Synthesis, in vitro and computational studies of protein tyrosine phosphatase 1B inhibition of a small library of 2-arylsulfonylaminobenzothiazoles with antihyperglycemic activity.
The 2-arylsulfonylaminobenzothiazole derivatives 1-27 were prepared using a one step reaction. The in vitro inhibitory activity of the compounds against protein tyrosine phosphatase 1B (PTP-1B) was evaluated. Compounds 4 and 16 are rapid reversible (mixed-type) inhibitors of PTP-1B with IC(50) values in the low micromolar range. The most active compounds (4 and 16) were docked into the crystal structure of PTP-1B. Docking results indicate potential hydrogen bond interactions between the nitro group in both compounds and the catalytic amino acid residues Arg 221 and Ser 216. Both compounds were evaluated for their in vivo antihyperglycemic activity in a type 2 diabetes mellitus rat model, showing significant lowering of plasma glucose concentration, during the 7h post-intragastric administration.
Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos, Mexico. gabriel_navarrete@uaem.mx
Gabriel
G
Navarrete-Vazquez
Paolo
P
Paoli
Ismael
I
León-Rivera
Rafael
R
Villalobos-Molina
Jose Luis
JL
Medina-Franco
Rolffy
R
Ortiz-Andrade
Samuel
S
Estrada-Soto
Guido
G
Camici
Daniel
D
Diaz-Coutiño
Itzell
I
Gallardo-Ortiz
Karina
K
Martinez-Mayorga
Hermenegilda
H
Moreno-Díaz
D000818:Animals; D052160:Benzothiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001786:Blood Glucose / Q000187:drug effects; D003198:Computer Simulation; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D008958:Models, Molecular; D011485:Protein Binding; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
D052160:Benzothiazoles; D001786:Blood Glucose; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1