dimensional macromolecule target [Figures 4-7].


In-silico docking based design and synthesis of [1H,3H] imidazo[4,5-b] pyridines as lumazine synthase inhibitors for their effective antimicrobial activity.

Harer SL, Bhatia MS - J Pharm Bioallied Sci (2014)

Hydrogen bond Interaction of 2-(2-nitrophenyl)-3H-imidazo[4,5-b]pyridine(1i) with GLU122C (2.348 A°, 2.528 A°)
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4231389&req=5

Figure 4: Hydrogen bond Interaction of 2-(2-nitrophenyl)-3H-imidazo[4,5-b]pyridine(1i) with GLU122C (2.348 A°, 2.528 A°)
Mentions: The crystal structures of the target protein was obtained from PDB and saved in standard three-dimensional coordinate format. The PDB is a repository for three-dimensional structural data of proteins and nucleic acids. This database provides the three-dimensional structure of all the proteins by NMR or by X-ray crystallography. After conducting adequate literature review lumazine synthase of M. tuberculosis (PDB entry code 2C92) was selected as the target for the present study. Preparation of ligands was done by drawing the structures using ChemSketch 12 (ACD) Advanced Chemistry Development (USA) and Chem Draw Ultra 7 Cambridge Soft Chem Draw Ultra in two-dimensional and saved as MDL Molfile format. Further conversion of ligands to three-dimensional format using VLife Engine tools of VlifeMDS 4.3 VLifesciences, A Division of NovaLead Pharma Pvt Ltd, Pune. Protein visualization was done by loading the structure in SWISS PDB viewer. Further the Energy Minimization was performed by VlifeMDS 4.3 docking suite. Docking simulations were performed with Biopredicta tool using grip docking mode. The number of docking runs was set to 10. Different types of binding interactions were studied between docked three-dimensional test ligands and three-dimensional macromolecule target [Figures 4-7].

Bottom Line: In-silico docking suggests H-bonding, hydrophobic interaction, charge interaction, aromatic interaction, and Vanderwaal forces responsible for stabilizing enzyme-inhibitor complex.Disc diffusion assay method was used for in vitro antimicrobial screening.The superiority of 1H imidazo [4,5-b] pyridine compounds having R' = Cl >No2 > NH2 at the phenyl/aliphatic moiety resident on the imidazopyridine, whereas leading 3H imidazo[4,5-b] pyridine compounds containing R/Ar = Cl > No2 > NH2> OCH3 substituents on the 2(nd) position of imidazole.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Chemistry, Bharati Vidyapeeth College of Pharmacy, Kolhapur, Maharashtra, India.

ABSTRACT

Purpose: The imidazopyridine moiety is important pharmacophore that has proven to be useful for a number of biologically relevant targets, also reported to display antibacterial, antifungal, antiviral properties. Riboflavin biosynthesis involving catalytic step of Lumazine synthase is absent in animals and human, but present in microorganism, one of marked advantage of this study. Still, this path is not exploited as antiinfective target. Here, we proposed different interactions between [1H,3H] imidazo[4,5-b] pyridine test ligands and target protein Lumazine synthase (protein Data Bank 2C92), one-step synthesis of title compounds and further evaluation of them for in vitro antimicrobial activity.

Materials and methods: Active pocket of the target protein involved in the interaction with the test ligands molecules was found using Biopredicta tools in VLifeMDS 4.3 Suite. In-silico docking suggests H-bonding, hydrophobic interaction, charge interaction, aromatic interaction, and Vanderwaal forces responsible for stabilizing enzyme-inhibitor complex. Disc diffusion assay method was used for in vitro antimicrobial screening.

Results and discussion: Investigation of possible interaction between test ligands and target lumazine synthase of Mycobacterium tuberculosis suggested 1i and 2f as best fit candidates showing hydrogen bonding, hydrophobic, aromatic and Vanderwaal's forces. Among all derivatives 1g, 1j, 1k, 1l, 2a, 2c, 2d, 2e, 2h, and 2j exhibited potent activities against bacteria and fungi compared to the standard Ciprofloxacin and Fluconazole, respectively. The superiority of 1H imidazo [4,5-b] pyridine compounds having R' = Cl >No2 > NH2 at the phenyl/aliphatic moiety resident on the imidazopyridine, whereas leading 3H imidazo[4,5-b] pyridine compounds containing R/Ar = Cl > No2 > NH2> OCH3 substituents on the 2(nd) position of imidazole.

No MeSH data available.


Related in: MedlinePlus