Synthesis and Biological Evaluation of Dantrolene-Like Hydrazide and Hydrazone Analogues as Multitarget Agents for Neurodegenerative Diseases.
ChemMedChem
; 16(18): 2807-2816, 2021 09 16.
Article
in En
| MEDLINE
| ID: mdl-34047061
ABSTRACT
Dantrolene, a drug used for the management of malignant hyperthermia, had been recently evaluated for prospective repurposing as multitarget agent for neurodegenerative syndromes, including Alzheimer's disease (AD). Herein, twenty-one dantrolene-like hydrazide and hydrazone analogues were synthesized with the aim of exploring structure-activity relationships (SARs) for the inhibition of human monoamine oxidases (MAOs) and acetylcholinesterase (AChE), two well-established target enzymes for anti-AD drugs. With few exceptions, the newly synthesized compounds exhibited selectivity toward MAOâ
B over either MAOâ
A or AChE, with the secondary aldimineâ
9 and phenylhydrazone 20 attaining IC50 values of 0.68 and 0.81â
µM, respectively. While no general SAR trend was observed with lipophilicity descriptors, a molecular simplification strategy allowed the main pharmacophore features to be identified, which are responsible for the inhibitory activity toward MAOâ
B. Finally, further inâ
vitro investigations revealed cell protection from oxidative insult and activation of carnitine/acylcarnitine carrier as concomitant biological activities responsible for neuroprotection by hits 9 and 20 and other promising compounds in the examined series.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Neuroprotective Agents
/
Neurodegenerative Diseases
/
Enzyme Inhibitors
/
Hydrazines
/
Hydrazones
Limits:
Humans
Language:
En
Journal:
ChemMedChem
Journal subject:
FARMACOLOGIA
/
QUIMICA
Year:
2021
Document type:
Article
Affiliation country:
Italia