Neutralization of haemorrhagic activity of viper venoms by 1-(3-Dimethylaminopropyl)-1-(4-Fluorophenyl)-3-Oxo-1, 3-dihydroisobenzofuran-5-carbonitrile

Sunitha, K. and Hemshekhar, M. and Gaonkar, Santosh L. and Santhosh, M. S. and Suresh Kumar, M. and Basappa and Shubha Priya Babu and Kemparaju, K. and Rangappa, K. S. and Nanjunda Swamy, S. and Girish, K. S. (2011) Neutralization of haemorrhagic activity of viper venoms by 1-(3-Dimethylaminopropyl)-1-(4-Fluorophenyl)-3-Oxo-1, 3-dihydroisobenzofuran-5-carbonitrile. BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY, 109 (4). pp. 292-299.

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Abstract

Viper envenomation undeniably induces brutal local manifestations such as haemorrhage, oedema and necrosis involving massive degradation of extracellular matrix at the bitten region and many a times results in dangerous systemic haemorrhage including pulmonary shock. Snake venom metalloproteases (SVMPs) are being considered to be the primary culprits for the venom-induced haemorrhage. As a consequence, the venom researchers and medical practitioners are in deliberate quest of SVMP inhibitors. In this study, we evaluated the inhibitory effect of 1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-3-oxo-1,3-dihydroisobenzofu ran-5-carbonitrile (DFD) on viper venom-induced haemorrhagic and PLA(2) activities. DFD effectively neutralized the haemorrhagic activity of the medically important viper venoms such as Echis carinatus, Echis ocelatus, Echis carinatus sochureki, Echis carinatus leakeyi and Crotalus atrox in a dose-dependent manner. The histological examinations revealed that the compound DFD effectively neutralizes the basement membrane degradation, and accumulation of inflammatory leucocytes at the site of Echis carinatus venom injection further confirms the inhibition of haemorrhagic activity. In addition, DFD dose dependently inhibited the PLA(2) activities of Crotalus atrox and E. c. leakeyi venoms. According to the docking studies, DFD binds to hydrophobic pocket of SVMP with the ki of 19.26 x 10(-9) (kcal/mol) without chelating Zn2+ in the active site. It is concluded that the clinically approved inhibitors of haemorrhagins could be used as a potent first-aid agent in snakebite management. Furthermore, a high degree of structural and functional homology between SVMPs and their relatives, the MMPs, suggests that DFD analogues may find immense value in the regulation of multifactorial pathological conditions like inflammation, cancer and wound healing.

Item Type:	Article
Subjects:	C Chemical Science > Biochemistry
Divisions:	Department of > Biochemistry
Depositing User:	Users 23 not found.
Date Deposited:	08 Aug 2019 10:18
Last Modified:	16 Jul 2022 07:09
URI:	http://eprints.uni-mysore.ac.in/id/eprint/2396

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