Neutralization of Haemorrhagic Activity of Viper Venoms by 1-(3-Dimethylaminopropyl)-1-(4-Fluorophenyl)-3-Oxo-1,3-Dihydroisobenzofuran-5-Carbonitrile

Kabburalli Sunitha, Mahadevappa Hemshekhar, Santosh Laxman Gaonkar, Martin Sebastin Santhosh, Muthuvel Suresh Kumar, S. Basappa, Babu Shubha Priya, Kempaiah Kemparaju, Kanchugarakoppal Subbegowda Rangappa, Shivananju Nanjunda Swamy, Kesturu Subbaiah Girish

Research output: Contribution to journalArticle

13 Citations (Scopus)

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-dihydroisobenzofuran-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 19.26×10 -9 (kcal/mol) without chelating Zn 2+ 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.

Original languageEnglish
Pages (from-to)292-299
Number of pages8
JournalBasic and Clinical Pharmacology and Toxicology
Volume109
Issue number4
DOIs
Publication statusPublished - 10-2011

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Viper Venoms
Snake Venoms
Venoms
Metalloproteases
Crotalus
Hemorrhage
Snake Bites
Degradation
First Aid
Chelation
Matrix Metalloproteinases
Basement Membrane
Wound Healing
Extracellular Matrix
diformyl dapsone
1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-3-oxo-1,3-dihydroisobenzofuran-5-carbonitrile
Shock
Edema
Catalytic Domain
Leukocytes

All Science Journal Classification (ASJC) codes

  • Toxicology
  • Pharmacology

Cite this

Sunitha, Kabburalli ; Hemshekhar, Mahadevappa ; Gaonkar, Santosh Laxman ; Sebastin Santhosh, Martin ; Suresh Kumar, Muthuvel ; Basappa, S. ; Priya, Babu Shubha ; Kemparaju, Kempaiah ; Rangappa, Kanchugarakoppal Subbegowda ; Nanjunda Swamy, Shivananju ; Girish, Kesturu Subbaiah. / Neutralization of Haemorrhagic Activity of Viper Venoms by 1-(3-Dimethylaminopropyl)-1-(4-Fluorophenyl)-3-Oxo-1,3-Dihydroisobenzofuran-5-Carbonitrile. In: Basic and Clinical Pharmacology and Toxicology. 2011 ; Vol. 109, No. 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-dihydroisobenzofuran-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 19.26×10 -9 (kcal/mol) without chelating Zn 2+ 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.",
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Sunitha, K, Hemshekhar, M, Gaonkar, SL, Sebastin Santhosh, M, Suresh Kumar, M, Basappa, S, Priya, BS, Kemparaju, K, Rangappa, KS, Nanjunda Swamy, S & Girish, KS 2011, 'Neutralization of Haemorrhagic Activity of Viper Venoms by 1-(3-Dimethylaminopropyl)-1-(4-Fluorophenyl)-3-Oxo-1,3-Dihydroisobenzofuran-5-Carbonitrile', Basic and Clinical Pharmacology and Toxicology, vol. 109, no. 4, pp. 292-299. https://doi.org/10.1111/j.1742-7843.2011.00725.x

Neutralization of Haemorrhagic Activity of Viper Venoms by 1-(3-Dimethylaminopropyl)-1-(4-Fluorophenyl)-3-Oxo-1,3-Dihydroisobenzofuran-5-Carbonitrile. / Sunitha, Kabburalli; Hemshekhar, Mahadevappa; Gaonkar, Santosh Laxman; Sebastin Santhosh, Martin; Suresh Kumar, Muthuvel; Basappa, S.; Priya, Babu Shubha; Kemparaju, Kempaiah; Rangappa, Kanchugarakoppal Subbegowda; Nanjunda Swamy, Shivananju; Girish, Kesturu Subbaiah.

In: Basic and Clinical Pharmacology and Toxicology, Vol. 109, No. 4, 10.2011, p. 292-299.

Research output: Contribution to journalArticle

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AU - Hemshekhar, Mahadevappa

AU - Gaonkar, Santosh Laxman

AU - Sebastin Santhosh, Martin

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AU - Priya, Babu Shubha

AU - Kemparaju, Kempaiah

AU - Rangappa, Kanchugarakoppal Subbegowda

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