title: New potent indole derivatives as hyaluronidase inhibitors.
abstract: 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 IC(50) values of these derivatives were determined in the range of 25-41 microm. The IC(50) value of the most active hyaluronidase inhibitor Vcpal (6-palmitoyl-L-ascorbic acid) was measured as 8.36 microm. 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.
authors.forename: Süreyya
authors.initials: S
authors.lastname: Olgen
authors.forename: Andre
authors.initials: A
authors.lastname: Kaessler
authors.forename: Doğu
authors.initials: D
authors.lastname: Nebioğlu
authors.forename: Joachim
authors.initials: J
authors.lastname: Jose
mesh_terms: D000818:Animals; D001205:Ascorbic Acid / Q000031:analogs & derivatives* / Q000737:chemistry; D001681:Biological Assay; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006801:Humans; D006821:Hyaluronoglucosaminidase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D007211:Indoles / Q000737:chemistry*
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D006821:Hyaluronoglucosaminidase; D001205:Ascorbic Acid; C031226:6-O-palmitoylascorbic acid