title: Discovery of neurotrophic agents based on hydroxycinnamic acid scaffold.
abstract: The number of people affected by neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease is rapidly increasing owing to the global increase in life expectancy. Small molecules with neurotrophic effects have great potential for management of these neurological disorders. In this study, different (C1-C12) alkyl ester derivatives of hydroxycinnamic acids (HCAs) were synthesized (a total of 30 compounds). The neurotrophic capacity of the test compounds was examined by measuring promotion of survival in serum-deprived conditions and enhancement of nerve growth factor (NGF)-induced neurite outgrowth in PC12 neuronal cells. p-Coumaric, ferulic, and sinapic acids and their esters did not alter cell survival, while caffeic acid and all its alkyl esters, especially decyl and dodecyl caffeate, significantly promoted neuronal survival at 25 μm. Methyl, ethyl, propyl, and butyl caffeate esters also significantly enhanced NGF-induced neurite outgrowth, among which the most effective ones were propyl and butyl esters, which at 5 μm led to 25- and 22-fold increases in the number of neurites, respectively. The findings of the docking study suggested phosphatidylinositol 3-kinase (PI3K) as the potential molecular target. In conclusion, our findings demonstrate that alkyl esters of caffeic acid can be useful as scaffolds for the discovery of therapeutic agents for neurodegenerative diseases.
authors.affiliation: Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.|Department of Pharmacology, School of Veterinary Medicine, Shiraz University, Shiraz, Iran.
authors.forename: Razieh
authors.initials: R
authors.lastname: Hosseini
authors.affiliation: Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.|Department of Pharmacology, School of Veterinary Medicine, Shiraz University, Shiraz, Iran.
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Moosavi
authors.affiliation: CIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal.
authors.forename: Hamid
authors.initials: H
authors.lastname: Rajaian
authors.affiliation: CIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal.
authors.forename: Tiago
authors.initials: T
authors.lastname: Silva
authors.affiliation: CIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal.
authors.forename: Diogo
authors.initials: D
authors.lastname: Magalhães E Silva
authors.affiliation: CIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal.
authors.forename: Pedro
authors.initials: P
authors.lastname: Soares
authors.affiliation: Department of Physiology and Pharmacology "Vittorio Erspamer", Sapienza University of Rome, Rome, Italy.
authors.forename: Luciano
authors.initials: L
authors.lastname: Saso
authors.affiliation: Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
authors.forename: Najmeh
authors.initials: N
authors.lastname: Edraki
authors.affiliation: Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
authors.forename: Ramin
authors.initials: R
authors.lastname: Miri
authors.affiliation: CIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal. fborges@fc.up.pt.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Borges
authors.affiliation: Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. firuzio@sums.ac.ir.
authors.forename: Omidreza
authors.initials: O
authors.lastname: Firuzi
mesh_terms: D000818:Animals; D003373:Coumaric Acids / Q000737:chemistry*; D055808:Drug Discovery; D062105:Molecular Docking Simulation; D020932:Nerve Growth Factor / Q000502:physiology; D016501:Neurites; D019636:Neurodegenerative Diseases / Q000188:drug therapy; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D016716:PC12 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051381:Rats
chemical_list: D003373:Coumaric Acids; D018696:Neuroprotective Agents; D020932:Nerve Growth Factor; D019869:Phosphatidylinositol 3-Kinases
keywords: Alkyl ester; hydroxycinnamic acids; neurodegenerative diseases; neurotrophic; synthesis