Structure-Based Design, Synthesis, Biological Evaluation, and Molecular Docking of Novel PDE10 Inhibitors With Antioxidant Activities.

Jinxuan Li,Qian Zhou,Ya-Lin Deng,Jing-Yi Chen,Deyan Wu,Hai-Bin Luo,Yinuo Wu

doi:10.3389/fchem.2018.00167

Abstract

Phosphodiesterase 10 is a promising target for the treatment of a series of central nervous system (CNS) diseases. Imbalance between oxidative stress and antioxidant defense systems as a universal condition in neurodegenerative disorders is widely studied as a potential therapy for CNS diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). To discover multifunctional pharmaceuticals as a treatment for neurodegenerative diseases, a series of quinazoline-based derivatives with PDE10 inhibitory activities and antioxidant activities were designed and synthesized. Nine out of 13 designed compounds showed good PDE10 inhibition at the concentration of 1.0 μM. Among these compounds, eight exhibited moderate to excellent antioxidant activity with ORAC (oxygen radical absorbance capacity) value above 1.0. Molecular docking was performed for better understanding of the binding patterns of these compounds with PDE10. Compound 11e, which showed remarkable inhibitory activity against PDE10 and antioxidant activity may serve as a lead for the further modification.

Highlights

Phosphodiesterases (PDEs) are a super enzyme family in charge of hydrolyzing the intracellular second messenger molecules 3′,5′-cyclic adenosine monophosphate and 3′,5′-cyclic guanosine monophosphate by degrading their phosphodiester bonds (Liu et al, 2001; Mehats et al, 2002; Castro et al, 2005; Bender and Beavo, 2006; Conti and Beavo, 2007; Houslay, 2010)
Papaverine, a natural drug used for the prevention of vasospasm in the clinic, has been proved to have good inhibitory activity toward PDE10A (IC50 = 10–300 nM) (Siuciak et al, 2006a)
Based on the structure of papaverine, several quinazoline compounds have been developed as PDE10A inhibitors such as compound 1 and compound 2 (Figure 1; Chappie et al, 2007; Helal et al, 2011)

Summary

Introduction

Phosphodiesterases (PDEs) are a super enzyme family in charge of hydrolyzing the intracellular second messenger molecules 3′,5′-cyclic adenosine monophosphate (cAMP) and 3′,5′-cyclic guanosine monophosphate (cGMP) by degrading their phosphodiester bonds (Liu et al, 2001; Mehats et al, 2002; Castro et al, 2005; Bender and Beavo, 2006; Conti and Beavo, 2007; Houslay, 2010) As both cAMP and cGMP are involved in various extracellular signals and biological processes, the inhibition of PDEs can improve abnormal physiological processes caused by the low concentration of cAMP and/or cGMP by inhibiting their degradation (Lugnier, 2006; Francis et al, 2011). The different expression of each subfamily on the organs and tissues makes specific PDE inhibitors have different therapeutic effects

Methods

Results

Conclusion