Synthesis of 2-{2-[(α/β-naphthalen-1-ylsulfonyl)amino]-1,3-thiazol-4-yl} acetamides with 11β-hydroxysteroid dehydrogenase inhibition and in combo antidiabetic activities.
Compounds 1-10 were designed using a bioisosteric approach and were prepared using a short synthetic route. The in vitro inhibitory activity of the compounds against 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) was evaluated. Compounds 5 (α-series) and 10 (β-series) had a moderate inhibitory enzyme activity (55.26% and 67.03% inhibition at 10 μM, respectively) and were as active as BVT.14225 (positive control). Both compounds have a piperidine ring in their structure, but the most active (10) was selected to establish its in vivo antidiabetic effect using a non insulin-dependent diabetes mellitus rat model. The antidiabetic activity of compound 10 was determined at 50 mg/kg single dose in an acute model, and also by short term sub-chronic administration for 5 days. The results indicated a significant decrease of plasma glucose levels, similar than BVT.14225. Additionally, a molecular docking of the most active compounds of each series into the ligand binding pocket of one subunit of human 11β-HSD1 was performed. In this model the oxygen atom of the sulfonamide make hydrogen bond interactions with the catalytic residues Ser170 and Ala172. We also observed important π-π interactions between the naphthyl group and Tyr177.
Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209, Mexico. Electronic address: gabriel_navarrete@uaem.mx.
Gabriel
G
Navarrete-Vázquez
Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209, Mexico.
Maria Guadalupe
MG
Morales-Vilchis
Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209, Mexico.
Samuel
S
Estrada-Soto
Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209, Mexico.
Juan José
JJ
Ramírez-Espinosa
Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209, Mexico.
Sergio
S
Hidalgo-Figueroa
Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209, Mexico.
Carlos
C
Nava-Zuazo
Centro de Investigaciones Químicas, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209, Mexico.
Hugo
H
Tlahuext
Centro de Investigaciones Químicas, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209, Mexico.
Ismael
I
Leon-Rivera
Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, FL 34987, USA.
José L
JL
Medina-Franco
Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, FL 34987, USA.
Fabian
F
López-Vallejo
Endocrinology Unit, Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, EH16 4TJ, UK.
Scott P
SP
Webster
Endocrinology Unit, Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, EH16 4TJ, UK.
Margaret
M
Binnie
Facultad de Química, Universidad Autónoma de Yucatán, Mérida, Yucatán 97150, Mexico.
Rolffy
R
Ortiz-Andrade
Instituto de Química Aplicada, Universidad del Papaloapan, Tuxtepec, Oaxaca 68301, Mexico.
Hermenegilda
H
Moreno-Diaz
D042842:11-beta-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors*; D000081:Acetamides / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D062105:Molecular Docking Simulation; D051381:Rats
D000081:Acetamides; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D042842:11-beta-Hydroxysteroid Dehydrogenases
Bioisostere; Diabetes; In silico; Sub-acute; Thiazole