Doğu Nebioğlu

Synthesis and receptor docking studies of N-substituted indole-2-carboxylic acid esters as a search for COX-2 selective enzyme inhibitors

A series of N-substituted indole-2-carboxylic acid esters have been prepared by replacing the benzoyl group of indomethacin with a benzyl and a phenyl group. The carbocyclic acid side chain was extended via creating an ester structure by using several dialkylaminoalkyl groups. The receptor docking studies were performed to investigate the docking mode of each compound by using DOCK 4.0. All the compounds were shown to be docked at the site where intact flurbiprofen was embedded for COX-1 and s-58 (1-phenylsulphonamide-3-trifluoromethyl-5-para-bromophenylpyrazole) for COX-2. It was predicted that N-phenyl-indole-2-carboxylic acid piperazine ester 22 can be a fairly strong COX-2 selective compound which was compared to the others. Other predicted COX-2 selective compounds included are N--H indole-2-carboxylic acid diethyl 30 and piperazine 34 esters. In view of these findings, compounds 22, 30 and 34 were chosen for the in vitro biological assays.

Synthesis and biological evaluation of N-substituted indole esters as inhibitors of cyclo-oxygenase-2 (COX-2)

A series of novel N-substituted indole carboxylic, acetic and propionic acid esters have been prepared as possible cyclo-oxygenase-2 (COX-2) enzyme inhibitors. Compounds 20, 23 were found slightly active against COX-2. The synthesis of indole carboxylic, acetic and propionic acid esters were furnished by using dicyclohexyl carbodiimide (DCC), dimethylamino pyridine (DMAP) as carboxylate activators. N-substitution of indole esters was verified with several benzyl and benzoyl group in presence of NaH in DMF, respectively.

New potent indole derivatives as hyaluronidase inhibitors.

Because of the physiologic importance of hyaluronidases, the identification of potent and selective inhibitors of hyaluronidases has become increasingly important. A variety of assay methods have been used for such a purpose, i.e. classical turbidimetric, viscometric and colorimetric. In this study, a modified enzymatic assay has been used to obtain a microtiter plate‐based sensitive activity screening. All inhibitors were tested in a stains‐all assay at pH 7 and in a Morgan‐Elson assay at pH 3.5. Among the tested compounds, 1, 2, 3, 6, 7, 8, 16, 17 and 18 showed good inhibition of more than 50%, so the IC50 values of these derivatives were determined in the range of 25–41 μm. The IC50 value of the most active hyaluronidase inhibitor Vcpal (6‐palmitoyl‐l‐ascorbic acid) was measured as 8.36 μm. All inhibitors including Vcpal showed twofold less activity at pH 3.5 in a Morgan‐Elson assay. Examination of substituent effects on the activity showed that para‐positions of benzamide needs to be chlorinated or fluorinated to obtain good inhibitory effect. It was found that the introduction of a p‐fluoro benzyl ring in the indole nitrogen has a positive effect for the inhibitory effects of both indole‐2‐ and 3‐carboxamide derivatives.

Evaluation of Indole Esters As Inhibitors of p60c-Src Receptor Tyrosine Kinase and Investigation of the Inhibition Using Receptor Docking Studies

Several indole esters were tested as inhibitors of tyrosine kinase p60c-Src. Compound (4) was found fairly active against the enzyme with IC50=1.34 μM. DOCK methodology was used to asses our inhibitors for their inhibitory potency against tyrosine kinase. The docking results showed that compounds (4), (25) and (26) were bound to the active site of the enzyme Lys 295 of p60c-Src tyrosine kinase. Both activity and docking studies showed a parallel result, with compound (4) having a better interaction with the enzyme active site and also greater activity than the other compounds, indicating a potential role as new lead inhibitor.

Research Letter: New Potent Indole Derivatives as Hyaluronidase Inhibitors

Because of the physiologic importance of hyaluronidases, the identification of potent and selective inhibitors of hyaluronidases has become increasingly important. A variety of assay methods have been used for such a purpose, i.e. classical turbidimetric, viscometric and colorimetric. In this study, a modified enzymatic assay has been used to obtain a microtiter plate‐based sensitive activity screening. All inhibitors were tested in a stains‐all assay at pH 7 and in a Morgan‐Elson assay at pH 3.5. Among the tested compounds, 1, 2, 3, 6, 7, 8, 16, 17 and 18 showed good inhibition of more than 50%, so the IC50 values of these derivatives were determined in the range of 25–41 μm. The IC50 value of the most active hyaluronidase inhibitor Vcpal (6‐palmitoyl‐l‐ascorbic acid) was measured as 8.36 μm. All inhibitors including Vcpal showed twofold less activity at pH 3.5 in a Morgan‐Elson assay. Examination of substituent effects on the activity showed that para‐positions of benzamide needs to be chlorinated or fluorinated to obtain good inhibitory effect. It was found that the introduction of a p‐fluoro benzyl ring in the indole nitrogen has a positive effect for the inhibitory effects of both indole‐2‐ and 3‐carboxamide derivatives.

Synthesis and evaluation of N-substituted indole-3-carboxamide derivatives as inhibitors of lipid peroxidation and superoxide anion formation

The in vitro antioxidant effects of novel N-substituted indole-3-carboxamides (I3CDs) 1-10 on rat liver microsomal NADPH-dependent lipid peroxidation (LP) levels and their free radicals scavenging properties were determined by the inhibition of superoxide anion formation (SOD). Among the synthesized compounds, 4, 5, 8 and 9 significantly inhibited SOD with an inhibition range at 84–100% at 10− 3 M concentration. The presence of halo substituents both ortho- and para- positions of these compounds resulted 100% inhibition of SOD. Comparison the activity results of halogenated and non-halogenated derivatives suggested that the halogenated compounds are more active than the non-halogenated compounds. On the other hand, the introduction of a para fluoro benzyl in the 1-position of indole (compounds 7, 8) has more impact on the SOD inhibition when the benzamide ring was mono halogenated. However, none of other compounds had a significant inhibitory effects on the level of lipid peroxidation.

Synthesis of N-substituted indole-2-carboxamides and investigation of their biochemical responses against free radicals.

The antioxidant role of novel N-substituted indole-2-carboxamides (I2CDs) was investigated for their inhibitory effects on superoxide anion (O2− ) and lipid peroxidation (LP). Among the synthesized I2CDs, 3, 4, 6, 8 and 9 significantly inhibited O2· − with an inhibition range at 70–98%. Examination of substituent effects on activity showed that both the ortho- and para-positions of the benzamide residue needs to be dichlorinated in order to get a maximum inhibitory effect on superoxide anion. In general, halogenated derivatives were found more active then the non-halogenated ones. However, none of the I2CDs had a significant inhibitory effects on the level of lipid peroxidation; only compounds 7 and 10 moderately decreased LP levels by over 50% at 10− 3 M concentrations.

Synthesis of new indole-2-carboxamide and 3-acetamide derivatives and evaluation their antioxidant properties.

In recent years, antioxidant compounds play an important role as a health-protecting factor. Antioxidants protect cells against the damaging effects of reactive oxygen species (ROS). An imbalance between antioxidants and ROS results in oxidative stress, which leads to cellular damage and it is linked to many vital diseases. It was shown that heme oxygenase (HO) provides efficient cytoprotection against oxidative stress. In this study, a series of indole-2-carboxamide and 3-acetamide derivatives was tested for in vitro effects on HO activity and 2,2-diphenyl-1-picrylhydrazyl (DPPH) inhibition. Among the synthesized compounds, N-[3-(dimethylamino)propyl]-1H-indole-2-carboxamide 3 was found as the most activator of HO and N-(2-(dimethylamino)ethyl)-2-(1H-indol-3-yl)acetamide 8 was found the most potent inhibitor for DPPH at 10−4 M concentration.

New Potent Indole Derivatives as Hyaluronidase Inhibitors: Indole Derivatives as Hyaluronidase Inhibitors

Because of the physiologic importance of hyaluronidases, the identification of potent and selective inhibitors of hyaluronidases has become increasingly important. A variety of assay methods have been used for such a purpose, i.e. classical turbidimetric, viscometric and colorimetric. In this study, a modified enzymatic assay has been used to obtain a microtiter plate‐based sensitive activity screening. All inhibitors were tested in a stains‐all assay at pH 7 and in a Morgan‐Elson assay at pH 3.5. Among the tested compounds, 1, 2, 3, 6, 7, 8, 16, 17 and 18 showed good inhibition of more than 50%, so the IC50 values of these derivatives were determined in the range of 25–41 μm. The IC50 value of the most active hyaluronidase inhibitor Vcpal (6‐palmitoyl‐l‐ascorbic acid) was measured as 8.36 μm. All inhibitors including Vcpal showed twofold less activity at pH 3.5 in a Morgan‐Elson assay. Examination of substituent effects on the activity showed that para‐positions of benzamide needs to be chlorinated or fluorinated to obtain good inhibitory effect. It was found that the introduction of a p‐fluoro benzyl ring in the indole nitrogen has a positive effect for the inhibitory effects of both indole‐2‐ and 3‐carboxamide derivatives.