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08 - İnsana Yakışır İş ve Ekonomik Büyüme

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İnsana Yakışır İş ve Ekonomik Büyüme İstikrarlı, kapsayıcı ve sürdürülebilir ekonomik büyümeyi, tam ve üretken istihdamı ve herkes için insana yakışır işleri desteklemek

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    PublicationOpen Access
    Synthesis and Evaluation of Quinazolin-4(3H)-one Derivatives as Multitarget Metabolic Enzyme Inhibitors: A Biochemistry-Oriented Drug Design
    (2023-07-01) Tokalı F. S.; Taslimi P.; Sadeghi M.; Şenol H.; ŞENOL, HALIL
    In this study, imines bearing quinazolin-4(3H)-one were synthesized and their inhibitory properties were investigated against some metabolic enzymes including Acetylcholinesterase (AChE), Butyrylcholinesterase (BChE), & alpha;-Glycosidase (& alpha;-Gly), and human Carbonic Anhydrase I-II (hCA I-II). All compounds had inhibitory strength with K-i values in the range of 38.55 & PLUSMN;4.08-159.05 & PLUSMN;10.68 nM and 41.04 & PLUSMN;6.73-177.12 & PLUSMN;8.06 nM against hCA I and hCA-II, respectively in comparison to the standard acetazolamide (AZA) K-i=125.15 & PLUSMN;0.78 nM (for hCA-I) and K-i=148.75 & PLUSMN;0.92 nM (for hCA-II). The compounds showed potent inhibitory activity against & alpha;-Gly enzyme with IC50 value 0.34-2.28 nM (standard inhibitor acarbose (ACR): 3.18 nM). Also, these analogs had potent inhibitory strength with K-i values in the range of 4.20 & PLUSMN;0.15-26.10 & PLUSMN;2.36 nM against AChE and 1.22 & PLUSMN;0.05-16.09 & PLUSMN;0.88 nM against BChE in comparison to the standard tacrine (TAC) K-i=37.62 & PLUSMN;6.86 nM (for AChE) and K-i=26.75 & PLUSMN;5.79 nM (for BChE). Additionally, the molecular docking and molecular dynamics simulation study was carried out for the determination of ligand-enzyme interactions. The docking scores of the most active compound were calculated as -7.31, -7.59, -6.66, -6.93 and -7.11 kcal/mol for AChE, BChE, hCA I, hCA II, and & alpha;-Gly, respectively.
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    PublicationOpen Access
    Synthesis and anticancer activity of novel derivatives of α,β‐unsaturated ketones based on oleanolic acid: in vitro and in silico studies against prostate cancer cells
    (2023-08-01) Şenol H.; Ghaffari-Moghaddam M.; Bulut Ş.; Akbaş F.; Köse A.; Topçu G.; ŞENOL, HALIL; AKBAŞ, FAHRİ; TOPÇU, GÜLAÇTI
    Herein, new derivatives of α,β-unsaturated ketones based on oleanolic acid (4 a-i) were designed, synthesized, characterized, and tested against human prostate cancer (PC3). According to the in vitro cytotoxic study, title compounds (4 a-i) showed significantly lower toxicity toward healthy cells (HUVEC) in comparison with the reference drug doxorubicin. The compounds with the lowest IC50 values on PC3 cell lines were 4 b (7.785 μM), 4 c (8.869 μM), and 4 e (8.765 μM). The results of the ADME calculations showed that the drug-likeness parameters were within the defined ranges according to Lipinski's and Jorgensen's rules. For the most potent compounds 4 b, 4 c, and 4 e, a molecular docking analysis using the induced fit docking (IFD) protocol was performed against three protein targets (PARP, PI3K, and mTOR). Based on the IFD scores, compound 4 b had the highest calculated affinity for PARP1, while compound 4 c had higher affinities for mTOR and PI3K. The MM-GBSA calculations showed that the most potent compounds had high binding affinities and formed stable complexes with the protein targets. Finally, a 50 ns molecular dynamics simulation was performed to study the behavior of protein target complexes under in silico physiological conditions.