TY - JOUR
T1 - Investigating alkyl nitrates as nitric oxide releasing precursors of multitarget acetylcholinesterase-monoamine oxidase B inhibitors
AU - Pisani, Leonardo
AU - Iacobazzi, Rosa Maria
AU - Catto, Marco
AU - Rullo, Mariagrazia
AU - Farina, Roberta
AU - Denora, Nunzio
AU - Cellamare, Saverio
AU - Altomare, Cosimo Damiano
PY - 2019/1/1
Y1 - 2019/1/1
N2 - Herein we envisaged the possibility of exploiting alkyl nitrates as precursors of alcohol-bearing dual inhibitors targeting acetylcholinesterase (AChE) and monoamine oxidase B (MAO B), key enzymes in neurodegenerative syndromes such as Alzheimer's disease (AD), through biotransformation unmasking an alcoholic function upon nitric oxide (NO) release. The cooperation to neuroprotection of low fluxes of NO and target enzymes’ inhibition by the alcohol metabolites might return a multitargeting effect. The in vitro screening towards ChEs and MAOs of a collection of 21 primary alcohols disclosed a subset of dual inhibitors, among which three diverse chemotypes were selected to study the corresponding nitrates. Nitrate 14 proved to be a brain permeant, potent AChE-MAO B inhibitor by itself. Moreover, it protected human SH-SY5Y lines against rotenone and hydrogen peroxide with a poor inherent cytotoxicity and showed a slow conversion profile to its alcohol metabolite 9d that still behaved as bimodal and neuroprotective molecule.
AB - Herein we envisaged the possibility of exploiting alkyl nitrates as precursors of alcohol-bearing dual inhibitors targeting acetylcholinesterase (AChE) and monoamine oxidase B (MAO B), key enzymes in neurodegenerative syndromes such as Alzheimer's disease (AD), through biotransformation unmasking an alcoholic function upon nitric oxide (NO) release. The cooperation to neuroprotection of low fluxes of NO and target enzymes’ inhibition by the alcohol metabolites might return a multitargeting effect. The in vitro screening towards ChEs and MAOs of a collection of 21 primary alcohols disclosed a subset of dual inhibitors, among which three diverse chemotypes were selected to study the corresponding nitrates. Nitrate 14 proved to be a brain permeant, potent AChE-MAO B inhibitor by itself. Moreover, it protected human SH-SY5Y lines against rotenone and hydrogen peroxide with a poor inherent cytotoxicity and showed a slow conversion profile to its alcohol metabolite 9d that still behaved as bimodal and neuroprotective molecule.
KW - Acetylcholinesterase
KW - Monoamine oxidase B
KW - Multitargeting agents
KW - Nitric oxide donor
UR - http://www.scopus.com/inward/record.url?scp=85055139328&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85055139328&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2018.10.016
DO - 10.1016/j.ejmech.2018.10.016
M3 - Article
C2 - 30366255
AN - SCOPUS:85055139328
VL - 161
SP - 292
EP - 309
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
SN - 0223-5234
ER -