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

摘要

Abstract 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, H 2 O 2 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 Display Omitted Highlights ? 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. ? Angiotensin converting enzyme was effectively inhibited by 5c, 5h, 5k and 5l. ? H 2 O 2 was readily scavenged by 5a-l. ? Cardiovascular protection was ensured by thrombolytic, HRBC membrane protection and cytotoxicity mechanisms.