Synthesis, characterization and bioactivity studies of novel 1,3,4-oxadiazole small molecule that targets basic phospholipase A^sub 2^ from Vipera russelli

Mol Cell Biochem (2017) 426:161175 DOI 10.1007/s11010-016-2888-6

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

Vivek Hamse Kameshwar1 Kumar J. R.2 Babu S. Priya3 S. Nanjunda Swamy1

Received: 4 July 2016 / Accepted: 15 November 2016 / Published online: 7 December 2016 Springer Science+Business Media New York 2016

Abstract Secretory phospholipase A2 (sPLA2) is a key enzyme participating in the inammatory cascade followed by the action of cyclooxygenase-2 and lipoxygenases. Therefore, inhibitors of sPLA2 could be used as potent anti-inammatory agents to treat the early phase of inammation. In this study, we have prepared the fenoprofen and ibuprofen analogs containing 1,3,4-oxadiazole nucleus and tested against Vipera russelli venoms basic sPLA2 (VRV

PL-VIIIa). Among the tested ligands 5(at),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 lM. Biophysical studies revealed that the 5m quenches the intrinsic uorescence of VRVPL-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 a-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-inammatory agent.

Keywords 1,3,4-Oxadiazole VRV-PL-VIIIa Anti-

inammation NSAIDs ANS

Introduction

Venom of venomous snakes acts as natural advance killer machines to kill its prey, among which V. russelli is one of the most dangerous species found in the Indian subcontinent and other parts of Asia, causing high morbidity and mortality rate among the big four venomous snakes [1]. Annual snakebite is a majorly neglected medical emergency reported in modern India representing about 45,900 annual deaths affecting to a very great degree...