Novel indole-2-carboxamide and cycloalkeno[1,2-b]indole derivatives. Structure-activity relationships for high inhibition of human LDL peroxidation.
Series of indole-2-carboxamide and cycloalkeno[1,2-b]indole derivatives were synthesized and evaluated in order to determine the necessary structural requirements for a high inhibition of human LDL copper-induced peroxidation. Various modulations were systematically performed on the indole and cycloalkeno[1,2-b]indole nuclei as well as on the carboxamide moiety. The best compounds (3c, 3e, 7c, 7f, 7h, 7g, and 7o) are between 5 and 30 times more active than probucol itself. Two of these compounds (3c and 7o) were selected for complementary in vitro and in vivo investigations, which have shown additional properties of interest for the treatment and the prevention of atherosclerosis injuries. Compound 3c was found to have some antiinflammatory properties while compound 7o was proved to protect endothelial cells from the direct cytotoxicity of oxidized LDL with some additional calcium channel blocking properties.
Kuehm-Caubere
C
C
Laboratoire de Chimie Organique I, URA CNRS 457, Faculté des Sciences,Université H. Poincaré, Vandoeuvre-les-Nancy, France.
Caubere
P
P
Jamart-Gregoire
B
B
Negre-Salvayre
A
A
Bonnefont-Rousselot
D
D
Bizot-Espiard
J G
JG
Pfeiffer
B
B
Caignard
D H
DH
Guardiola-Lemaitre
B
B
Renard
P
P
D000577:Amides / Q000737:chemistry*; D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D002264:Carboxylic Acids; D003300:Copper / Q000378:metabolism; D003516:Cycloparaffins / Q000737:chemistry* / Q000378:metabolism; D015232:Dinoprostone / Q000096:biosynthesis; D018684:Glycine Agents / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000378:metabolism; D007476:Ionophores / Q000494:pharmacology; D007975:Leukotriene B4 / Q000096:biosynthesis; D015227:Lipid Peroxidation; D008077:Lipoproteins, LDL / Q000378:metabolism*; D011817:Rabbits; D013329:Structure-Activity Relationship
D000577:Amides; D002264:Carboxylic Acids; D003516:Cycloparaffins; D018684:Glycine Agents; D007211:Indoles; D007476:Ionophores; D008077:Lipoproteins, LDL; C058980:indole-2-carboxylic acid; D007975:Leukotriene B4; D000001:Calcimycin; D003300:Copper; D015232:Dinoprostone