This study analyzes the inhibitory effects of newly synthesized compounds of the K1-12 series on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes comparatively using IC50 and K-i parameters. Initially, a series of novel 5-fluoroindolylmethylene hydrazone derivatives (K1-12) were designed and synthesized. The structures of the synthesized compounds were elucidated using 1H and 13C NMR spectroscopy as well as mass spectrometric analyses. Subsequently, their inhibitory effects on AChE and BChE were evaluated in vitro. Molecular docking studies performed for all compounds with AChE and BChE enzymes, and pi interactions and conventional hydrogen bonds were involved in protein-ligand interactions. The molecular dynamics (MD) simulation study of the compound with the highest binding potential to the AChE and BChE structures, K10, disclosed that the complexes obtained from docking would be stable. Moreover, the compound is predicted to have a greater tendency to remain within the binding site of the BChE structure. The density functional theory (DFT) study resulted in similar levels of chemical stability and reactivity for the relatively active compounds. The findings revealed that, especially, the K5 and K10 compounds exhibited higher inhibitory activity than donepezil against BChE and AChE, respectively. The results indicate that these compounds could be potential agents for the treatment of neurodegenerative diseases in the future.

In this study, ten original 3,5-disubstituted-1,2,4-oxadiazole derivatives were successfully synthesized and characterized by mass spectrometry and 1H and 13C NMR spectroscopy. The potential of these compounds to inhibit butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) was assessed, and the results were reported as IC50 and K-i values. The compounds' Ki values ranged from 21.82 f 7.87 to 83.67 f 22.16 nM against BChE and from 9.52 f 2.10 to 34.99 f 11.33 nM against AChE. Consequently, it was found that all compounds, except 4f, demonstrated more effective inhibitory action against BChE than donepezil, and that 4g, 4e, and 4i demonstrated more effective inhibitory activity against AChE than donepezil. All compounds were subjected to molecular docking against AChE and BChE, and hydrogen bonding and It-interactions between the compounds and the enzymes were observed. Stabilities of enzyme-compound complexes generated from the docking were investigated by molecular dynamics (MD) simulation. The generated complexes were determined to be stable during the simulation period. To further deepen our understanding, computational DFT analysis revealed key insights into the structures, electronic properties, and reactivity of these materials. To broaden our research, absorption, distribution, metabolism, excretion, and toxicity (ADMET) calculations of the compounds were also carried out.

Acetylcholinesterase (AChE) is a key serum esterase with antiatherosclerotic effects by preventing lipid peroxide oxidation. AChE inhibitors also serve as therapeutic targets for Alzheimer's disease. Newly developed halosubstituted quinolinecarboxaldehyde-hydrazone derivatives (1a-1 s) show significant pharmacological potential due to their broad biological activities. This study evaluated the inhibitory effects of halo-substituted quinolinecarboxaldehyde-hydrazone derivatives on AChE. Acetylcholine esterase IC50 values ranged from 0.143 to 2.015 mu M, and Ki values from 0.078 +/- 0.030 to 1.074 +/- 0.105 mu M. Tacrine served as the positive control. Molecular docking studies revealed that compounds 1b and 1k displayed pi-pi interactions (pi-alkyl, pi-pi stacking) and conventional hydrogen bonding. The molecular dynamics simulation study disclosed that compounds 1b and 1k formed stable complexes with the enzyme structure. Moreover, the density functional theory study demonstrated that the active compounds had similar electrical property and reactivity. Together with this, compound 1e was anticipated to exhibit the highest chemical stability among the compounds investigated. All of the compounds were shown to have a high absorption from the gastrointestinal tract and to meet Lipinski's criterion in SwissADME. As a result, it was determined that new halo-substituted quinoline carboxaldehyde-hydrazone derivatives showed strong inhibition effect on this enzyme. In comparison to the reference chemical Tacrine, 1k had the most potent inhibitory activity against AChE. In this context, we anticipate that the findings of this study will aid in identifying the adverse effects of both existing and novel quinolinecarboxaldehyde-hydrazonebased pharmaceutical drugs under development. Additionally, it should be effective in the production of novel AChE inhibitors.

ABSTRACT In vitro anticholinesterase activities of a series of 1,2,3‐triazole derivatives, 9 ( a ‐ e ) and 10 ( f ‐ l ), were evaluated against electric eel acetylcholinesterase ( ee AChE) and equine serum butyrylcholinesterase ( eq BuChE), using donepezil as a reference inhibitor. Enzyme inhibitory activities were characterized by IC 50 , inhibition constants ( K i ), and inhibition mechanisms. All target compounds exhibited potent inhibitory activity against both enzymes. 9e demonstrated the highest activity against ee AChE ( K i = 7.69 ± 1.24 nM), outperforming donepezil ( K i = 25.28 ± 5.79 nM). 9b showed the strongest inhibition against eq BuChE ( K i = 3.36 ± 0.67 nM), whereas donepezil displayed comparatively weak activity ( K i = 43.48 ± 10.36 nM). To further elucidate ligand–enzyme interactions, molecular docking, molecular dynamics simulation (MDS), MM/GBSA, and structure–activity relationship studies were performed. Docking results indicated that all target compounds exhibited higher binding affinities for both the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE than for BuChE. MDS and MM/GBSA analyses confirmed the stability of the selected complexes, without significant fluctuations over 50 ns, and showed that while 9e was selective for h AChE‐CAS, 9b bound similarly to both h BuChE sites. Taken together, all target compounds, particularly 9e and 9b , may serve as novel dual AChE/BuChE inhibitor candidates.

Introduction: The genus Tanacetum has a long history of use and is well known for its traditional applications in food, medicine, cosmetics, and agriculture. The biological effects of Tanacetum armenum were investigated, and its phytochemical profiles were analysed. Methods: Phytochemical analysis was conducted using liquid chromatography-mass spectrometry/mass spectrometry, and antioxidant, target enzyme inhibition, and antigenotoxic effects were evaluated. The antiproliferative effects and mechanisms of the extracts were investigated in vitro, and the possible mechanisms of the main compounds were analysed in silico. Results: Phytochemical profile analysis revealed significantly higher levels of chlorogenic acid (64.894 mg/g extract), quinic acid (45.377 mg/g extract), and 1,5-dicaffeoylquinic acid (18.150 mg/g extract). The methanol extract (IC50:116.56 +/- 2.84 & micro;g/mL) exhibited strong tyrosinase enzyme inhibition than ethylacetate (IC50:184.04 +/- 3.02 & micro;g/mL) and aqueous extracts (IC50:340.84 +/- 3.46 & micro;g/mL). The aqueous extract (IC50:328.23 +/- 4.22 & micro;g/mL) showed the highest inhibition of acetylcholinesterase, while the methanol extract (IC50:504.87 +/- 4.78 & micro;g/mL) demonstrated the highest inhibition of butyrylcholinesterase. The ethylacetate extract exhibited the strongest antimicrobial effect against Staphylococcus aureus, with a MIC value of 62.5 & micro;g/mL. The extracts did not show any genotoxic effects. The ethyl acetate extract exhibited significant cytotoxic effects (IC50:25.00-108.16 & micro;g/mL) against cancer cell lines (p < 0.001). To investigate the mechanism by which the extracts inhibit MCF-7 cell viability, the expression levels of the cyclin E1 and caspase-8 were evaluated using western blot analysis. In addition, a colony formation assay was performed, and migration potential was analysed using a scratch wound healing assay. Using in silico approaches, the molecular docking and binding parameter values of cyclin E1 and caspase-8 were calculated. Chlorogenic acid was found to have the best binding value and mode of in silico interaction with the target crystal structures. The docking scores calculated from these binding parameter values were -7.824 kcal/mol for the cyclin E1 (8H6P) target, -7.126 kcal/mol for the caspase-8 (3KJQ) target, and -8.182 kcal/mol for the human oestrogen receptor (3ERT) target. Conclusion: T. armenum, which has demonstrated a strong cytotoxic effect through in vitro and in silico mechanism studies, can be considered a promising potential natural resource for cancer treatment.

Alzheimer's disease (AD), the most worrisome neurological condition in the world, is one of the primary causes of dementia and is characterized by cognitive and memory loss. This disease is multifactorial, and there is currently no cure, although treatments based on the cholinergic hypothesis have been successful in relieving symptoms. This study examined the inhibitory effects of 11 compounds with a sulfonamide group at position 5 of the benzoxazole ring system on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Two of these 11 compounds are original, and FT-IR, 1H NMR, 13C NMR, and mass spectrometry were used to characterize their structures. The compounds showed significantly greater biological activity as inhibitors of both AChE and BChE than the reference drug, donepezil. In particular, 2a showed the highest activity against AChE with a Ki value of 7.45 +/- 2.79 nM, and 1b showed the highest activity against BChE with a Ki value of 3.37 +/- 0.68 nM. Furthermore, a molecular docking study was performed to investigate the interaction modes of the active compounds with the active sites of the crystal structures of AChE and BChE. Hydrogen bond and pi interactions were observed in the protein-ligand interactions. The stabilities of the complexes obtained from docking were assessed using a molecular dynamics (MD) simulation. The MD simulation revealed that the complexes remained stable throughout. Density functional theory (DFT) analysis was also conducted to determine the compounds' most stable conformers and investigate their chemical stability and reactivity.

Objective: In this study, novel 5-fluoroindolylmethylene hydrazone derivatives were synthesized and assessed for their potential inhibitory effects on human carbonic anhydrase I and II (hCA I and II) enzymes through both in vitro and in silico approaches. Material and Method: Accordingly, starting from 5-fluoroindole, 5-fluoroindole-3-carboxaldehyde was synthesized. The target final compounds were then obtained by condensing substituted phenylhydrazine with 5-fluoroindole-3-carboxaldehyde, resulting in three Schiff base derivatives (2a, 2b, and 2c). Result and Discussion: The synthesized compounds demonstrated effective inhibition of cytosolic carbonic anhydrase isoforms hCA I and II, with Ki values ranging from 32.28±7.09 to 74.86±10.90 nM for hCA I and 8.79±1.92 to 60.40±14.64 nM for hCA II. Among them, compound 2a exhibited the most potent inhibitory effect on both isoenzymes. In vitro results were verified with the results obtained by docking studies and interactions with enzymes were demonstrated. These novel 5-fluoroindolylmethylene hydrazone derivatives show promise as potent inhibitors of cytosolic CA isoenzymes.

In this study, a new series of 2-substituted-5-methylsulfonylbenzoxazole derivatives (C1-C16) were successfully synthesized. The structures of the compounds were confirmed by FT-IR, 1H NMR, 13C NMR, and mass spectroscopy, and the results for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzyme inhibitory activity were reported as IC₅₀ and Ki values. The compounds' Ki values against AChE ranged from 7.55 ± 2.88 to 87.39 ± 11.67 nM, and their Ki values against BChE ranged from 3.23 ± 0.64 to 107.86 ± 13.38 nM. Accordingly, all compounds except C1, C2, C11, and C12 were found to be more effective than donepezil against AChE, and all compounds except C1, C5, and C12 were found to be more effective than donepezil against BChE. Molecular docking studies were performed for all compounds against the AChE and BChE enzymes. Conventional hydrogen bonds and π interactions (π-π stacked, π-π T-shaped, π-alkyl, π-sigma, π-cation) were observed in the interactions of the compounds with the target enzymes. Molecular dynamics (MD) simulation of complexes formed by compounds with the highest inhibition activity on the two enzymes affirmed formation of stable complexes. Additionally, the molecular electrostatic potential (MEP) map of all compounds and the extent to which the HOMO-LUMO energy gaps affect the reactivity, stability, and inhibitor profiles of these compounds were investigated using density functional theory (DFT) studies, a computational analysis method. The study proves that 2-substituted-5-methylsulfonylbenzoxazole derivatives exhibit potent and selective cholinesterase inhibition.

Alzheimer's disease (AD), the most prevalent form of dementia, leads to progressive cognitive decline due to pathological hallmarks including amyloid plaques, neurofibrillary tangles, synaptic loss, neuroinflammation, and neuronal cell death, highlighting the urgent need for multitarget therapeutic strategies. The p38α mitogen-activated protein kinase (p38α MAPK) pathway is a key regulator of neuroinflammation and has been implicated in AD pathogenesis. Additionally, dysregulation of p38α MAPK is associated with tumorigenesis, making it a promising target for both neurodegenerative and proliferative diseases. In this article, a series of benzoxazole derivatives is designed and synthesized to evaluate their dual inhibitory potential against p38α MAPK and acetylcholinesterase (AChE), aiming for a multifaceted therapeutic approach to AD. A total of 31 compounds are synthesized and assessed for their antiproliferative activity, p38α MAPK inhibition, and AChE inhibitory effects. In vitro assays demonstrate that several compounds exhibit potent dual inhibition of p38α MAPK and AChE, while molecular docking studies provide insights into their binding interactions within the active sites. These findings suggest that benzoxazole-based scaffolds offer a promising framework for the development of dual-acting inhibitors targeting both neuroinflammation and tumorigenesis. Further in vivo and mechanistic studies are warranted to explore their therapeutic potential.

This study presents the first comprehensive analysis of the phytochemical profile and biological activities of root and stalk extracts from endemic Onosma discedens Hausskn. ex Bornm. (OD). The extracts of OD were analyzed by liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS), and 16 phenolics, including vanillic acid (2077.1332 µg/g extract in root) and hesperidin (1185.3621 µg/g extract in stalk), were detected. In antioxidant activity tests, DPPH• radical scavenging activity of root extract (IC50: 60.69 µg/mL) was found to be higher than stalk extract (IC50: 95.66 µg/mL), but both extracts showed lower activity than standard antioxidants. In antiproliferative activity assays, the OD extract exhibited low cytotoxicity against MCF7 cell lines, with an IC50 value exceeding 500 µg/mL. The stem extract was more effective on the butyrylcholinesterase (BChE) enzyme (IC50: 546.09 ± 0.533 µg/mL) than on the acetylcholinesterase (AChE) enzyme (IC50: 721.156 ± 0.410 µg/mL). When the plant is evaluated as a whole, it has a dual inhibitory effect on both cholinesterase enzymes. Molecular docking analyses confirmed the interactions of vanillic acid and hesperidin with target enzymes. As a result, it was revealed that OD, which has a rich structure in phenolic compounds and significant bioactivity due to its cholinesterase inhibitory effect, can be utilized to treat neurodegenerative illnesses like Alzheimer's.

In this study, the in vitro effects of some indole Schiff bases on acetylcholinesterase and human carbonic anhydrase isoforms I and II were investigated. A series of N-methylindole hydrazide/hydrazone derivatives (1a-1t) were tested on these enzymes. The interactions of the synthesized indole derivatives with target enzymes were studied by molecular docking methodology. The results revealed that indole derivative Schiff base compounds inhibited the enzymes significantly. Ki values for hCAI isoenzyme were determined to be in the range of 36.18 ± 3.07-224.29 ± 5.78 nM; for the hCAII isoenzyme in the range of 31.30 ± 2.63-201.64 ± 7.25 nM; for acetylcholinesterase in the range of 6.82 ± 0.72-110.30 ± 9.26 nM. Compared to the control compound Acetazolamide (AZA), 1k and 1p were found to have the best inhibitory effect for hCAI; 1p was found to be the best inhibitory effect for hCAII. Compared to the control compound Tacrine (TAC), 1s showed the best inhibitory effect for AChE. In vitro results were verified with the results obtained by docking studies and interactions with enzymes were demonstrated.Communicated by Ramaswamy H. Sarma.

In this study, inhibitions of some cytosolic enzymes were evaluated. Inhibitors of these enzymes can help illuminate and treat many related diseases (Alzhaimer, Parkinson's, Glaucoma, etc.). It is aimed to minimize drug side effects with multiple effects in one molecule. For this purpose in vitro effects of two benzothiophene Schiff bases on cholinesterases (AChE and BuChE) and human carbonic anhydrase isoforms (CAI and CAII) were investigated. Molecular modeling studies were carried out to elucidate the inhibition mechanism of two effective compounds on these enzymes. Then, two benzothiophene Schiff bases (1a and 1b compounds) were tested in vitro on these enzymes. The in vitro study results supported the in silico study results. Obtained results revealed that the benzothiophene derivatives inhibited the enzymes significantly. Ki values for CAI isoenzyme were determined to be in the range of 58.82 ± 7.96-126.28 ± 26.22 nM; for the CAII isoenzyme in the range of 27.86 ± 3.76-74.30 ± 7.89 nM; for acetylcholinesterase in the range of 1.31 ± 0.39-2.16 ± 1.01 nM; for butyrylcholinesterase in the range of 1.80 ± 0.27-2.01 ± 1.67 nM. Compared to the AZA control compound, 1b has demonstrated more strong inhibitory effect against CAI and CAII. Wherease compared with other control compound Tacrine, both compounds showed more potent inhibitory effect for cholinesterases (AChE and BuChE).

In this study, p(CTP-co-MMCA) microparticles, a novel cyclomatrix polyphosphazene, were synthesized. Among the p(CTP-co-MMCA) polymeric structures, p(CTP-co-MMCA) (1 : 3) with a high surface amine group was found to be in the form of microparticles after detailed structural and morphological characterization. These microparticles were modified with Au0 and Ag0 nanoparticles using two different green reductants. The antimicrobial activities of p(CTP-co-MMCA) microparticles and their Au0 and Ag0 composites against P.Aeruginosa ATCC 27853, S.Aureus ATCC 6538 and C.Albicans were investigated. Metal composites were found to have better antimicrobial activity. Cyclomatrix p(CTP-co-MMCA) microparticles with antimicrobial properties and their Au0 and Ag0 composites were also used for the release of Ceftriaxone sodium and RNA. Cyclomatrix p(CTP-co-MMCA) microparticles and its Au0 and Ag0 composites retained 48.21 +/- 5.34 mg/g, 49.36 +/- 6.95 mg/g and 23.95 +/- 6.45 mg/g ceftriaxone sodium, respectively, while they retained 79.15 +/- 6.85 mg/g, 47.49 +/- 6.24 mg/g and 57.47 +/- 9.48 mg/g RNA, respectively. Release studies revealed that the presence of Au0 and Ag0 nanoparticles imparted a slower release behavior to p(CTP-co-MMCA) microparticles. The release studies revealed that the presence of Au0 and Ag0 nanoparticles imparted a slower release behavior to the p(CTP-co-MMCA) microparticles. We prepared cyclomatrix polyphosphazene microparticles with surface amine groups by a simple one-step ultrasonic assisted method. We then decorated these particles with Au0 and Ag0 nanoparticles via green synthesis. We examined the drug and RNA release behavior and antimicrobial properties of all obtained microparticles.image

In this study, we investigate the inhibitory potential of a series of hydrazide derivatives bearing different substituents with the pyridazine structure (5 a-i and 6 a-f) against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) using a modified Ellman's method. The inhibitory profiles of the synthesized compounds were assessed by comparing their IC50 and Ki values. Our results demonstrate that all the compounds exhibit significant inhibitory activity against both AChE and BChE when compared to the reference compound, tacrine. Particularly, compound 6 a exhibited the highest activity against Electrophorus electricus AChE (EeAChE) with a Ki value of 3.26 nM, while compound 5 a displayed the most potent inhibition against equine BChE (eqBChE) with a Ki value of 0.94 nM. The compounds did not possess significant cytotoxicity action using the MTT assay on the cancer cell lines. The DPPH assays revealed that all the compounds have moderate antioxidant activities. Furthermore, molecular docking studies provided valuable insights into the interaction mechanisms of these compounds within the active sites of AChE and BChE crystal structures (PDB ID: 4EY7 and 4BDS, respectively). The above results indicated that the pyridazine-based compounds were a promising functional agent for the treatment of Alzheimer's disease. This study reveals the potential of hydrazide derivatives, each with distinct substituents on the pyridazine structure, as potent enzyme inhibitors (AChE and BChE) with antioxidant properties. The provided structural insights, inhibitory profiles, and molecular docking results emphasize their therapeutic potential for neurological disorders. These findings lay the groundwork for subsequent exploration and drug development within the domain of pyridazine compounds. image

Discovering new compounds capable of inhibiting physiologically and metabolically significant drug targets or enzymes is of paramount importance in biological chemistry. With this aim, new 5-nitroimidazole derivatives (1-4) were designed and synthesized, and their inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) were discovered using acetyl (butyryl) thiocholine and Ellman's reagents for spectrophotometric assay. The inhibitory profiles of the synthesized compounds were assessed by comparing their IC50 and Ki values. Results demonstrate significant inhibitory activity of all synthesized compounds against both AChE and BuChE compared to the reference compound, donepezil. Notably, compound 4 exhibited dual inhibition of these enzymes, showing the highest activity against Electrophorus electricus AChE (EeAChE) with a Ki value of 0.024±0.009 nM and against equine BuChE (eqBuChE) with a Ki value of 0.087±0.017 nM. Furthermore, molecular modeling was conducted to study the interaction modes of the most potent compound (4) and donepezil in the active site of their related enzymes' crystal structures (PDB ID: 4EY7 and 4BDS, respectively). Additionally, drug-likeness, ADME, and toxicity profiles of the compounds and metronidazole were predicted. The above results indicated that the dual inhibition of these enzymes is considered as a promising strategy for the treatment of neurological disorder especially Alzheimer's disease.

Alzheimer's Disease (AD) is the most common type of dementia that develops with age, threatens the quality of life, is increases in number around the world, and has no effective treatment. The most important therapeutic targets in drug development studies for the treatment of AD are acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. The inadequacy of existing AChE and BChE inhibitors in the treatment of AD has led to the need to identify new AChE/BChE inhibitors with fewer side effects. In this study, considering the pharmacological importance indole derivatives, inhibition effects of some indole derivative molecules (a-e) on AChE and BChE activity were investigated. IC50 values of a-e against AChE were found to be 0.480 µM, 1.682 µM, 0.916 µM, 1.093 µM, 0.340 µM, respectively. On the other hand, IC50 values of compounds a-e on BChE activity were determined as 2.18 µM, 4.49 µM, 2.28 µM, 6.36 µM, 1.940 µM, respectively. As a result, it was seen that indole derivatives (a-e) showed strong inhibition effect on both enzymes. Additionally, these inhibition results were supported by molecular modelling studies. As a conclusion, results of this study will contribute to studies on the synthesis of new indole-derived AChE and BChE inhibitors for the treatment of AD.

A series of novel (p-chlorophenyl)-3(2H)pyridazinone compounds were synthesized starting from p-chloroacetophenone as AChE/BChE inhibitors. The chemical structures of all the compounds were identified by spectral analysis. Cholinesterase inhibition activity studies and in silico studies of compounds designed to eliminate the symptomatic effects of Alzheimer's disease and slow down neurodegeneration were evaluated. According to the results obtained, it was revealed that N-substituted-(p- chlorophenyl)pyridazin-3(2H)-one derivatives inhibited enzymes significantly. K-i values were found for acetylcholinesterase in the range of 10.2 +/- 4.0-20.9 +/- 7.6 nM and for butyrylcholinesterase in the range of 0.70 +/- 0.34-1.67 +/- 1.12 nM. Compound 5e showed the best effect on AChE activity compared to Tacrine. Also, compound 5b showed the best effect in BChE inhibition. The interactions of the synthesized compounds with the best experimental activities against AChE, BChE, respectively, were investigated by in silico approaches. In molecular docking, 5b compound with AChE crystal structure (PDB ID:1ACJ), binding site and binding parameters of 5e compound with BChE crystal structure were investigated in detail. The results indicated that compound 5b and 5e could be a promising lead compound for further development as a therapeutic agent for Alzheimer's disease.

Alzheimer hastalığı (AH), demansın en yaygın nedeni olan kronik nörodejeneratif bir hastalıktır. Hastalığa yakalanma riski yaşla birlikte artar. Hastalığın histopatolojisi incelendiğinde senil amiloid plakları, nörofibriler yumak oluşumu, sinaps-nöron kaybı ve beyinde belirgin atrofi saptanır. Alzheimer hastalığında asetilkolin sentezinden sorumlu olan kolin asetil transferaz düzeyindeki azalma %58-90'dır. Mevcut ilaçlar hastalığın ilerlemesini durduramadığından, hastalığın temel nedenini hedef alan yeni ilaçlara büyük ihtiyaç vardır. Bu çalışmada asetilkolinesteraz inhibisyonu gösteren triazol-piridazinon türevi bileşikler sentezlenmiştir ve enzim inhibisyonları araştırılmıştır. Bileşik 6e, 0.049 ± 0.014 µM Ki değeri ile en güçlü inhibitör etkiyi göstermiştir (Takrin Ki= 0.226 ± 0.025 µM). Ayrıca sentezlenen tüm bileşikler için in-silico çalışmalar yapıldı.

In this study, a series of N-substituted-(p-tolyl)pyridazin-3(2H)-one derivatives were synthesized and evaluated for their AChE inhibitory activity. The chemical structures of novel compounds 5(a-m) were confirmed by H-1-NMR, C-13-NMR, IR and HRMS analysis. In order to eliminate the symptomatic effects of Alzheimer's disease, the proposed compounds were evaluated by acetylcholinesterase inhibition activity study in accordance with the cholinergic hypothesis. The results revealed that the N-substituted-(p-tolyl)pyridazin-3(2H)-one derivatives inhibited the enzymes significantly. K-i values for acetylcholinesterase in the range of 0.56 +/- 0.15-4.12 +/- 1.42 mu M. Compound 5 h demonstrated the greatest in AChE activity compared with tacrine (0.56 +/- 0.15 mu M). Molecular docking studies were performed for all compounds that compared tacrine in AChE activity in-vitro. As a result of molecular docking studies (Delta G(Bind), docking score, XP Gscore, Glide energy, Glide emodel), 5 f, 5 g and 5 h compounds showed good inhibitory properties in the AChE active site as in silico.

Alzheimer’s disease is a progressive and fatal neurodegenerative disease affecting the elderly population accompanied by a decrease in cholinergic transmission, impairing cognitive functions. Acetylcholine deficiency is important in the development of disease symptoms. Inhibition of acetylcholinesterase, an important enzyme in acetylcholine hydrolysis, is one of the important drug targets to increase acetylcholine levels. In this study, we aimed to develop acetylcholinesterase inhibitor compounds. For this, we synthesized compounds 6(a–e) bearing 3(2H)-pyridazinone and 1,2,4-triazole ring structures. We determined the IC50, Ki and inhibition types of N-substituted-(p-methoxyphenyl)pyridazin-3(2H)-one derivatives that we synthesized and elucidated their structures. The compound with the best AChE activity was compound 6b (Ki = 3.73 ± 0.9 nM) with the p-methylphenyl group it carried and showed competitive inhibition. Kinetic study was also performed for the compounds with the highest BChE 6a (Ki = 0.95 ± 0.16 nM) inhibitory activities. Molecular docking studies have shown that the p-methylphenyl group is indeed active in the hinge region of the AChE crystal structure as a result of experimental activity. In addition, the best free binding energy (ΔGBind), docking score and Glide score values were determined by examining the interactions with AChE crystal structure for compound 6b and with BChE crystal structure for 6a in silico approaches.