Synthetic Guaiacol Derivatives as Promising Myeloperoxidase Inhibitors Targeting Atherosclerotic Cardiovascular Disease

Abstract

Myeloperoxidase (MPO) is known to cause oxidative stress and inflammation leading to cardiovascular disease (CVD) complications. MPO‐mediated oxidation of lipoproteins leads to dysfunctional entities altering the landscape of lipoprotein functionality. The specificity of guaiacol derivatives toward preventing MPO‐mediated oxidation to limit MPO's harmful effects is unknown. Diligent in silico studies were accomplished for a portfolio of compounds with guaiacol as a building block. The compounds’ activity toward MPO inhibition was also validated. The role of these chemical entities in controlling MPO‐mediated oxidation of lipoproteins (LDL and HDL) was shown to agree with our approach of developing powerful MPO inhibitors. The mechanism of MPO inhibition was demonstrated to be reversible in nature. This study reveals that there is great potential for guaiacol derivatives as therapeutics for CVD by modulating lipid profiles, reducing atherosclerotic plaque burden, and subsequently optimizing cardiovascular functions.

Oxidative Stress Parameters as Biomarkers of Cardiovascular Disease towards the Development and Progression

“…High-density lipoprotein (HDL) is a primary target for oxidative modification in CAD patients [ 17 ]. Recent reviews highlighted the ability of MPO in inducing changes and impairing HDL, which resulted in a loss of cardioprotective effect and initiation of pro-inflammatory processes [ 12 , 18 ]. Both 3-Cl-Tyr and 3-NO-Tyr have been shown to impair the ATP-binding cassette transporter (ABCA1)-dependent cholesterol efflux activity which causes excessive cholesterol accumulation in arteries and activates foam cell formation [ 19 , 20 ].…”

“…Low-density lipoprotein (LDL) is routinely used for cardiovascular risk assessment clinically with high levels indicating greater risk of CVD [ 25 ]. In the presence of hydrogen peroxidase, MPO can induce oxidative modification on LDL and release oxidised LDL (ox-LDL) [ 18 ]. While the normal LDL only specified one type of receptor, ox-LDL had a higher affinity towards several receptors that greatly aided with its uptake to macrophages and endothelial cells.…”

Synthesis, Structural Elucidation, In Silico and In Vitro Studies of New Class of Methylenedioxyphenyl-Based Amide Derivatives as Potential Myeloperoxidase Inhibitors for Cardiovascular Protection

“…The established method from scientific literature was followed for in vitro antioxidant, ex vivo anti-inflammatory, and in vitro α-GD, DPP-4, and MPO enzymatic inhibition studies. − Ascorbic acid and aceclofenac were used as positive controls for antioxidant and anti-inflammatory studies, respectively. For α-GD, DPP-4, and MPO enzymatic inhibition studies, acarbose, sitagliptin, and salicylhydroxamic acid were used as positive controls, respectively.…”

A perspective on automated advanced continuous flow manufacturing units for the upgrading of biobased chemicals toward pharmaceuticals

“…Furthermore, the synthesis of promising inhibitors to treat cardiovascular diseases was performed by Rajagopaland coworkers in 2020. This was done through the phenol moiety of coniferyl alcohol derivatives or ferulic acid, its carboxylic acid counterparts, under the form of alpha-beta unsaturated amides, hydrazines, esters and hydroxamic acids [13].…”