title: Protective effect of novel substituted nicotine hydrazide analogues against hypoxic brain injury in neonatal rats via inhibition of caspase.
abstract: In hypoxic-ischemic injury of the brain of neonates, the level of caspase-3 was found to be aberrantly activated. Its overexpression leads to the alteration of cytoskeleton protein fodrin and loss of DNA repair enzyme which ultimately results in neurological impairment and disability. Concerning this, the present study was intended to develop novel nicotine hydrazide analogues as caspase inhibitors via efficient synthetic route. These compounds were subsequently tested for inhibitory activity against caspase-3 and -7 where they exhibit highly potent activity against caspase-3 revealing compound 5k as most potent inhibitor (IC50=19.4±2.5μM). In Western blot analysis, 5k considerably inhibits the overexpression of caspase-3. The aryl nicotinate of compound 5k, as indicated by molecular docking was found to engage His121 and critical enzyme thiols, i.e., Cys163 of caspase-3 for its potent activity. Moreover, histopathological examination of brain tissues and hippocampus neurons showed that compound 5k considerably improves the brain injury and exert neuroprotective effects in hypoxic-ischemic (HI). In brain homogenate, 5k significantly improves the activity of MDA, SOD, GSH-Px, CAT and T-AOC to exert its beneficial effect against oxidative stress induced by HI injury.
authors.affiliation: Department of Pediatrics, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510700, China. Electronic address: dengchangbo@163.com.
authors.forename: Chang-Bo
authors.initials: CB
authors.lastname: Deng
authors.affiliation: Department of Pediatrics, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510700, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Pediatrics, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510700, China.
authors.forename: Lu-Yi
authors.initials: LY
authors.lastname: Li
authors.affiliation: Department of Pediatrics, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510700, China.
authors.forename: Feng-Jie
authors.initials: FJ
authors.lastname: Sun
mesh_terms: D000818:Animals; D053148:Caspase 3 / Q000378:metabolism*; D053179:Caspase 7 / Q000378:metabolism*; D061945:Caspase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy* / Q000378:metabolism; D015394:Molecular Structure; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D009538:Nicotine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D061945:Caspase Inhibitors; D018696:Neuroprotective Agents; C000621211:nicotine hydrazide; D009538:Nicotine; D053148:Caspase 3; D053179:Caspase 7
keywords: Docking; Ischemic injury; Nicotine hydrazide; Synthesis