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Eur J Med Chem. 2018 Oct 5;158:34-50. doi: 10.1016/j.ejmech.2018.08.098. Epub 2018 Sep 3.

Design, synthesis and identification of novel substituted 2-amino thiazole analogues as potential anti-inflammatory agents targeting 5-lipoxygenase.

Author information

1
Department of Chemistry, School of Advanced Sciences, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India; Bioengineering and Drug Design Lab, Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology, Madras, Tamil Nadu, 600036, India.
2
Bioengineering and Drug Design Lab, Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology, Madras, Tamil Nadu, 600036, India. Electronic address: mukeshd@iitm.ac.in.
3
Department of Chemistry, School of Advanced Sciences, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India. Electronic address: slmanju@vit.ac.in.

Abstract

Human 5-Lipoxygenase (5-LOX) is a key enzyme targeted for asthma and inflammation. Zileuton, the only drug against 5-LOX, was withdrawn from the market due to several problems. In the present study, the performance of rationally designed conjugates of thiazole (2) and thiourea (3) scaffolds from our previously reported 2-amino-4-aryl thiazole (1) is reported. They are synthesized (total 31 derivatives), characterized, and tested against the 5-LOX enzyme in vitro and the mode of action of the most active ones are determined. Compound 2m exhibited an IC50 of 0.9 ± 0.1 μM acting through competitive (non-redox) mechanism, unlike Zileuton, and found to be devoid of radical scavenging properties. Computational studies are in good agreement with the experimental data supporting its mechanism of action. Another lead molecule from the thiourea series (3), 3f, exhibited an IC50 of 1.4 ± 0.1 μM against 5-LOX whose mode of action is redox type (non-competitive). It is promising to note that the activities displayed by both the lead inhibitors, 2m and 3f, are better than the commercial drug, Zileuton (IC50 = 1.5 ± 0.3 μM). These inhibitors could be further developed as drugs against inflammation.

KEYWORDS:

5-Lipoxygenase; Design; Inflammation; Pharmacophore/docking; Thiazoles

PMID:
30199704
DOI:
10.1016/j.ejmech.2018.08.098
[Indexed for MEDLINE]

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