Morpholine-modified thiosemicarbazones and thiazolidin-4-ones against Alzheimer’s key enzymes: From synthesis to inhibition

Demir, Yeliz; Senol, Halil; ULUÇAY, Orhan; Atesoglu, S. Seyma; TOKALI, FEYZİ SİNAN

doi:10.1016/j.compbiolchem.2025.108683

Morpholine-modified thiosemicarbazones and thiazolidin-4-ones against Alzheimer’s key enzymes: From synthesis to inhibition

Yazarlar (5)
Yeliz Demir Ardahan Üniversitesi, Türkiye
Halil Senol Bezmiâlem Vakıf Üniversitesi, Türkiye
Dr. Öğr. Üyesi Orhan ULUÇAY Kurum Bilgileri Mühendislik-Mimarlık Fakültesi Biyomühendislik Biyomühendislik Özgeçmiş Sayfası İletişim Bilgileri: (474)225-1150 Kafkas Üniversitesi, Türkiye
S. Seyma Atesoglu Bezmiâlem Vakıf Üniversitesi, Türkiye
Doç. Dr. Feyzi Sinan TOKALI Kurum Bilgileri Kars Meslek Yüksekokulu Malzeme ve Malzeme İşleme Teknolojileri Polimer Teknolojisi Özgeçmiş Sayfası İletişim Bilgileri: (474)225-1150 Kafkas Üniversitesi, Türkiye

Devamını Göster

Özet

Inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) is a key therapeutic approach in the management of Alzheimer's disease and other neurodegenerative disorders. A novel series of phenolic Mannich base-derived thiosemicarbazones and their cyclized thiazolidin-4-one analogs incorporating morpholine moieties were synthesized and characterized. Enzyme inhibition kinetics were evaluated against AChE and BChE, with cytotoxicity assessed on the BEAS-2B cell line. The most potent inhibitors were further examined via molecular docking, MM-GBSA binding free energy decomposition, and 250 ns molecular dynamics (MD) simulations to elucidate their binding mechanisms and stability. Compounds 12 (AChE, Ki = 32.83 ± 4.45 nM) and 6 (BChE, Ki = 30.13 ± 5.78 nM) exhibited the highest inhibitory activities without notable cytotoxicity at their effective concentrations. Kinetic analyses revealed competitive inhibition. Computational studies demonstrated that morpholine tertiary amine groups played a pivotal role in anchoring the ligands via persistent cation–π and hydrogen-bond interactions with key active site residues. In silico ADME analysis indicated that most of the synthesized compounds possess favorable pharmacokinetic properties. This combined in vitro and in silico study identifies compounds 6 and 12 as promising lead structures for cholinesterase inhibition, highlighting the critical contribution of tertiary amine moieties to binding affinity and selectivity.

Anahtar Kelimeler

Makale Türü	Özgün Makale
Makale Alt Türü	SSCI, AHCI, SCI, SCI-Exp dergilerinde yayınlanan tam makale
Dergi Adı	Computational Biology and Chemistry
Dergi ISSN	1476-9271 Wos Dergi Scopus Dergi
Dergi Tarandığı Indeksler	SCI-Expanded
Dergi Grubu	Q1
Makale Dili	İngilizce
Basım Tarihi	01-2025
Cilt No	120
Sayı	1
Doi Numarası	10.1016/j.compbiolchem.2025.108683
Makale Linki	https://doi.org/10.1016/j.compbiolchem.2025.108683

BM Sürdürülebilir Kalkınma Amaçları

Atıf Sayıları
SCOPUS	1
Google Scholar	2

Morpholine-modified thiosemicarbazones and thiazolidin-4-ones against Alzheimer’s key enzymes: From synthesis to inhibition

Akademisyenler > Orhan ULUÇAY > Yayın Detayı

Morpholine-modified thiosemicarbazones and thiazolidin-4-ones against Alzheimer’s key enzymes: From synthesis to inhibition

Paylaş