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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

Riboflavin biosynthesis pathway
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Figure 1: Riboflavin biosynthesis pathway

Mentions: Lumazine synthase and riboflavin synthase catalyze the last two steps in the biosynthesis of riboflavin (4) [Figure 1]. The biosynthetic pathway starts off from one molecule of guanosine triphosphate,[567] which is converted to 5-amino-6-ribitylamino-2,4 (1H,3H)-pyrimidinedione (1) by a sequence of ring opening, deamination, reduction, and dephosphorylation.[89] Lumazine synthase catalyzes the condensation of 3,4-dihydroxy-2-butanone 4-phosphate (2) with 5-amino-6-ribitylamino-2,4-(1H,3H) pyrimidinedione (1) yielding 6,7-dimethyl-8-D-ribityllumazine (3).[10111213141516171819] The final process in the biosynthesis of riboflavin (4) involves a mechanistically unusual dismutation of two molecules of 6,7-dimethyl-8-D-ribityllumazine (3) that results in the formation of one molecule of riboflavin and one molecule of the pyrimidinedione derivative (1).[2021222324] Although the precise details remain to be established, the lumazine synthase-catalyzed reaction most likely proceeds along a mechanistic pathway involving the formation of the Schiff base (5), phosphate elimination affording (6), tautomerization to (7), ring closure, and dehydration to yield the lumazine (3) [Figure 2].[9] Variations of this mechanism are possible depending on the Schiff base geometry and possible isomerization, conformational changes, and the timing of phosphate elimination.


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)

Riboflavin biosynthesis pathway
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Riboflavin biosynthesis pathway
Mentions: Lumazine synthase and riboflavin synthase catalyze the last two steps in the biosynthesis of riboflavin (4) [Figure 1]. The biosynthetic pathway starts off from one molecule of guanosine triphosphate,[567] which is converted to 5-amino-6-ribitylamino-2,4 (1H,3H)-pyrimidinedione (1) by a sequence of ring opening, deamination, reduction, and dephosphorylation.[89] Lumazine synthase catalyzes the condensation of 3,4-dihydroxy-2-butanone 4-phosphate (2) with 5-amino-6-ribitylamino-2,4-(1H,3H) pyrimidinedione (1) yielding 6,7-dimethyl-8-D-ribityllumazine (3).[10111213141516171819] The final process in the biosynthesis of riboflavin (4) involves a mechanistically unusual dismutation of two molecules of 6,7-dimethyl-8-D-ribityllumazine (3) that results in the formation of one molecule of riboflavin and one molecule of the pyrimidinedione derivative (1).[2021222324] Although the precise details remain to be established, the lumazine synthase-catalyzed reaction most likely proceeds along a mechanistic pathway involving the formation of the Schiff base (5), phosphate elimination affording (6), tautomerization to (7), ring closure, and dehydration to yield the lumazine (3) [Figure 2].[9] Variations of this mechanism are possible depending on the Schiff base geometry and possible isomerization, conformational changes, and the timing of phosphate elimination.

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