5-Arylidene-2-phenylimino-4-thiazolidinones as PTP1B and LMW-PTP inhibitors.
As part of a project aimed at identifying effective low molecular weight nonphosphorus monoanionic inhibitors of PTPs, we have synthesized 4-[(5-arylidene-4-oxo-2-phenyliminothiazolidin-3-yl)methyl]benzoic acids (4) and evaluated their inhibitory activity against human PTP1B and LMW-PTP enzymes. The introduction of a 2-phenylimino moiety onto the 4-thiazolidinone ring was designed to enhance the inhibitor/enzyme affinity by means of further favourable interactions with residues of the active site and the surrounding loops. Some of the compounds (4a-d, f) showed interesting inhibition levels in the low micromolar range. The 5-arylidene moiety of acids 4 proved to markedly influence the potency of these inhibitors. Molecular modeling experiments inside the binding sites of both enzymes were performed.
Ottanà
Rosaria
R
Dipartimento Farmaco-chimico, University of Messina, Polo Universitario dell'Annunziata, Messina, Italy. ottana@pharma.unime.it
Maccari
Rosanna
R
Ciurleo
Rosella
R
Paoli
Paolo
P
Jacomelli
Michela
M
Manao
Giampaolo
G
Camici
Guido
G
Laggner
Christian
C
Langer
Thierry
T
D001565:Benzoates / Q000138:chemical synthesis / Q000494:pharmacology; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008970:Molecular Weight; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053778:Thiazolidines / Q000138:chemical synthesis* / Q000494:pharmacology*
D001565:Benzoates; D004791:Enzyme Inhibitors; D011518:Proto-Oncogene Proteins; D053778:Thiazolidines; C490429:ACP1 protein, human; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases