Natural phenol carbamates: Selective BuChE/FAAH dual inhibitors show neuroprotection in an Alzheimer's disease mouse model.

Autor: Rong K; School of Pharmacy, Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, Hefei, 230032, PR China., Li Z; School of Pharmacy, Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, Hefei, 230032, PR China., Wu X; School of Pharmacy, Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, Hefei, 230032, PR China., Gao S; School of Pharmacy, Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, Hefei, 230032, PR China., Zhao J; School of Pharmacy, Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, Hefei, 230032, PR China., Yang J; School of Pharmacy, Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, Hefei, 230032, PR China., Jiang X; School of Pharmacy, Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, Hefei, 230032, PR China., Zhang J; Anhui Province Key Laboratory of Occupational Health, Anhui No. 2 Provincial People's Hospital, Hefei, 230041, PR China. Electronic address: hfzj2552@163.com., Tang W; School of Pharmacy, Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, Hefei, 230032, PR China; Anhui Province Key Laboratory of Occupational Health, Anhui No. 2 Provincial People's Hospital, Hefei, 230041, PR China. Electronic address: ahmupharm@126.com.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2024 Oct 28; Vol. 281, pp. 117003. Date of Electronic Publication: 2024 Oct 28.
DOI: 10.1016/j.ejmech.2024.117003
Abstrakt: FAAH inhibition can indirectly enhance endocannabinoid signaling to therapeutic levels, effectively preventing or slowing its progression of Alzheimer's disease (AD). Hence, the search for effective dual FAAH/cholinesterase inhibitors is considerable need for disease-modifying therapies. To this aim, we designed, synthesized, and tested three series of natural phenol carbamates. The majority of carbamates proved to be potent on a single target, amongst them, compound D12 containing paeonol motif was identified as an effective dual BuChE/FAAH inhibitor, with well-balanced nanomolar activity (IC 50  = 81 and 400 nM for hBuChE and hFFAH, respectively). D12 possessed BBB penetrating ability, benign safety, neuroprotection and pseudo-irreversible BuChE inhibition (K d  = 2.11 μM, k 2  = 2.27 min -1 ), showing good drug-like properties. D12 also modulated the BV2 microglial polarization to inhibit neuroinflammation. In vivo study verified that D12 improved Aβ 1-41 -induced learning impairments in AD mouse model for both short- and long-term memory responses. Thus, the dual activity of D12 could lead to a potentially more effective treatment for the counteraction of AD progression.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors declare that they have no conflict of interests.
(Copyright © 2024 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: