Synthesis, characterization and bioactivity studies of novel 1,3,4-oxadiazole small molecule that targets basic phospholipase A2 from Vipera russelli

Vivek Hamse Kameshwar; Kumar J R; Babu S Priya; S Nanjunda Swamy

doi:10.1007/s11010-016-2888-6

Synthesis, characterization and bioactivity studies of novel 1,3,4-oxadiazole small molecule that targets basic phospholipase A₂ from Vipera russelli

Mol Cell Biochem. 2017 Feb;426(1-2):161-175. doi: 10.1007/s11010-016-2888-6. Epub 2016 Dec 7.

Authors

Vivek Hamse Kameshwar¹, Kumar J R², Babu S Priya³, S Nanjunda Swamy⁴

Affiliations

¹ Department of Biotechnology, JSS Science and Technology University, Mysuru, 570006, India.
² Department of Biochemistry, Faculty of Life Sciences, JSS University, Mysuru, India.
³ Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysuru, 570006, India.
⁴ Department of Biotechnology, JSS Science and Technology University, Mysuru, 570006, India. nanju_chem@yahoo.com.

PMID: 27928710
DOI: 10.1007/s11010-016-2888-6

Abstract

Secretory phospholipase A₂ (sPLA₂) is a key enzyme participating in the inflammatory cascade followed by the action of cyclooxygenase-2 and lipoxygenases. Therefore, inhibitors of sPLA₂ could be used as potent anti-inflammatory agents to treat the early phase of inflammation. In this study, we have prepared the fenoprofen and ibuprofen analogs containing 1,3,4-oxadiazole nucleus and tested against Vipera russelli venom's basic sPLA₂ (VRV-PL-VIIIa). Among the tested ligands 5(a-t),2-(2-chlorophenyl)-5-(1-(4-phenoxyphenyl) ethyl)-1,3,4-oxadiazole (5m) inhibited the catalytic activity of VRV-PL-VIIIa with an IC₅₀ value of 11.52 µM. Biophysical studies revealed that the 5m quenches the intrinsic fluorescence of VRV-PL-VIIIa, in a concentration dependent manner. Also, the compound 5m affected VRV-PL-VIIIa conformation, which was observed by circular dichroism spectra that recorded the prominent shift in the α-helix peak and the random coil formation of VRV-PL-VIIIa. Further, molecular docking analysis revealed that the compound 5m possess strong hydrophobic interactions at catalytic triad region of the VRV-PL-VIIIa. Evident to in vitro and in silico studies, 5m strongly inhibited the hemolysis of red blood cells. Our in vivo pharmacological studies revealed that the compound 5m inhibited the edematogenic activity of VRV-PL-VIIIa in mouse foot pad. Additionally, the 5m inhibited VRV-PL-VIIIa-induced myotoxicity and lung hemorrhage in mice. Overall, our ADMET results depicted that 5m possess better druggable property. Thus, this study explored the new fenoprofen and ibuprofen analog 5m as the lead-structure that serves as an anti-inflammatory agent.

Keywords: 1,3,4-Oxadiazole; ANS; Anti-inflammation; NSAIDs; VRV-PL-VIIIa.

MeSH terms

Animals
Enzyme Inhibitors* / chemical synthesis
Enzyme Inhibitors* / chemistry
Enzyme Inhibitors* / pharmacology
Fenoprofen* / analogs & derivatives
Fenoprofen* / chemical synthesis
Fenoprofen* / chemistry
Fenoprofen* / pharmacology
Group II Phospholipases A2* / antagonists & inhibitors
Group II Phospholipases A2* / chemistry
Group II Phospholipases A2* / toxicity
Hemolysis / drug effects
Ibuprofen* / analogs & derivatives
Ibuprofen* / chemical synthesis
Ibuprofen* / chemistry
Ibuprofen* / pharmacology
Male
Mice
Molecular Docking Simulation
Oxadiazoles* / chemical synthesis
Oxadiazoles* / chemistry
Oxadiazoles* / pharmacology
Protein Structure, Secondary

Substances

Enzyme Inhibitors
Oxadiazoles
1,3,4-oxadiazole
Group II Phospholipases A2
VRV-PL-VIIIa phospholipase A2, Vipera russelli
Fenoprofen
Ibuprofen