Design and synthesis of neuroprotective methylthiazoles and modification as NO-chimeras for neurodegenerative therapy.
Learning and memory deficits in Alzheimer's disease (AD) result from synaptic failure and neuronal loss, the latter caused in part by excitotoxicity and oxidative stress. A therapeutic approach is described that uses NO-chimeras directed at restoration of both synaptic function and neuroprotection. 4-Methylthiazole (MZ) derivatives were synthesized, based upon a lead neuroprotective pharmacophore acting in part by GABA(A) receptor potentiation. MZ derivatives were assayed for protection of primary neurons against oxygen-glucose deprivation and excitotoxicity. Selected neuroprotective derivatives were incorporated into NO-chimera prodrugs, coined nomethiazoles. To provide proof of concept for the nomethiazole drug class, selected examples were assayed for restoration of synaptic function in hippocampal slices from AD-transgenic mice, reversal of cognitive deficits, and brain bioavailability of the prodrug and its neuroprotective MZ metabolite. Taken together, the assay data suggest that these chimeric nomethiazoles may be of use in treatment of multiple components of neurodegenerative disorders, such as AD.
Department of Medicinal Chemistry and Pharmacognosy, University of Illinois College of Pharmacy, University of Illinois at Chicago , 833 S. Wood Street, Chicago, Illinois 60612-7231, United States.
Zhihui
Z
Qin
Jia
J
Luo
Lawren
L
VandeVrede
Ehsan
E
Tavassoli
Mauro
M
Fa'
Andrew F
AF
Teich
Ottavio
O
Arancio
Gregory R J
GR
Thatcher
D000544:Alzheimer Disease / Q000188:drug therapy / Q000235:genetics / Q000523:psychology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001682:Biological Availability; D001921:Brain / Q000378:metabolism; D057930:Click Chemistry; D003072:Cognition Disorders / Q000188:drug therapy; D005947:Glucose / Q000172:deficiency; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018716:Molecular Mimicry; D009154:Mutation; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009569:Nitric Oxide / Q000737:chemistry*; D010100:Oxygen / Q000378:metabolism; D061251:Primary Cell Culture; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000378:metabolism; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D009435:Synaptic Transmission / Q000187:drug effects; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014018:Tissue Distribution
D016564:Amyloid beta-Protein Precursor; D018696:Neuroprotective Agents; D011355:Prodrugs; D011963:Receptors, GABA-A; D054852:Small Molecule Libraries; D013844:Thiazoles; D009569:Nitric Oxide; D005947:Glucose; D010100:Oxygen