Design, synthesis and docking studies of benzimidazole derivatives as potential EGFR inhibitors.

In this study, a series of benzimidazoles bearing thiosemicarbazide chain or triazole and thiadiazole rings were designed and synthesized. Crystal and molecular structure of the compound 5c has been characterized by single crystal X-ray crystallographic analysis. EGFR kinase inhibitory potencies of synthesized compounds were compared with erlotinib in vitro and most of the compounds exhibited significant activities. Cell culture studies were also carried out for selected compounds and 12b was found to be the most active compound. To understand the binding mode of synthesized benzimidazoles, three compounds (12b, 16, 16c) were selected and placed on the binding site of EGFR tyrosine kinase based on their kinase inhibitor potencies and cell culture studies. Docking study indicated that compound 12b showed two-hydrogen bonding interactions with residues of LYS721 and THR830 at the binding pocket.

Synthesis and Pharmacologic Evaluation of Some Benzimidazole Acetohydrazide Derivatives as EGFR Inhibitors.

OBJECTIVES: In this study, some novel 2-(2-phenyl)-1H-benzo[d]imidazol-1-yl)-N'-(arylmethylene) acetohydrazide derivatives (1-12) were designed and synthesized. MATERIALS AND METHODS: Compounds 1-12 were obtained by condensing 2-(2-phenyl)-1H-benzo[d]imidazol-1-yl)acetohydrazide (III) with the corresponding aromatic aldehyde derivatives in the presence of catalytic amounts of hydrochloric acid in ethanol. RESULTS: Following the structure elucidation, epidermal growth factor receptor kinase inhibitor activity was measured. The ADP-GloTM kinase assay determines kinase activity based on the quantification of the amount of ADP produced during a kinase reaction. CONCLUSION: Almost all of the compounds' kinase inhibitor activities were rather limited.

Identification of a novel series of N-phenyl-5-[(2-phenylbenzimidazol-1-yl)methyl]-1,3,4-oxadiazol-2-amines as potent antioxidants and radical scavengers.

In this study, some novel 5-[[2-(phenyl/p-chlorophenyl)-benzimidazol-1-yl]-methyl]-N-substituted phenyl-1,3,4-oxadiazol-2-amine derivatives (28-45) with an oxadiazole ring were synthesized. The antioxidant properties and radical scavenging activities of the compounds were investigated employing various in vitro systems: hepatic microsomal NADPH-dependent inhibition of lipid peroxidation levels, scavenging of DPPH free radicals, and inhibition of microsomal ethoxyresorufin O-deethylase activity (EROD). Compounds 34 and 41 were found to be good scavengers of DPPH radicals (76% and 84%) when compared to BHT (90%). Almost all of the compounds examined were found to possess a good inhibitor effect on the microsomal EROD activity. Moreover, 32 and 41 were more active analogs (97% and 98%) on the microsomal EROD activity than caffeine (85%).

Design and one-pot and microwave-assisted synthesis of 2-amino/5-aryl-1,3,4-oxadiazoles bearing a benzimidazole moiety as antioxidants.

In this study, two new series of 2-amino-1,3,4-oxadiazoles and 5-aryl-1,3,4-oxadiazoles carrying a benzimidazole moiety were synthesized. The antioxidant properties of these compounds were investigated in vitro by the determination of the microsomal NADPH-dependent inhibition of lipid peroxidation levels (LP), the microsomal ethoxyresorufin O-deethylase activity (EROD), and DPPH radical scavenger effects. Among the tested compounds, 2-[(2-(4-chlorophenyl)-1H-benzo[d]imidazole-1-yl)methyl]-5-(4-fluorophenyl)-1,3,4-oxadiazole (9) was found to be the most active compound in all three in vitro systems.

Synthesis and evaluation of antioxidant properties of novel 2-[2-(4-chlorophenyl) benzimidazole-1-yl]-N-(2-arylmethylene amino) acetamides and 2-[2-(4-chlorophenyl) benzimidazole-1-yl]-N-(4-oxo-2-aryl-thiazolidine-3-yl) acetamides-I.

Our approach was to synthesize and examine the antioxidant properties of some new 2-[2-(4-chlorophenyl)benzimidazole-1-yl]-N-(2-arylmethyleneamino) acetamide (1-18) and 2-[2-(4-chlorophenyl)benzimidazole-1-yl]-N-(4-oxo-2-aryl-thiazolidine-3-yl)acetamide (1t-18t) derivatives. Their in vitro effects on rat liver microsomal NADPH-dependent lipid peroxidation levels (LP assay) and microsomal ethoxyresorufin O-deethylase activities (EROD assay) were determined. The free radical scavenging properties of the compounds were also examined in vitro determining the interaction of 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical. The compounds showed significant effects in the above tests.

Synthesis and antioxidant properties of novel N-methyl-1,3,4-thiadiazol-2-amine and 4-methyl-2H-1,2,4-triazole-3(4H)-thione derivatives of benzimidazole class.

Some novel 1-methyl-4-(2-(2-substitutedphenyl-1H-benzimidazol-1-yl)acetyl)thiosemicarbazides (16a-20a), 5-[(2-(substitutedphenyl)-1H-benzimidazol-1-yl)methyl]-N-methyl-1,3,4-thiadiazol-2-amines (17b-20b), and 5-[(2-(substitutedphenyl)-1H-benzimidazol-1-yl)methyl-4-methyl-2H-1,2,4-triazole-3(4H)-thiones (16c-20c) were synthesized and tested for antioxidant properties by using various in vitro systems. Compounds 16a-20a were found to be a good scavenger of DPPH radical (IC(50), 26 microM; IC(50), 30 microM; IC(50), 43 microM; IC(50), 55 microM; IC(50), 74 microM, respectively) when compared to BHT (IC(50), 54 microM). Noteworthy results could not be found on superoxide radical. Compound 19b, which is the most active derivative inhibited slightly lipid peroxidation (28%) at 10(-3)M concentration. Compound 17c inhibited the microsomal ethoxyresorufin O-deethylase (EROD) activity with an IC(50)=4.5 x 10(-4)M which is similarly better than the specific inhibitor caffeine IC(50)=5.2 x 10(-4)M.

Synthesis and antioxidant capacities of some new benzimidazole derivatives.

In this study, we prepared some new oxadiazolyl benzimidazole derivatives and investigated their antioxidant properties by determination of microsomal NADPH-dependent inhibition of lipid peroxidation levels (LP assay) and microsomal ethoxyresorufin O-deethylase activity (EROD assay). Some of these compounds 20, 23 had slightly inhibitory effects (28%) on the lipid peroxidation levels at 10(-3 )M concentration lower than standard BHT (65%). 5-[2-(Phenyl)-benzimidazol-1-yl-methyl]-2-mercapto-[1,3,4]-oxadiazole 16 was found to be more active than caffeine on the ethoxyresorufin O-deethylase activity with an IC(50 )value of 2.0 6 10(-4 )M.

Synthesis, antifungal and antioxidant screening of some novel benzimidazole derivatives.

Some novel benzimidazole derivatives were synthesized and their in vitro effects on rat liver microsomal NADPH-dependent lipid peroxidation (LP) level, ethoxyresorufin O-deethylase (EROD) and antifungal activities were determined. A significant decrease in male rat liver microsomal LP level was noted by compounds 4c (52%), 4e (58%) and 4h (43%) at 10(-3) M concentration. Compounds 4c (100.0%), 4h (100.0%), 5c (98.0%) and 5h (100.0%) inhibited the microsomal ethoxyresorufin O-deethylase (EROD) enzyme activity better than that of the specific inhibitor caffeine (85%). Among these compounds, only compounds 4b and 4h exhibited moderate activity against C. albicans whereas the others had weak effects.

Synthesis, antioxidant and radical scavenging activities of novel benzimidazoles.

The synthesis and antioxidant evaluation of some novel benzimidazole derivatives (10-24) are described. Antioxidant properties of the compounds were investigated employing various in vitro systems viz., microsomal NADPH-dependent inhibition of lipid peroxidation (LP), interaction of 2,2-diphenyl-1-picrylhydrazyl (DPPH) and scavenging of superoxide anion radical. Compounds 12 and 13 showed very good antioxidant capacity and were 17-18-fold more potent than BHT (IC50 2.3 x 10(-4) M) with 1.3 x 10(-5) M and 1.2 x 10(-5) M IC50 values, respectively, by interaction of the stable DPPH free radical.

Antibacterial 4-amino-N-(5-methylisoxazol-3-yl)-N-[(4-oxo-2-phenyl-4H-1-benzopyran-6-yl)methyl]benzenesulfonamide.

In the molecule of the title compound, C26H21N3O5S, a new type of sulfonamide derivative with potential antibacterial activity, the flavone moiety is almost planar. The isoxazole and aminophenyl rings are also planar and make dihedral angles of 77.0 (2) and 81.4 (1) degrees , respectively, with the best plane of the flavone ring system. The crystal structure is stabilized by intra- and intermolecular hydrogen bonds.

Synthesis and antioxidant properties of novel benzimidazole derivatives.

Some novel benzimidazole derivatives carrying thiosemicarbazide and triazole moieties at the N1 position were synthesized and their in vitro effects on rat liver microsomal NADPH-dependent lipid peroxidation (LP) levels determined by measuring the formation of 2-thiobarbituric acid reactive substance. The free radical scavenging properties of the compounds were also examined in vitro by determining the capacity to scavenge superoxide anion formation and the interaction with the stable free radical 2,2-diphenyl-1-picrylhydrazyl (DPPH). The compounds showed a significant effect in the above tests except to scavenge superoxide anion formation.

Antioxidant properties of flavone-6(4')-carboxaldehyde oxime ether derivatives.

The in vitro antioxidant properties of some flavone-6(4)-carboxaldehyde oxime ether derivatives (Ia-f, IIa-f) were determined by their effects on the rat liver microsomal NADPH-dependent lipid peroxidation (LP) levels by measuring the formation of 2-thiobarbituric acid reactive substances. The free radical scavenging properties of the compounds were also examined in vitro by determining their capacity to scavenge superoxide anions and interact with the stable free radical 2, 2-diphenyl-1-picrylhydrazyl (DPPH). The most active compounds, IIb (Flavone-4'-carboxaldehyde-O-ethyl oxime) and Id (Flavone-6-carboxaldehyde-O-[2-(1-pyrolidino) ethyl] oxime), caused 98 and 79% inhibition of superoxide anion production and DPPH stable free radical at 10(-3) M, respectively.

Evaluation of the antioxidant effects of some flavonylthiazolidinediones by determining their effects on lipid peroxidation, superoxide anion formation, and 2,2-diphenyl-1-picrylhydrazyl stable free radical.

The in vitro antioxidant effects of some flavonylthiazolidinediones (Ia-d, IIa-d) on rat liver microsomal NADPH-dependent lipid peroxidation (LP) levels were determined by measuring the formation of 2-thiobarbituric acid reactive substance. The free radical-scavenging properties of the compounds were examined in vitro by determining the capacity to scavenge superoxide anion formation and of the interaction with the stable free radical 2,2-diphenyl-1-picrylhydrazyl (DPPH). The compounds had no inhibitory effects on LP. However, they had variable inhibitory influence on superoxide anion production and DPPH radical in a concentration-dependent manner. The most active compound, 3-(2,5-dimethoxyphenacyl)-5-[2-phenyl-4H-4-oxo-1-benzopyran-6-yl)methylenyl]-thiazolidine-2,4-dione, Id showed 98% inhibition of superoxide anion production and 95% inhibition of DPPH stable free radical at 10(-3) M.

Synthesis and antioxidant properties of some novel benzimidazole derivatives on lipid peroxidation in the rat liver.

Some benzimidazole derivatives namely 1-[(substituted thiocarbamoylhydrazine carbonyl) methyl]-2-phenyl-1H-benzimidazoles (1a-13a), N-[(2-phenylbenzimidazol-1-yl methyl)-[1,3,4]-thiadiazole-2-yl]-substituted phenyl amines (1b-13b) and 5-(2-phenyl benzimidazol-1-yl-methyl)-4-substituted phenyl-4H-1,2,4-triazole-3-thiones (1c-13c) were synthesized, and their in vitro effects on the rat liver microsomal NADPH-dependent lipid peroxidation (LP) levels were determined. The most active compound 10a caused an 84% inhibition of LP at 10(-3) M, which is better than that of butylated hydroxytoluene (BHT) (65%).

Synthesis and antimicrobial activities of some new benzimidazole derivatives.

Some benzimidazolylbenzamides were synthesized and their antimicrobial activities against Staphylococcus aureus, Streptococcus faecalis, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa and Candida albicans evaluated. It was shown that the compound 14 exhibited the best activity against B. subtilis, P. aeruginosa and C. albicans.

Synthesis and hypoglycemic activity of some substituted flavonyl thiazolidinedione derivatives--fifth communication: flavonyl benzyl substituted 2,4-thiazolidinediones.

A new series of 3-benzyl(p-substituted benzyl)-5-[3'-(4H-4-oxo-1-benzopyran-2-yl)-benzylidene]-2,4-thiazolidinediones (8a-e) were synthesized. These products were prepared by Knoevenagel reaction from 3'-flavone carboxaldehyde and 3-substituted 2,4-thiazolidinediones. In vitro insulinotropic activity was determined for compounds 6a-e, 7a-e, 8b and 8c.