Tripathi_2019_Eur.J.Med.Chem_183_111707

Reference

Title : Design and development of molecular hybrids of 2-pyridylpiperazine and 5-phenyl-1,3,4-oxadiazoles as potential multifunctional agents to treat Alzheimer's disease - Tripathi_2019_Eur.J.Med.Chem_183_111707
Author(s) : Tripathi A , Choubey PK , Sharma P , Seth A , Tripathi PN , Tripathi MK , Prajapati SK , Krishnamurthy S , Shrivastava SK
Ref : Eur Journal of Medicinal Chemistry , 183 :111707 , 2019
Abstract : The diverse nature of Alzheimer's disease (AD) has prompted researchers to develop multi-functional agents. Herein, we have designed and synthesized molecular hybrids of 2-pyridylpiperazine and 5-phenyl-1,3,4-oxadiazoles. Biological activities of synthesized compounds suggested significant and balanced inhibitory potential against target enzymes. In particular, compound 49 containing 2,4-difluoro substitution at terminal phenyl ring considered as most potential lead with inhibition of acetylcholinesterase (hAChE, IC50=0.054muM), butyrylcholinesterase (hBChE, IC50=0.787muM) and beta-secretase-1 (hBACE-1, IC50=0.098muM). The enzyme kinetics study of 49 against hAChE suggested a mixed type of inhibition (Ki=0.030muM). Also, 48 and 49 showed significant displacement of propidium iodide from the peripheral anionic site (PAS) of hAChE, excellent blood-brain barrier (BBB) permeability in parallel artificial membrane permeation assay (PAMPA), and neuroprotective ability against SH-SY5Y neuroblastoma cell lines. Further, 49 also exhibited anti-Abeta aggregation activity in self- and AChE-induced thioflavin T assay, which was ascertained by morphological characterization by atomic force microscopy (AFM). Moreover, in vivo behavioral studies signified learning and memory improvement by compound 49 in scopolamine- and Abeta-induced cognitive dysfunctions performed on Y-maze and Morris water maze. The ex vivo studies suggested decreased AChE activity and antioxidant potential of compound 49, with good oral absorption characteristics ascertained by pharmacokinetic studies.
ESTHER : Tripathi_2019_Eur.J.Med.Chem_183_111707
PubMedSearch : Tripathi_2019_Eur.J.Med.Chem_183_111707
PubMedID: 31561043

Citations formats

Tripathi A, Choubey PK, Sharma P, Seth A, Tripathi PN, Tripathi MK, Prajapati SK, Krishnamurthy S, Shrivastava SK (2019)
Design and development of molecular hybrids of 2-pyridylpiperazine and 5-phenyl-1,3,4-oxadiazoles as potential multifunctional agents to treat Alzheimer's disease
Eur Journal of Medicinal Chemistry 183 :111707

Tripathi A, Choubey PK, Sharma P, Seth A, Tripathi PN, Tripathi MK, Prajapati SK, Krishnamurthy S, Shrivastava SK (2019)
Eur Journal of Medicinal Chemistry 183 :111707

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    [paper] => Tripathi_2019_Eur.J.Med.Chem_183_111707
    [author] => Tripathi A || Choubey PK || Sharma P || Seth A || Tripathi PN || Tripathi MK || Prajapati SK || Krishnamurthy S || Shrivastava SK
    [year] => 2019
    [title] => Design and development of molecular hybrids of 2-pyridylpiperazine and 5-phenyl-1,3,4-oxadiazoles as potential multifunctional agents to treat Alzheimer's disease
    [journal] => Eur Journal of Medicinal Chemistry
    [volume] => 183
    [page] => 111707
    [medline] => 31561043
    [abstract] => Tripathi_2019_Eur.J.Med.Chem_183_111707
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            [content] => The diverse nature of Alzheimer's disease (AD) has prompted researchers to develop multi-functional agents. Herein, we have designed and synthesized molecular hybrids of 2-pyridylpiperazine and 5-phenyl-1,3,4-oxadiazoles. Biological activities of synthesized compounds suggested significant and balanced inhibitory potential against target enzymes. In particular, compound 49 containing 2,4-difluoro substitution at terminal phenyl ring considered as most potential lead with inhibition of acetylcholinesterase (hAChE, IC50=0.054muM), butyrylcholinesterase (hBChE, IC50=0.787muM) and beta-secretase-1 (hBACE-1, IC50=0.098muM). The enzyme kinetics study of 49 against hAChE suggested a mixed type of inhibition (Ki=0.030muM). Also, 48 and 49 showed significant displacement of propidium iodide from the peripheral anionic site (PAS) of hAChE, excellent blood-brain barrier (BBB) permeability in parallel artificial membrane permeation assay (PAMPA), and neuroprotective ability against SH-SY5Y neuroblastoma cell lines. Further, 49 also exhibited anti-Abeta aggregation activity in self- and AChE-induced thioflavin T assay, which was ascertained by morphological characterization by atomic force microscopy (AFM). Moreover, in vivo behavioral studies signified learning and memory improvement by compound 49 in scopolamine- and Abeta-induced cognitive dysfunctions performed on Y-maze and Morris water maze. The ex vivo studies suggested decreased AChE activity and antioxidant potential of compound 49, with good oral absorption characteristics ascertained by pharmacokinetic studies.
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