Substituted pyrrol-1-ylacetic acids that combine aldose reductase enzyme inhibitory activity and ability to prevent the nonenzymatic irreversible modification of proteins from monosaccharides.
Starting from the known inhibitory activity of (3-benzoylpyrrol-1-yl)acetic acid (I) and (2-benzoylpyrrol-1-yl)acetic acid (II), a series of 3-aroyl and 2,4-bis-aroyl derivatives (54-75) were synthesized and tested for inhibition of aldose reductase, an enzyme involved in the appearance of diabetic complications. It was found that a number of the tested compounds exhibited considerable activity in the micromolar range. Important structural features for the potent compounds is the presence of substituents with relatively low Hammett sigma values and/or moieties which increase their overall aromatic area. The most active derivative was the [2,4-bis(4-methoxybenzoyl)pyrrol-1-yl]acetic acid (75), with potency favorably compared to known ARIs such as tolrestat, epalrestat, zopolrestat, and fidarestat. Four selected derivatives were also evaluated for their ability to interfere with the oxidative modification of serum albumin in an in vitro experimental glycation model of diabetes mellitus. All of them showed considerable activity, comparable to the known inhibitor trolox. Our results, taken together, indicate that compound 75 combines favorably two biological activities directly connected to a number of pathological conditions related to the chronic diabetes mellitus.
Nicolaou
Ioannis
I
Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece.
Demopoulos
Vassilis J
VJ
D000085:Acetates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D003920:Diabetes Mellitus / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D005632:Fructose / Q000737:chemistry; D008297:Male; D009005:Monosaccharides / Q000737:chemistry / Q000378:metabolism*; D010084:Oxidation-Reduction; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D012709:Serum Albumin / Q000737:chemistry; D013329:Structure-Activity Relationship
C471170:(2,4-bis(4-methoxybenzoyl)pyrrol-1-yl)acetic acid; D000085:Acetates; D004791:Enzyme Inhibitors; D009005:Monosaccharides; D011506:Proteins; D011758:Pyrroles; D012709:Serum Albumin; D005632:Fructose; D000449:Aldehyde Reductase