Protein tyrosine phosphatase 1B (PTP1B) plays a vital role in the regulation of insulin sensitivity and dephosphorylation of the insulin receptor, so PTP1B inhibitors may be potential agents to treat type 2 diabetes. In this work, a series of novel imidazolidine-2,4-dione derivatives were designed, synthesized and assayed for their PTP1B inhibitory activities. These compounds exhibited potent activities with IC50 values at 0.57-172 μM. A 3D-QSAR study using CoMFA and CoMSIA techniques was carried out to explore structure activity relationship of these molecules. The CoMSIA model was more predictive with q(2) = 0.777, r(2) = 0.999, SEE = 0.013 and r(2)pred = 0.836, while the CoMFA model gave q(2) = 0.543, r(2) = 0.998, SEE = 0.029 and r(2)pred = 0.754. The contour maps derived from the best CoMFA and CoMSIA models combined with docking analysis provided good insights into the structural features relevant to the bioactivity, and could be used in the molecular design of novel imidazolidine-2,4-dione derivatives.
Keywords: CoMFA/CoMSIA; Docking; Imidazolidine-2,4-dione; PTP1B; Synthesis.
Copyright © 2015 Elsevier Masson SAS. All rights reserved.