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

• Published in: European journal of medicinal chemistry Vol. 158; pp. 34 - 50
• Main Authors: Sinha, Shweta, Doble, Mukesh, Manju, S.L.
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 05-10-2018
• Subjects: 5-Lipoxygenase; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - pharmacology; Arachidonate 5-Lipoxygenase - metabolism; Design; Drug Design; Humans; Inflammation; Inflammation - drug therapy; Lipoxygenase Inhibitors - chemistry; Lipoxygenase Inhibitors - pharmacology; Molecular Docking Simulation; Pharmacophore/docking; Structure-Activity Relationship; Thiazoles; Thiazoles - chemistry; Thiazoles - pharmacology; AA; DPPH; DMSO; 5-HPETE; LT; Inflammation; EDTA; Design; PMSF; LB; 5-Lipoxygenase; Thiazoles; Ph; 13(S) HpODE; TMS; DMF; 5-LOX; Pharmacophore/docking
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2018.08.098

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 Zileuton, the only drug against 5-LOX, was withdrawn from the market due to several problems.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.
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•Novel thiazoles/thioureas are designed via pharmacophore modeling against 5-LOX.•Most compounds found active against 5-LOX in vitro enzyme inhibition studies.•The best compound, 2m, from thiazole series acts as a competitive 5-LOX inhibitor.•The most potent thiourea, 3f, inhibits 5-LOX via non-competitive (redox) mechanism.•Docking studies demonstrate binding mode of the competitive inhibitors.