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Therapeutic investigations of novel indoxyl-based indolines: A drug target validation and Structure-Activity Relationship of angiotensin-converting enzyme inhibitors with cardiovascular regulation and thrombolytic potential

Publication date:

1 December 2017

Source:European Journal of Medicinal Chemistry, Volume 141

Author(s): A. Manikandan, Pearl Moharil, M. Sathishkumar, C. Muñoz-Garay, A. Sivakumar

A family of 12 members of Naphthalene-2-ol-indolin-2-one-thiocarbamides (5a-l) with pharmacological potentials of cardiovascular modulator were efficiently synthesized and evaluated. These compounds show inhibitory activity on angiotensin-converting enzyme (ACE), which is a principal constituent of the renin–angiotensin system and causative source for hypertension (HTN) (elevated blood pressure) and congestive heart failure (CHF), a parameter that was tested in this report. Prior to this, to get more insight into the binding mode and inhibition of human ACE C-domain (PDB ID: 2XY9) and N-domain (PDB ID: 3NXQ) compounds 5a-l was docked into the active site of them. The established inhibitory constant (Ki) (range 40–500 nM) and least binding affinities (−18.52 to −30.57 kcal/mol) indicated the therapeutic selectivity of compounds 5a-l towards ACE C-domain inhibition over ACE N-domain. The cytotoxicity effect of most potent compounds among 5a-l were tested in normal breast cells and MCF-7 cell lines. Simultaneously, H2O2 induced antioxidant and DNA damage assessment was executed. Eventually, a thrombolytic activity followed by a human red blood cell (HRBC) membrane stabilization study to ensure the relaxation of blood and stabilization of RBC was executed. Structure-Activity Relationship (SAR) study discloses the potential of 5c, 5h, and 5k as cardiovascular protective therapeutic agents among 5a-l.
Graphical abstract

Authors:   Author(s): A. Manikandan, Pearl Moharil, M. Sathishkumar, C. Muñoz-Garay, A. Sivakumar
Journal:   European Journal of Medicinal Chemistry
Volume:   141
Year:   2017
Pages:   417
DOI:   10.1016/j.ejmech.2017.09.076
Publication date:   14-Oct-2017
Facts, background information, dossiers
  • relaxation
  • Pearl
  • naphthalene
  • medicinal chemistry
  • inhibitors
  • hypertension
  • heart failures
  • DNA damage
  • cytotoxicity
  • cells
  • blood pressure
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