Synthesis, bioactivity, 3D-QSAR studies of novel dibenzofuran derivatives as PTP-MEG2 inhibitors

Abstract

PTP-MEG2 plays a critical role in the diverse cell signalling processes, so targeting PTP-MEG2 is a promising strategy for various human diseases treatments. In this study, a series of novel dibenzofuran derivatives was synthesized and assayed for their PTP-MEG2 inhibitory activities. 10a with highest inhibitory activity (320 nM) exhibited significant selectivity for PTP-MEG2 over its close homolog SHP2, CDC25 (IC50 > 50 μM). By means of the powerful ''HipHop'' technique, a 3D-QSAR study was carried out to explore structure activity relationship of these molecules. The generated pharmacophore model revealed that the one RA, three Hyd, and two HBA features play an important role in binding to the active site of the target protein-PTP-MEG2. Docking simulation study indicated that 10a achieved its potency and specificity for PTP-MEG2 by targeting unique nearby peripheral binding pockets and the active site. The absorption, distribution, metabolism and excretion (ADME) predictions showed that the 11 compounds hold high potential to be novel lead compounds for targeting PTP-MEG2. Our findings here can provide a new strategy or useful insights for designing the effective PTP-MEG2 inhibitors.

Keywords: 3D-QSAR; PTP-MEG2; dibenzofuran; docking; synthesis.

Scheme 1. Reagents and conditions

(i) n-BuLi, Ph3PCH3Br, THF, 96%; (ii) Pd/C, H2, 4 atm, MeOH, 91%; (iii) I2, Ag2SO4, MeOH, 90%; (iv) (Ph3P)2PdCl2, CuI, Et3N, THF, prop-2-yn-1-ol, 84%; (v) MnO2, DCM, 80%; (vi) Toluene, overnight, 67%; (vii) Ac2O,NaOAc, hydroquinone, reflux, 78%.

Scheme 2. Reagents and conditions

(viii) MeONa, MeOH, 62%; (ix) HNEt2, MeOH; (x) K2CO3, R1-Br, acetone; (xi) K2CO3, R2-Br, acetone.

Figure 1

(A) Illustration to show the hypo3 generated by Hypogen. The best Hypogen model hypo-3-PTP-MEG2 mapped with Compound 10a. The features are colored coded with green, hydrogen-bond acceptor; cyan, hydrophobic; brown, ring aromatic. (B) Interaction of the receptor with the docked Compound 10a. The green dotted lines indicate the H-bond interactions of the receptor with Compound 10a. The purple dotted lines indicate the hydrophobic interactions of the receptor with Compound 10a.

Figure 2. PTP-MEG2 inhibitors used in common feature pharmacophore generation