Synthesis and SAR studies of 3-allyl-4-prenyloxyaniline amides as potent 15-lipoxygenase inhibitors.
15-Lipoxygenases are one of the nonheme iron-containing proteins with ability of unsaturated lipid peroxidation in animals and plants. The critical role of the enzymes in formation of inflammations, sensitivities and some of cancers has been demonstrated in mammalians. Importance of the 15-lipoxygenases leads to development of mechanistic studies, products analysis and synthesis of their inhibitors. In this work new series of the 3-allyl-4-allyoxyaniline amides and 3-allyl-4-prenyloxyaniline amides were designed, synthesized and their inhibitory potency against soybean 15-lipoxygenase were determined. Among the synthetic amides, 3-allyl-4-(farnesyloxy)-adamantanilide showed the most potent inhibitory activity by IC(50) value of 0.69 μM. SAR studies showed that in spite of prenyl length increases, the effects of the amide size and its electronic properties on the inhibitory potency became predominant. The SAR studies was also showed that the orientation of allyl and prenyloxy moieties toward Fe core of the SLO active site pocket is the most suitable location for enzyme inhibition.
Department of Chemistry, School of Sciences, Ferdowsi University of Mashhad, Mashhad, Iran.
Atena
A
Jabbari
Mahdieh
M
Davoodnejad
Maliheh
M
Alimardani
Amir
A
Assadieskandar
Ali
A
Sadeghian
Hadi
H
Safdari
Jebraeel
J
Movaffagh
Hamid
H
Sadeghian
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000814:Aniline Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D013025:Glycine max / Q000201:enzymology; D013329:Structure-Activity Relationship
D000577:Amides; D000814:Aniline Compounds; D016859:Lipoxygenase Inhibitors; D001093:Arachidonate 15-Lipoxygenase; C023650:aniline