Selected Class of Enamides Bearing Nitro Functionality as Dual-Acting with Highly Selective Monoamine Oxidase-B and BACE1 Inhibitors.

Anusree Venkidath,Bijo Mathew,Jong Min Oh,Ahmed Khames,Ginson George,Nicola Gambacorta,Elham Amin,Mohamed A Abdelgawad,Ajeesh Vengamthodi,Hoon Kim,Shebina P Rasheed,Orazio Nicolotti,Sanal Dev

doi:10.3390/molecules26196004

Abstract

A small series of nitro group-bearing enamides was designed, synthesized (NEA1–NEA5), and evaluated for their inhibitory profiles of monoamine oxidases (MAOs) and β-site amyloid precursor protein cleaving enzyme 1 (β-secretase, BACE1). Compounds NEA3 and NEA1 exhibited a more potent MAO-B inhibition (IC50 value = 0.0092 and 0.016 µM, respectively) than the standards (IC50 value = 0.11 and 0.14 µM, respectively, for lazabemide and pargyline). Moreover, NEA3 and NEA1 showed greater selectivity index (SI) values toward MAO-B over MAO-A (SI of >1652.2 and >2500.0, respectively). The inhibition and kinetics studies suggested that NEA3 and NEA1 are reversible and competitive inhibitors with Ki values of 0.013 ± 0.005 and 0.0049 ± 0.0002 µM, respectively, for MAO-B. In addition, both NEA3 and NEA1 showed efficient BACE1 inhibitions with IC50 values of 8.02 ± 0.13 and 8.21 ± 0.03 µM better than the standard quercetin value (13.40 ± 0.04 µM). The parallel artificial membrane permeability assay (PAMPA) method demonstrated that all the synthesized derivatives can cross the blood–brain barrier (BBB) successfully. Docking analyses were performed by employing an induced-fit docking approach in the GLIDE module of Schrodinger, and the results were in agreement with their in vitro inhibitory activities. The present study resulted in the discovery of potent dual inhibitors toward MAO-B and BACE1, and these lead compounds can be fruitfully explored for the generation of newer, clinically active agents for the treatment of neurodegenerative disorders.

Highlights

The development of a new class of molecules for the complex pathology of neurodegenerative disorders, like Alzheimer’s disease (AD) and Parkinson’s disease (PD), is one of the most complicated zones in medicinal chemistry [1]
The spectral data are provided in the Supplementary Materials
It is noteworthy that the -Cl atom on the ppara pposition in NNEEAA22 rreesulted in tthhe wweeakening of MMAO-B inhibitory activiittyy

Summary

Introduction

The development of a new class of molecules for the complex pathology of neurodegenerative disorders, like Alzheimer’s disease (AD) and Parkinson’s disease (PD), is one of the most complicated zones in medicinal chemistry [1]. Multi-target-directed ligands (MTDLs) have led to a new paradigm that has emerged in recent times, in which the newly designed molecular scaffold is able to bind to different types of biologic targets that are interconnected with similar biochemical pathways [2,3]. Selective inhibitions by MAO-B inhibitors are considered to be a promising neuronal pharmacotherapy for AD and PD [7]. Many scaffolds, like chalcones, coumarins, chromones, pyrazolines, quinazolines, isatins, and thiazolidinones, which are derivatives of FDA approved MAO-B inhibitors, showed selective, reversible, and competitive types of MAO-B inhibition [10,11,12,13,14,15,16,17,18]

Methods

Results

Conclusion