Sürdürülebilir Kalkınma Amaçları
Yayınlar
- MakaleYalnız künye2026Scopus SJRQ2Synthesis, biological evaluation, and computational analysis of chromone-based carboxamides targeting Alzheimer’s disease
Kilic, Burcu; Aksakal, Fatma; Dogruer, Deniz S.
Alzheimer's disease (AD) is among the most serious long-term health problems of the last few decades. Regrettably, the current lack of treatment options for AD has made it a highly sought-after topic of drug development research. The utilization of multitarget directed ligand design (MTDL) has been the primary focus of research on developing pharmaceuticals for AD. By this approach, we designed novel cholinesterase inhibitors (ChEI) that may also exhibit additional monoamine oxidase (MAO) inhibitory, antioxidant, and metal chelator properties. Within the scope of the current work, twenty N-(2-(tertiaryamine-substituted)ethyl)-4-oxo-4H-chromene-2/3-carboxamide derivatives were synthesized and characterized. Subsequently, we conducted biological investigations for enzyme inhibitory (ChEs and MAO), antioxidant, and metal-chelating activities. Furthermore, we assessed the in silico physicochemical parameters of the compounds to evaluate their drug-likeness or druggability. Additionally, comprehensive computational studies were conducted, including density functional theory (DFT)-based frontier molecular orbital (FMO) analysis, global chemical reactivity descriptors, and molecular electrostatic potential (MEP) surface analysis, along with molecular docking, to elucidate the electronic properties, reactive sites, and binding interactions of the compounds with ChE enzymes.
- MakaleYalnız künye2024Scopus SJRQ2Multifunctional anti-Alzheimer's agents: Synthesis, biological evaluation, and molecular docking study of new 2-phenoxyacetamide/3-phenoxypropanamide/4-oxobutanamide derivatives
Shakila, Shakila; Kilic, Burcu; Bardakkaya, Merve; Aksakal, Fatma; Sagkan, Rahsan Ilikci; Dogruer, Deniz S.
In the current study, three series of new compounds were designed and synthesized through hit optimization, based on the hit compound with a structure (E)-N-(4-{[benzyl(methyl)amino]methyl}thiazol-2-yl)-3-(3,4-dimethoxyphenyl)prop‑2-enamide, which was found as a potential multifunctional anti-Alzheimer agent in our previous study. Then, the biological activities of synthesized compounds (4a-c, 13a-b and 15a-c) were evaluated. The results indicated that 4b, a 2-phenoxyacetamide derivative, exhibited good multifunctional activities. Namely, compound 4b displayed better BChE inhibition (BChE IC50 = 2.10 µM) and antioxidant activity (ORAC = 1.18 Trolox equivalents) compared to the hit compound (BChE IC50 = 14.70 µM, ORAC = 0.5 Trolox equivalents). Additionally, 4b was able to chelate all tested biometals and it also exhibited a neuroprotective effect (63 %), comparable to reference ferulic acid (77 %) while maintaining its safety upon PC12 cell line. When it comes to lowering the levels of TNF-α, NO, IL-1β, and IL-6, 4b performed better activity, relative to the other synthesized compounds. Subsequently, in silico studies such as physicochemical properties, density functional theory (DFT) computational approach and molecular docking studies were performed.
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İncele - MakaleAçık Erişim2023Scopus SJRQ2Synthesis and evaluation of multitarget new 2-aminothiazole derivatives as potential anti-Alzheimer's agents
Bardakkaya, Merve; Kilic, Burcu; Sagkan, Rahsan Ilıkcı; Aksakal, Fatma; Shakila, Shakila; Dogruer, Deniz S.
In this study, two diverse series of 2-aminothiazole-based multitarget compounds, one propenamide and the other propanamide derivatives, were designed and synthesized. Subsequently, their anticholinesterease and antioxidant (ORAC) activities were tested. Among them, compound 3e was the most potent acetylcholinesterase (AChE) inhibitor (AChE IC50 = 0.5 μM, butyrylcholinesterase [BChE] IC50 = 14.7 μM) and compound 9e was the most potent BChE inhibitor (AChE IC50 = 3.13 μM, BChE IC50 = 0.9 μM). Kinetic experiments showed that both compounds were mixed-type inhibitors. According to the anticholinesterease activity results, five compounds (3e, 4e, 5e, 9d, and 9e) were selected for further activity studies, all of which are dual cholinesterase inhibitors. Then, selected compounds were investigated in terms of their metal chelation activity. Moreover, their neuroprotective effects against H2O2-induced damage in the PC12 cell line were evaluated at 10 μM and the results showed that the neuroprotective effect of 3e was 53% compared with the reference ferulic acid (77%). 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) results of selected compounds revealed that the compounds were noncytotoxic. Additionally, 3e was more effective in reducing lipopolysaccharides-induced interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), and nitric oxide (NO) production in the human monocyte derived from patient with acute monocytic leukemia cell line compared with other selected compounds. Finally, a molecular docking study was also performed.
AtıfScopus27WoS24OpenAlex28
İncele - MakaleYalnız künye2023Scopus SJRQ1New thiourea and benzamide derivatives of 2-aminothiazole as multi-target agents against Alzheimer's disease: Design, synthesis, and biological evaluation
Kilic, Burcu; Bardakkaya, Merve; Ilıkcı Sagkan, Rahsan; Aksakal, Fatma; Shakila, Shakila; Dogruer, Deniz S.
In this study, two series of compounds were designed and synthesized, bearing thiourea and benzamide derivatives at position 2 of 4-subtituted-2-aminothiazole, respectively. Then, the inhibition potency of all final compounds for cholinesterase enzymes were evaluated. Among the thiourea derivatives, 3c (IC50 = 0.33 μM) was identified as the most potent and selective butyrylcholinesterase inhibitor. Additionally, benzamide derivative 10e (AChE IC50 = 1.47 and BChE IC50 = 11.40 μM) was found as a dual cholinesterase inhibitor. The type of inhibition for both compounds was determined by kinetic studies and the results showed that the compounds were mixed type inhibitors. Moreover, all title compounds were investigated in terms of their antioxidant (DPHH, ORAC) and metal chelator activities. In addition, the neuroprotective effects of selected compounds (3c, 3e, 6c, 6e and 10e) against H2O2-induced damage in the PC12 cell line were tested. The experimental findings demonstrated that thiourea-derived 6e (40.4 %) and benzamide-derived 10e (37.8 %) have a neuroprotective effect of about half as ferulic acid at 10 μM. Subsequently, the cytotoxicity of selected compounds was examined by the MTT assay, and the compounds were found not to have cytotoxic effect on the PC12 cell line in 24 h. Additionally, compounds 6e and 10e were also found to be more effective in inhibiting the release of IL-1β, IL-6, TNF-α and NO compared to other selected compounds in this study.
AtıfScopus39WoS32OpenAlex39İncele