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Design, synthesis and identification of novel substituted 2-amino thiazole analogues as potential anti-inflammatory agents targeting 5-lipoxygenase. 2018

Shweta Sinha, and Mukesh Doble, and S L Manju
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.

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 Zileuton, the only drug against 5-LOX, was withdrawn from the market due to several problems.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.

UI MeSH Term Description Entries
D007249 Inflammation A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function. Innate Inflammatory Response,Inflammations,Inflammatory Response, Innate,Innate Inflammatory Responses
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000893 Anti-Inflammatory Agents Substances that reduce or suppress INFLAMMATION. Anti-Inflammatory Agent,Antiinflammatory Agent,Agents, Anti-Inflammatory,Agents, Antiinflammatory,Anti-Inflammatories,Antiinflammatories,Antiinflammatory Agents,Agent, Anti-Inflammatory,Agent, Antiinflammatory,Agents, Anti Inflammatory,Anti Inflammatories,Anti Inflammatory Agent,Anti Inflammatory Agents
D001094 Arachidonate 5-Lipoxygenase An enzyme that catalyzes the oxidation of arachidonic acid to yield 5-hydroperoxyarachidonate (5-HPETE) which is rapidly converted by a peroxidase to 5-hydroxy-6,8,11,14-eicosatetraenoate (5-HETE). The 5-hydroperoxides are preferentially formed in leukocytes. 5-Lipoxygenase,Arachidonic Acid 5-Lipoxygenase,LTA4 Synthase,Leukotriene A Synthase,Leukotriene A4 Synthase,Leukotriene A4 Synthetase,5 Lipoxygenase,5-Lipoxygenase, Arachidonate,5-Lipoxygenase, Arachidonic Acid,Arachidonate 5 Lipoxygenase,Arachidonic Acid 5 Lipoxygenase,Synthase, LTA4,Synthase, Leukotriene A,Synthase, Leukotriene A4,Synthetase, Leukotriene A4
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D013844 Thiazoles Heterocyclic compounds where the ring system is composed of three CARBON atoms, a SULFUR and NITROGEN atoms. Thiazole
D015195 Drug Design The molecular designing of drugs for specific purposes (such as DNA-binding, enzyme inhibition, anti-cancer efficacy, etc.) based on knowledge of molecular properties such as activity of functional groups, molecular geometry, and electronic structure, and also on information cataloged on analogous molecules. Drug design is generally computer-assisted molecular modeling and does not include PHARMACOKINETICS, dosage analysis, or drug administration analysis. Computer-Aided Drug Design,Computerized Drug Design,Drug Modeling,Pharmaceutical Design,Computer Aided Drug Design,Computer-Aided Drug Designs,Computerized Drug Designs,Design, Pharmaceutical,Drug Design, Computer-Aided,Drug Design, Computerized,Drug Designs,Drug Modelings,Pharmaceutical Designs
D016859 Lipoxygenase Inhibitors Compounds that bind to and inhibit that enzymatic activity of LIPOXYGENASES. Included under this category are inhibitors that are specific for lipoxygenase subtypes and act to reduce the production of LEUKOTRIENES. 5-Lipoxygenase Inhibitor,Lipoxygenase Inhibitor,12-Lipoxygenase Inhibitors,15-Lipoxygenase Inhibitors,5-Lipoxygenase Inhibitors,Arachidonate 12-Lipoxygenase Inhibitors,Arachidonate 15-Lipoxygenase Inhibitors,Arachidonate 5-Lipoxygenase Inhibitors,Inhibitors, Lipoxygenase,12 Lipoxygenase Inhibitors,12-Lipoxygenase Inhibitors, Arachidonate,15 Lipoxygenase Inhibitors,15-Lipoxygenase Inhibitors, Arachidonate,5 Lipoxygenase Inhibitor,5 Lipoxygenase Inhibitors,5-Lipoxygenase Inhibitors, Arachidonate,Arachidonate 12 Lipoxygenase Inhibitors,Arachidonate 15 Lipoxygenase Inhibitors,Arachidonate 5 Lipoxygenase Inhibitors,Inhibitor, 5-Lipoxygenase,Inhibitor, Lipoxygenase,Inhibitors, 12-Lipoxygenase,Inhibitors, 15-Lipoxygenase,Inhibitors, 5-Lipoxygenase,Inhibitors, Arachidonate 12-Lipoxygenase,Inhibitors, Arachidonate 15-Lipoxygenase,Inhibitors, Arachidonate 5-Lipoxygenase
D062105 Molecular Docking Simulation A computer simulation technique that is used to model the interaction between two molecules. Typically the docking simulation measures the interactions of a small molecule or ligand with a part of a larger molecule such as a protein. Molecular Docking,Molecular Docking Simulations,Molecular Docking Analysis,Analysis, Molecular Docking,Docking Analysis, Molecular,Docking Simulation, Molecular,Docking, Molecular,Molecular Docking Analyses,Molecular Dockings,Simulation, Molecular Docking

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