In Vitro and In Silico Screening of 2,4,5-Trisubstituted Imidazole Derivatives as Potential Xanthine Oxidase and Acetylcholinesterase Inhibitors, Antioxidant, and Antiproliferative Agents

Eduardo Noriega-Iribe,Iván Córdova-Guerrero,Victor Wagner Barajas-Carrillo,Rocio Alejandra Chávez-Santoscoy,Daniel Chávez,Raúl Díaz-Molina,Laura Díaz-Rubio,José M Padrón,Ricardo Salazar-Aranda,Arturo Estolano-Cobián,Victor García-González

doi:10.3390/app10082889

Abstract

The employment of privileged scaffolds in medicinal chemistry supplies scientists with a solid start in the search for new and improved therapeutic molecules. One of these scaffolds is the imidazole ring, from which several derivatives have shown a wide array of biological activities. A series of 2,4,5-triphenyl imidazole derivatives were synthesized, characterized, and evaluated in vitro as antioxidant molecules using 1,1-diphenyl-2-picrylhydrazyl (DPPH.) and 2-2′-azino-bis-(3-ethylbenzothiazoline-6-sulfonate) (ABTS.+) assays, acetylcholinesterase (AChE) and xanthine oxidase (XO) inhibitors as well as antiproliferative agents. Additional in silico studies such as docking and determination of their absorption, distribution, metabolism, and excretion (ADME) properties were calculated. Compounds 3 and 10 were the most active antioxidants in both the DPPH and ABTS assays (EC50 of 0.141 and 0.174 mg/mL, and 0.168 and 0.162 mg/mL, respectively). In the enzymatic inhibition, compound 1 showed the best activity, inhibiting 25.8% of AChE at a concentration of 150 μg/mL, and compound 3 was the most active XO inhibitor with an IC50 of 85.8 μg/mL. Overall, against the six different evaluated cancerous cell lines, molecules 2, 10, and 11 were the most antiproliferative compounds. In silico predictions through docking point out 11, and ADME analysis to 11 and 12, as good candidates for being lead compounds for further derivations.

Highlights

Imidazole (1,3-diaza-2,4-cyclopentadiene) is a heterocyclic aromatic compound that can be found in many biological molecules such as histidine, histamine, or in natural nucleotides
Based on the broad literature for the biological activities of imidazole derivatives and the above-mentioned structure–activity relationship (SAR) strategy, in this work, we present the synthesis of 2,4,5-triphenylimidazoles with substitutions in their A ring to perform an initial screening of their activities as antiproliferative, antioxidant, AChE, and xanthine oxidase (XO) inhibitor compounds, in order to find new leaders with these biological profiles
Both in the DPPH and ABTS assays, imidazole presented EC50 of >15 and >10 mg/mL, respectively (Table 1), which compared to most of the results shown by its derivatives, suggests that the 2,4,5-triphenyl substitution in the imidazole heterocyclic is relevant for the antioxidant activity

Summary

Introduction

Imidazole (1,3-diaza-2,4-cyclopentadiene) is a heterocyclic aromatic compound that can be found in many biological molecules such as histidine, histamine, or in natural nucleotides. It is a highly versatile pharmacophore; there are several reports of a wide range of biological activities in molecules containing an imidazole motif such as antifungal, antituberculosis, antibiotic, cytotoxic, anti-inflammatory, antioxidant, and analgesic, amongst many others [1,2,3,4]. Imidazole derivatives, being di-, tri-, and tetra-substituted, have shown antioxidant activity through different antioxidant methodologies [5,6,7] This is a useful property to counteract oxidative stress, a condition when reactive oxygen species (ROS) overcome the natural cellular antioxidant defense system. Imidazole bearing molecules have been evaluated as AChEI with interesting results [13]

Methods

Discussion

Conclusion