Functionalized imidazolium and benzimidazolium salts as paraoxonase 1 inhibitors: Synthesis, characterization and molecular docking studies
Graphical abstract
Introduction
Paraoxonase 1 (PON1) is the best studied member of the mammalian enzyme family including PON1, PON2 and PON3. PON1 is the calcium-dependent and high-density lipoprotein (HDL) associated enzyme that has 355 amino acids with a molecular mass of 43 kDA.1, 2, 3 PON1 catalyses the hydrolysis of lactones,4 thiolactones,5 aromatic esters6 and organophosphates,7 but physiological substrate of this enzyme is still unknown. PON1 is a key enzyme in metabolism especially for two reasons; (i) it hydrolyses organophosphates such as serin and soman and protects the nervous system against the neurotoxicity of organophosphates7 and (ii) it prevents the oxidation of low-density lipoproteins and reduced levels of oxidized lipids are involved in the initiation of atherosclerosis so decreased activity of PON 1 was acknowledged as a risk for atherosclerosis.3 Therefore all factors affecting on PON1 activity have to be well understood. It is known that almost all chemical reactions in metabolism of living organisms are catalyzed by enzymes and they are important drug targets and effects of bioactive compounds on PON1 activity must also be examined.
Heterocyclic rings are widely found in the structures of large number of natural products and they are part of various biologically active compounds so synthesis of heterocyclic compounds is important target for organic chemists. Therefore, synthesis and biological evaluation of heterocyclic compounds are still the subject of intensive research area.8, 9, 10, 11, 12, 13, 14, 15 In addition, cyclic structures are more conformationally restricted than their acyclic analogues and this fact make them more selective and bioactive.16, 17
Azoles and coumarins are well known and widely investigated class of compounds among the heterocyclic compounds. Imidazole, triazole and benzimidazole derived compounds have attracted great interest due to their wide range of pharmacological properties including anticancer, antitumor, antimicrobial, antiviral, anti-inflammatory and anticoagulant.8, 9, 10, 11, 12, 13 Coumarin derivatives have been widely investigated owing to their diverse pharmacological properties such as anticoagulant, anticancer, anti-HIV, antimicrobial14, 15 and carbonic anhydrase inhibitor.18 As shown, these small heterocyclic compounds act as highly functional scaffolds and their vital role in drug design cannot be denied.
In our previous paper, we reported the inhibition of PON1 by some hydroxy coumarin-benzimidazole hybrid compounds (doi:10.3109/14756366.2015.1043297)19 In the present study, we have synthesized nine imidazolium and eight benzimidazolium derivatives which containing coumarin, triazole, benzimidazole, benzoxazinone and some aryl or alkyl groups as substituent. The synthesized compounds were characterized by IR, NMR, elemental analysis and single-crystal X-ray diffraction. Among the various activities of these compounds, anti-coagulant effects of coumarin and benzimidazole derivatives make them more attractive especially for interactions with PON. Herein, we examined the in vitro effects of these twenty compounds which were functionalized with different substituents. Moreover, in order to determine the probable binding interactions, molecular docking studies were performed on PON1 active site.
Section snippets
Synthesis and spectral characterization of compounds (1a–5g)
Compounds C1–3 were synthesized by the procedure described in literature by Frasinyuk20 as shown in Scheme 1. Synthesis and structures of imidazolium salts (1a–3c) and benzimidazolium salts (5a–g) were outlined in Scheme 2, Scheme 3, respectively. These compounds were synthesized by direct quaternization of 1-alkylimidazole and 1-alkylbenzimidazole derivatives with different alkyl chlorides in DMF. All compounds were obtained in good yields between 54% and 95%. In 1H NMR spectra of imidazolium
Conclusion
In summary, nine imidazolium salts and seven benzimidazolium salts were synthesized in good yields and well characterized. All compounds were subjected to PON1 inhibition assay with paraoxon as substrate. Results showed that twelve compounds inhibited PON1 and IC50 values were determined for active compounds. Among them, compound 1c was found out as most active and kinetic evaluation revealed that PON1 is inhibited by 1c in competitive manner. Molecular docking studies were performed for
Experimental
Chemicals and solvents were purchased from Sigma Aldrich, Merck (Istanbul-Turkey). 6-(chloroacetyl)-2H-1,4-benzoxazine-3(4H)-one, 1-(chloromethyl)-1H-benzo[d][1,2,3]triazole, 2-(chloromethyl)-1H-benzo[d]imidazole were supplied commercially and used without further purification. Melting points were determined by Electrothermal-9200 melting point apparatus. The FT-IR spectra were recorded on an ATR unit in the range of 400–4000 cm−1 with a Perkin Elmer Spectrum 100 Spectrophotometer. The 1H NMR
Acknowledgement
The authors declare no competing financial interest.
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