Dataset Information

Imidazo[1,2-a]pyridines That Directly Interact with Hepatitis C NS4B: Initial Preclinical Characterization.

ABSTRACT: A series of imidazo[1,2-a]pyridines which directly bind to HCV Non-Structural Protein 4B (NS4B) is described. This series demonstrates potent in vitro inhibition of HCV replication (EC50 < 10 nM), direct binding to purified NS4B protein (IC50 < 20 nM), and an HCV resistance pattern associated with NS4B (H94N/R, V105L/M, F98L) that are unique among reported HCV clinical assets, suggestive of the potential for additive or synergistic combination with other small molecule inhibitors of HCV replication.

SUBMITTER: Shotwell JB

PROVIDER: S-EPMC4025644 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Imidazo[1,2-a]pyridines That Directly Interact with Hepatitis C NS4B: Initial Preclinical Characterization.

Shotwell J Brad JB Baskaran Subramanian S Chong Pek P Creech Katrina L KL Crosby Renae M RM Dickson Hamilton H Fang Jing J Garrido Dulce D Mathis Amanda A Maung Jack J Parks Derek J DJ Pouliot Jeffrey J JJ Price Daniel J DJ Rai Roopa R Seal John W JW Schmitz Uli U Tai Vincent W F VW Thomson Michael M Xie Mi M Xiong Zhiping Z ZZ Peat Andrew J AJ

ACS medicinal chemistry letters 20120524 7

A series of imidazo[1,2-a]pyridines which directly bind to HCV Non-Structural Protein 4B (NS4B) is described. This series demonstrates potent in vitro inhibition of HCV replication (EC50 < 10 nM), direct binding to purified NS4B protein (IC50 < 20 nM), and an HCV resistance pattern associated with NS4B (H94N/R, V105L/M, F98L) that are unique among reported HCV clinical assets, suggestive of the potential for additive or synergistic combination with other small molecule inhibitors of HCV replicat ...[more]

PMID: 24900511

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Project description:Background?-Bromination of the side chain of aromatic ketones using NBS in the presence of p-toluenesulfonic acid (p-TsOH) in acetonitrile is very common. However, regioselective bromination of bis and tris(?-bromoacetophenones) with NBS in the presence of p-TsOH in acetonitrile under microwave irradiation is quite novel. The bis- and tris(?-bromoacetophenones) are used in synthesis of bis and tris(heterocycles). bis(heterocycles) have received a great deal of attention, because many biologically active natural and synthetic products have molecular symmetry. The use of the pressurized microwave irradiation is very advantageous to many syntheses and provide a large rate enhancement.ResultsBis and tris(?-bromoacetophenones) were obtained as single monobrominated derivatives in a shorter time than the conventional conditions. The results clearly demonstrate the better reactivity and selectivity of NBS/p-TsOH/CH3CN as a brominating mixture under microwave conditions. The reaction of bis and tris(?-bromoacetophenone) with 2-aminopyridine and 2-aminopyrimidine proceeded smoothly in a mixture of anhydrous ethanol and DMF under reflux or using 300 W/105°C/ 20 min microwave irradiation conditions to afford the corresponding bis(imidazo[1,2-a]pyridine), bis(imidazo[1,2-a]pyrimidine) and tris(imidazo[1,2-a]pyridine) derivatives in moderate to excellent yields. The carbonyl analogue of the targeted bis(imidazopyridines) could be synthesized by the reaction of N,N-dimethyl-N'-(pyridin-2-yl)formimidamide with bis(?-bromoacetophenone) in refluxing ethanol. The structures of the newly synthesized compounds were confirmed by their spectral data as well as their elemental analyses.ConclusionIn conclusion, selective ?-bromination of bis- and tris(acetophenones) has been accomplished efficiently utilizing NBS/p-TsOH/CH3CN under microwave irradiation. In addition, a facile synthesis of novel series of bis- and tris(imidazopyridine) and bis(imidazopyrimidine) derivatives.

Dataset Information

Imidazo[1,2-a]pyridines That Directly Interact with Hepatitis C NS4B: Initial Preclinical Characterization.

Publications

Imidazo[1,2-a]pyridines That Directly Interact with Hepatitis C NS4B: Initial Preclinical Characterization.

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