Indole based cyclooxygenase inhibitors: Synthesis, biological evaluation, docking and NMR screening

• Type: Article in International Scientific Journal
• Date: 2012

Authors

Monica S Estevao (Author) Other; Luisa C R Carvalho (Author) Other; Marisa Freitas (Author) Other; Ana Gomes (Author) Other; Aldino Viegas (Author) Other; Joao Manso (Author) Other; Stefan Erhardt (Author) Other; Eduarda Fernandes (Author) FFUP; Eurico J Cabrita (Author) Other; Manuel M B Marques (Author) Other

Journal

Title: European Journal of Medicinal Chemistry

Vol. 54

Pages: 823-833

ISSN: 0223-5234

Publisher: Elsevier

Indexing

ISI Web of Knowledge - 25 Citations

Scopus - 27 Citations

Scientific classification

FOS: Medical and Health sciences > Basic medicine

Other information

Authenticus ID: P-002-79S

DOI: 10.1016/j.ejmech.2012.06.040

Abstract (EN): The close structural similarity between the two cyclooxygenase (COXs) isoforms and the absence of selective inhibitors without side effects continues to stimulate the development of novel approaches towards selective anti-inflammatory drugs. In the present study a small library of new indolic compounds involving two different substitutions patterns at the indole scaffold was synthesized. In order to establish a relation between the spatial distribution of known functional groups related with inhibitory activity, two substitution patterns were explored: one with substituents at N-1, C-3, C-5 positions and another at C-2, C-3 and C5 positions. Accordingly, indole positions C-5, C-3 and N-1 were substituted with: sulfonamide or methylsulfone at C-5, p-halo-benzyl group at C-3, and an alkyl chain with a trifluoromethyl group at N-1. Alternatively, a p-halo-benzyl group was introduced at C-2, leaving the indolic nitrogen free. Inhibitory studies were performed and the activity results obtained against both COXs isoforms were rationalized based on docking and NMR studies. Docking studies show that dialkyation at C-2 and C-3 favors a binding with an orientation similar to that of the known selective inhibitor SC-558. From the tested compounds, this substitution pattern is correlated with the highest inhibitory activity and selectivity: 70% COX-2 inhibition at 50 mu M, and low COX-1 inhibition (18 +/- 9%). Additionally, Saturation Transfer Difference NMR experiments reveal different interaction patterns with both COXs isoforms that may be related with different orientations of the sulfonamide group in the binding pocket. Despite the moderated inhibitory activities found, this study represents an innovative approach towards COXs inhibitory activity rationalization and to the design of anti-inflammatory drugs.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 11