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Synthesis, biological evaluation, molecular docking, and MD simulation of novel 2,4-disubstituted quinazoline derivatives as selective butyrylcholinesterase inhibitors and antioxidant agents.
Sadeghian, Sara; Razmi, Raziyeh; Khabnadideh, Soghra; Khoshneviszadeh, Mehdi; Mardaneh, Pegah; Talashan, Arman; Pirouti, Arman; Khebre, Fatemeh; Zahmatkesh, Zahra; Rezaei, Zahra.
Afiliação
  • Sadeghian S; Department of Medicinal Chemistry, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
  • Razmi R; Department of Medicinal Chemistry, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
  • Khabnadideh S; Department of Medicinal Chemistry, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
  • Khoshneviszadeh M; Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
  • Mardaneh P; Department of Medicinal Chemistry, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
  • Talashan A; Department of Medicinal Chemistry, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
  • Pirouti A; Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
  • Khebre F; Department of Medicinal Chemistry, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
  • Zahmatkesh Z; Department of Medicinal Chemistry, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
  • Rezaei Z; Department of Medicinal Chemistry, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
Sci Rep ; 14(1): 15577, 2024 07 06.
Article em En | MEDLINE | ID: mdl-38971857
ABSTRACT
Alzheimer's disease is the most prevalent neurodegenerative disorder characterized by significant memory loss and cognitive impairments. Studies have shown that the expression level and activity of the butyrylcholinesterase enzyme increases significantly in the late stages of Alzheimer's disease, so butyrylcholinesterase can be considered as a promising therapeutic target for potential Alzheimer's treatments. In the present study, a novel series of 2,4-disubstituted quinazoline derivatives (6a-j) were synthesized and evaluated for their inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinestrase (BuChE) enzymes, as well as for their antioxidant activities. The biological evaluation revealed that compounds 6f, 6h, and 6j showed potent inhibitory activities against eqBuChE, with IC50 values of 0.52, 6.74, and 3.65 µM, respectively. These potent compounds showed high selectivity for eqBuChE over eelAChE. The kinetic study demonstrated a mixed-type inhibition pattern for both enzymes, which revealed that the potent compounds might be able to bind to both the catalytic active site and peripheral anionic site of eelAChE and eqBuChE. In addition, molecular docking studies and molecular dynamic simulations indicated that potent compounds have favorable interactions with the active sites of BuChE. The antioxidant screening showed that compounds 6b, 6c, and 6j displayed superior scavenging capabilities compared to the other compounds. The obtained results suggest that compounds 6f, 6h, and 6j are promising lead compounds for the further development of new potent and selective BuChE inhibitors.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Quinazolinas / Butirilcolinesterase / Inibidores da Colinesterase / Simulação de Dinâmica Molecular / Simulação de Acoplamento Molecular / Antioxidantes Limite: Animals / Humans Idioma: En Revista: Sci Rep Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Irã

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Quinazolinas / Butirilcolinesterase / Inibidores da Colinesterase / Simulação de Dinâmica Molecular / Simulação de Acoplamento Molecular / Antioxidantes Limite: Animals / Humans Idioma: En Revista: Sci Rep Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Irã
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