Design and synthesis of novel series of pyrrole based chemotypes and their evaluation as selective aldose reductase inhibitors. A case of bioisosterism between a carboxylic acid moiety and that of a tetrazole.
Pyrrolyl-propionic and butyric-acid derivatives 1 and 2 were synthesized in order to study the effect of the variation of the methylene chain in comparison to the previously reported pyrrolyl-acetic acid compound I, which was found as potent aldose reductase inhibitor, while the pyrrolyl-tetrazole derivatives 3-5 were prepared as a non-classical bioisosteres of a carboxylic acid moiety. Also, pyrrolyl-tetrazole isomers 6 and 7 without an alkyl chain between the two aromatic rings were synthesized. The in vitro aldose reductase inhibitory activity of the prepared 1-7 compounds were estimated and compared with that of the initial compound (I). Overall, the data indicate that the presented chemotypes 6 and 7 are a promising lead compounds for the development of selective aldose reductase inhibitors, aiming to the long-term complications of diabetes mellitus.
Pegklidou
Kyriaki
K
Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece.
Koukoulitsa
Catherine
C
Department of Chemistry, University of Athens, Zographou 15784, Greece.
Nicolaou
Ioannis
I
Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece.
Demopoulos
Vassilis J
VJ
Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece.
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D002264:Carboxylic Acids / Q000737:chemistry*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D008297:Male; D015394:Molecular Structure; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000737:chemistry*
D002264:Carboxylic Acids; D004791:Enzyme Inhibitors; D011758:Pyrroles; D013777:Tetrazoles; C045574:1H-tetrazole; D000449:Aldehyde Reductase