1,2,4-Triazole-based benzothiazole/benzoxazole derivatives: Design, synthesis, p38α MAP kinase inhibition, anti-inflammatory activity and molecular docking studies

Sana Tariq; Payal Kamboj; Ozair Alam; Mohd Amir

doi:10.1016/j.bioorg.2018.09.015

1,2,4-Triazole-based benzothiazole/benzoxazole derivatives: Design, synthesis, p38α MAP kinase inhibition, anti-inflammatory activity and molecular docking studies

Bioorg Chem. 2018 Dec:81:630-641. doi: 10.1016/j.bioorg.2018.09.015. Epub 2018 Sep 8.

Authors

Sana Tariq¹, Payal Kamboj¹, Ozair Alam¹, Mohd Amir²

Affiliations

¹ Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India.
² Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India. Electronic address: mamir_s2003@yahoo.co.in.

PMID: 30253336
DOI: 10.1016/j.bioorg.2018.09.015

Abstract

Novel N-(benzothiazol/oxazol-2-yl)-2-[(5-(phenoxymethyl)-4-aryl-4H-1,2,4-triazol-3-yl)thio] acetamide derivatives (5a-n) were synthesized and investigated for in vitro anti-inflammatory activity and p38α MAP kinase inhibition. Compounds showing good in vitro activities (5a, 5b, 5d, 5e, 5i, 5k and 5l) were studied for their in vivo anti-inflammatory activity using carrageenan induced rat paw edema model. Compound 5b emerged as the most active compound with an edema inhibition of 84.43%. It also showed improved GI safety profile with lower ulcer severity index and lipid peroxidation potential. Also, p38α MAP kinase assay of 5b showed superior inhibitory potency (IC₅₀:0.031 ± 0.14 µM) than the standard SB 203580 (IC₅₀:0.043 ± 0.14 µM). To predict their binding mode compounds were also docked against p38α MAP kinase enzyme. Compound 5b and SB 203580 showed hinge region interaction with MET 109.

Keywords: Anti-inflammatory; Benzoxazole; Docking; Ulcerogenicity; p38α MAP kinase.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis
Anti-Inflammatory Agents, Non-Steroidal / chemistry*
Anti-Inflammatory Agents, Non-Steroidal / pharmacology
Anti-Inflammatory Agents, Non-Steroidal / therapeutic use*
Benzothiazoles / chemical synthesis
Benzothiazoles / chemistry*
Benzothiazoles / pharmacology
Benzothiazoles / therapeutic use*
Benzoxazoles / chemical synthesis
Benzoxazoles / chemistry
Benzoxazoles / pharmacology
Benzoxazoles / therapeutic use
Edema / drug therapy
Edema / enzymology
Molecular Docking Simulation
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology
Protein Kinase Inhibitors / therapeutic use
Rats, Wistar
Triazoles / chemical synthesis
Triazoles / chemistry*
Triazoles / pharmacology
Triazoles / therapeutic use*
p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*
p38 Mitogen-Activated Protein Kinases / metabolism

Substances

Anti-Inflammatory Agents, Non-Steroidal
Benzothiazoles
Benzoxazoles
Protein Kinase Inhibitors
Triazoles
1,2,4-triazole
p38 Mitogen-Activated Protein Kinases