Design and Synthesis of Novel 2-Amino-5-hydroxyindole Derivatives That Inhibit Human 5-Lipoxygenase

Abstract

Compounds that inhibit 5-lipoxygenase (5-LO), the key enzyme in the biosynthesis of leukotrienes (LTs), possess potential for the treatment of inflammatory and allergic diseases as well as of atherosclerosis and cancer. Here we present the design and the synthesis of a series of novel 2-amino-5-hydroxyindoles that potently inhibit isolated human recombinant 5-LO as well as 5-LO in polymorphonuclear leukocytes, exemplified by ethyl 2-[(3-chlorophenyl)amino]-5-hydroxy-1H-indole-3-carboxylate (3n, IC(50) value congruent with 300 nM). Introduction of an aryl/arylethylamino group or 4-arylpiperazin-1-yl residues into position 2 of the 5-hydroxyindoles was essential for biological activity. Whereas the 4-arylpiperazin-1-yl derivatives were more potent in cell-free assays as compared to intact cell test systems, aryl/arylethylamino derivatives inhibited 5-LO activity in intact cells and cell-free assays almost equally well. On the basis of their 5-LO inhibitory properties, these novel 2-amino-5-hydroxyindoles represent potential candidates for the pharmacological intervention with LT-associated diseases.

Nenitzescu 5‐Hydroxyindole Synthesis

“…A summary of these reports is listed in Table 2 [26][27][28][29][30][31][32][33][34][35][36][37][38][39]. A summary of these reports is listed in Table 2 [26][27][28][29][30][31][32][33][34][35][36][37][38][39].…”

A Simple Copper‐Catalyzed Cascade Synthesis of 2‐Amino‐1H‐indole‐3‐carboxylate Derivatives

“…[8,9] The 2-amino-1H-indole-3-carboxylate derivatives are found to be biologically active molecules and important intermediates for construction of medicinal molecules. [10,11] Unfortunately, only a few of examples were reported for their synthe-A C H T U N G T R E N N U N G sis, [11a,12] and the starting materials often are not readily available and difficult to prepare. Volovenko et al attempted a synthesis of 2-amino-6-nitroindoles via the reaction of 2-halo-5-nitroanilines and substituted acetonitriles, [13] the result showed that only 2-fluoro-5-nitroaniline containing a strong electron-withdrawing group (nitro) was effective, however, other 2-haloanilines did not work, so the method could not construct diverse 2-amino-1H-indole derivatives.…”

Structural optimization and biological evaluation of 1,5-disubstituted pyrazole-3-carboxamines as potent inhibitors of human 5-lipoxygenase

“…In search of pharmacological agents that suppress the biosynthesis of LTs, different types of small molecular inhibitors of 5-LOX have been developed in the past two decades, such as redox inhibitors, iron-chelator agents and non-redox competitive inhibitors 10 , 11 . To date, despite considerable efforts devoted to the development of efficient and safe drugs that target the 5-LOX pathway, only one 5-LOX inhibitor, Zileuton ( 1 , Scheme 1 ), has been approved for asthma treatment 12 , although it still exhibits several drawbacks, including liver toxicity and unfavorable pharmacokinetic profile with a short half-life 3 .…”