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. 2020 Mar 2;25(5):1118.
doi: 10.3390/molecules25051118.

An Improved Synthesis of Key Intermediate to the Formation of Selected Indolin-2-Ones Derivatives Incorporating Ultrasound and Deep Eutectic Solvent (DES) Blend of Techniques, for Some Biological Activities and Molecular Docking Studies

Mohd Imran  1 , Md Afroz Bakht  2 , Abida Khan  1 , Md Tauquir Alam  1 , El Hassane Anouar  2 , Mohammed B Alshammari  2 , Noushin Ajmal  3 , Archana Vimal  4 , Awanish Kumar  4 , Yassine Riadi  5
Affiliations

An Improved Synthesis of Key Intermediate to the Formation of Selected Indolin-2-Ones Derivatives Incorporating Ultrasound and Deep Eutectic Solvent (DES) Blend of Techniques, for Some Biological Activities and Molecular Docking Studies

Mohd Imran et al. Molecules. .

Abstract

We have developed a new idea to synthesize a key intermediate molecule by utilizing deep eutectic solvent (DES) and ultrasound in a multistep reaction to ensure process cost-effectiveness. To confirm the stability of reagents with DES, electronic energies were calculated at the B3LYP/6-31+G(d,p) level of theory. DES stabilized the reagents mainly due to strong intermolecular hydrogen bonding. Key intermediate (3) and final compounds (4a-n) were synthesized in a higher yield of 95% and 80%-88%, respectively. Further, final compounds (4a-n) were assessed for their anti-inflammatory, analgesic, ulcerogenic, and lipid peroxidation. The compounds 4f, 4g, 4j, 4l, and 4m showed good anti-inflammatory activity, while 4f, 4i, and 4n exhibited very good analgesic activity as compared to the standard drug. The ulcerogenicity of selected compounds was far less than the indomethacin. The ligands had also shown a good docking score (4f = -6.859 kcal/mol and 4n = -7.077 kcal/mol) as compared to control indomethacin (-6.109 kcal/mol) against the target protein COX-2. These derivatives have the potential to block this enzyme and can be used as NSAID. The state-of-art DFT theory was used to validate the lipid peroxidation mechanism of the active compounds which was in good agreement with the variations of BDEs and IP of the tested compounds.

Keywords: DES; DFT; analgesic; anti-inflammatory; lipid peroxidation; molecular docking; thiazole-indole; ulcerogenic; ultrasound.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Scheme 1
Scheme 1
The proposed mechanism involved in the formation of key intermediate, 3-(2-(4-(2-oxochroman-3-yl) thiazol-2-yl) hydrazono) indolin-2-one (3) using deep eutectic solvent (DES).
Figure 1
Figure 1
Energetic diagram of starting materials in the presence and absence of DES (dotted lines).
Figure 2
Figure 2
Optimized structure with the numbering of In-H synthesized derivatives.
Figure 3
Figure 3
Ramachandran plot validating the prepared protein structure of cyclooxygenase (COX-2) from (a) mouse (PDB ID 3NT1) (b) human (PDB ID: 5F19).
Figure 3
Figure 3
Ramachandran plot validating the prepared protein structure of cyclooxygenase (COX-2) from (a) mouse (PDB ID 3NT1) (b) human (PDB ID: 5F19).
Figure 4
Figure 4
Predicted binding site in COX-2 (target protein) from (a) mouse (PDB ID 3NT1) (b) human (PDB ID: 5F19).
Figure 5
Figure 5
Test ligands and control drug (a) 4f, (b) 4n, (c) Indomethacin, docked inside the binding pocket of COX-2 from a mouse.
Figure 6
Figure 6
Test ligands and control drug (a) 4f, (b) 4n, (c) Indomethacin, docked inside the binding pocket of COX-2 from the human.
Figure 7
Figure 7
Ligand interaction diagram of test ligand/control drug (a) 4f, (b) 4n, (c) Indomethacin, with the target protein COX-2 from the mouse.
Figure 8
Figure 8
Ligand interaction diagram of test ligand/control drug (a) 4f, (b) 4n, (c) Indomethacin, with the target protein COX-2 from the human.
Scheme 2
Scheme 2
Schematic representation of the synthesis of compounds (4a–n) via key intermediate (3) isolated from deep eutectic solvent and ultrasound blend of technique.
See this image and copyright information in PMC

References

    1. Kumar N., Sharma C.S., Ranawat M.S., Singh H.P., Chauhan L.S., Dashora N. Synthesis, analgesic and anti-inflammatory activities of novel mannich bases of benzimidazoles. J. Pharm. Invest. 2015;45:65–71. doi: 10.1007/s40005-014-0145-0. - DOI
    1. Almasirad A., Mousavi Z., Tajik M., Assarzadeh M.J., Shafiee A. Synthesis, analgesic and anti-inflammatory activities of new methyl-imidazolyl-1,3,4-oxadiazoles and 1,2,4-triazoles. Daru. J. Pharm. Sci. 2014;22:1–8. doi: 10.1186/2008-2231-22-22. - DOI - PMC - PubMed
    1. Salgın-Gökşen U., Gökhan-Kelekçi N., Göktaş Ö., Köysal Y., Kılıç E., Işık S., Aktay G., Özalp M. 1-Acylthiosemicarbazides, 1,2,4-triazole-5(4H)-thiones, 1,3,4-thiadiazoles and hydrazones containing 5-methyl-2-benzoxazolinones: Synthesis, analgesic anti-inflammatory and antimicrobial activities. Bioorg. Med. Chem. 2007;15:5738–5751. doi: 10.1016/j.bmc.2007.06.006. - DOI - PubMed
    1. Kumar H., Javed S.A., Khan S.A., Amir M. 1,3,4-Oxadiazole/thiadiazole and 1,2,4-triazole derivatives of biphenyl-4yloxy acetic acid: Synthesis and preliminary evaluation of biological properties. Eur. J. Med. Chem. 2008;43:2688–2698. doi: 10.1016/j.ejmech.2008.01.039. - DOI - PubMed
    1. Marnett L.J., Kalgutkar A.S. Cyclooxygenase 2 inhibitors: Discovery, selectivity and the future. Trends Pharmacol. Sci. 1999;20:465–469. doi: 10.1016/S0165-6147(99)01385-1. - DOI - PubMed

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