Indole based cyclooxygenase inhibitors: synthesis, biological evaluation, docking and NMR screening.
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 μM, 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.
REQUIMTE-CQFB, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, Monte de Caparica, 2829-516 Caparica, Portugal.
Mónica S
MS
Estevão
Luísa C R
LC
Carvalho
Marisa
M
Freitas
Ana
A
Gomes
Aldino
A
Viegas
João
J
Manso
Stefan
S
Erhardt
Eduarda
E
Fernandes
Eurico J
EJ
Cabrita
M Manuel B
MM
Marques
D000818:Animals; D060326:Chemistry Techniques, Synthetic; D051545:Cyclooxygenase 1 / Q000737:chemistry / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000737:chemistry / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D062105:Molecular Docking Simulation; D011487:Protein Conformation
D016861:Cyclooxygenase Inhibitors; D007211:Indoles; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2