Multifunctional Cinnamic Acid Derivatives.

Aikaterini Peperidou,Efstathia Voulgari,Eleni Pontiki,Konstantinos Avgoustakis,Dimitra Hadjipavlou-Litina

doi:10.3390/molecules22081247

Aikaterini Peperidou, Efstathia Voulgari + Show 3 more

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https://doi.org/10.3390/molecules22081247

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Abstract

Our research to discover potential new multitarget agents led to the synthesis of 10 novel derivatives of cinnamic acids and propranolol, atenolol, 1-adamantanol, naphth-1-ol, and (benzylamino) ethan-1-ol. The synthesized molecules were evaluated as trypsin, lipoxygenase and lipid peroxidation inhibitors and for their cytotoxicity. Compound 2b derived from phenoxyphenyl cinnamic acid and propranolol showed the highest lipoxygenase (LOX) inhibition (IC50 = 6 μΜ) and antiproteolytic activity (IC50 = 0.425 μΜ). The conjugate 1a of simple cinnamic acid with propranolol showed the higher antiproteolytic activity (IC50 = 0.315 μΜ) and good LOX inhibitory activity (IC50 = 66 μΜ). Compounds 3a and 3b, derived from methoxylated caffeic acid present a promising combination of in vitro inhibitory and antioxidative activities. The S isomer of 2b also presented an interesting multitarget biological profile in vitro. Molecular docking studies point to the fact that the theoretical results for LOX-inhibitor binding are identical to those from preliminary in vitro study.

Highlights

The biological interest of cinnamic acids (CAs), ferulic, caffeic and other phenolic CAs has been identified by many research groups and attributed to their anti-inflammatory [1,2,3], anti-oxidative [4], anti-tumor [5], anti-microbial [6], multiple cytoprotective actions ameliorating neuro inflammation in neurogenerative diseases [7], anti-hypertensive and anti-hyperlipidemic activities minimizing the oxidation of low-density lipoprotein (LDL) [8].Cinnamic acid significantly reduces the body weight of obese rats and inhibits angiotensin converting enzyme (ACE) activity in serum [9]
Combining three moieties: the enoyl-acyl backbone part, drugs and the drug-like molecules attached to the functionality of the CAs (Schemes 1–4) following Lipinski's rules
The synthesis of 3,4-dimethoxycaffeic acid (3) was based on the methylation of caffeic acid using Me2 SO4 .The physicochemical and spectroscopic data of the obtained acids were identical to those given in the literature

Summary

Introduction

Cinnamic acid significantly reduces the body weight of obese rats and inhibits angiotensin converting enzyme (ACE) activity in serum [9]. It improves vasoconstriction and hypertension complications presenting a cardioprotective profile [9]. Acknowledging CA derivatives’ multiple and high efficacy, their potential for improving human health either as a single molecule and/or in combination with other drugs in the form of hybrids seems to be broad. Hybrid drugs combine two drug entities in a single molecule, capable of interacting simultaneously with multiple targets, directly or following metabolism supporting the philosophy of polypharmacology [10,11]. Polypharmacology, which is emerging as the new paradigm of drug discovery [12,13,14,15,16] includes:

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