Acetylphenyl-substituted imidazolium salts: synthesis, characterization, in silico studies and inhibitory properties against some metabolic enzymes

Herein, we present how to synthesize thirteen new 1-(4-acetylphenyl)-3-alkylimidazolium salts by reacting 4-(1-H-imidazol-1-yl)acetophenone with a variety of benzyl halides that contain either electron-donating or electron-withdrawing groups. The structures of the new imidazolium salts were conformed using different spectroscopic methods (1H NMR, 13C NMR, 19F NMR, and FTIR) and elemental analysis techniques. Furthermore, these compounds’ the carbonic anhydrase (hCAs) and acetylcholinesterase (AChE) enzyme inhibition activities were investigated. They showed a highly potent inhibition effect toward AChE and hCAs with Ki values in the range of 8.30 ± 1.71 to 120.77 ± 8.61 nM for AChE, 16.97 ± 2.04 to 84.45 ± 13.78 nM for hCA I, and 14.09 ± 2.99 to 69.33 ± 17.35 nM for hCA II, respectively. Most of the synthesized imidazolium salts appeared to be more potent than the standard inhibitor of tacrine (TAC) against AChE and Acetazolamide (AZA) against CA. In the meantime, to prospect for potential synthesized imidazolium salt inhibitor(s) against AChE and hCAs, molecular docking and an ADMET-based approach were exerted.


Introduction
Since the discovery of N-heterocyclic carbene (NHC) by Arduengo et al. three decades ago, the field of organic and organometallic chemistry has developed significantly due to the extraordinary uses of NHC ligands [1,2].NHCs could form more stable complexes with the majority of transition metals than heterocycles with P, O, and S atoms.Furthermore; the metal-carbene bond is more reactive than the metal-phosphine bond in other metal complexes, such as phosphine complexes [3].Both σ-bonds with inductive effects and π-bonds with resonance effects influence the stability of NHCs.Because they are better σ-donating ligands than known trialkyl phosphines, these ligands have been identified as promising candidates for biological activities and various oxidation states [4,5].
Imidazoles and benzimidazoles are important N-heterocyclic compounds because of their interesting framework.These compounds are mostly found in alkaloids and have biological activities such as antimicrobial [6,7], antifungal [8], antiviral [9], anti-inflammatory [10], antitumor [11], and anticancer properties [12].Several of these heterocyclic compounds, particularly, those with fused tricyclic or bicyclic rings, have important medical applications [13][14][15][16].Furthermore, these salts have found quite important application fields across a wide range of chemical reactions.For example, they have been utilized to produce chiral zwitterionic carbene precursors [17] and as curing agents for epoxy resins [18].Imidazolium salts play a significant role in biological activity work, but they are also widely employed in chemical synthesis as ionic liquids that can be used as solvents or electrolytes in green chemistry [19].Imidazolium salts are bioactive azole-based compounds derived from imidazole.As ligands, imidazoles, could bond with metals or form hydrogen bonds with drugs and proteins [20,21].Furthermore, imidazolium salts can interact electrostatically with biological molecules [22,23].
Today's modern pharmaceutical industry has a significant demand for drug-like molecules with favorable chemical properties and biological activity [24,25].Recent research has revealed that it is critical to impart certain structural features to fluorine-containing molecules [26].As a result of the advancements, around 300 fluorinecontaining drugs have been approved and are currently being used all over the world [27].Furthermore, half of the fluorine-containing drugs are blockbusters [28].
The acetyl group, also known as the acyl group in organic chemistry, has the chemical formula CH 3 CO and the abbreviation Ac (not to be confused with the element actinium) [29].Many biologically active chemicals, such as acetylcysteine, acetyl-CoA, acetaminophen (also known as paracetamol), acetylsalicylic acid (commonly known as aspirin), acetyl-L-carnitine, and the neurotransmitter acetylcholine have an acetyl group in their structure.In organisms, acetyl groups are frequently transferred from acetyl-CoA to other organic molecules.Acetyl-CoA serves as an intermediate in both biological synthetase and the degradation of many organic molecules.Acetyl-CoA is also formed by the action of pyruvate dehydrogenase on pyruvic acid during the second step of cellular respiration, pyruvate decarboxylation.Acetylation is a common method of modifying histones and other proteins.On the DNA level, for example, histone acetylation by acetyltransferases causes chromatin architecture to expand, allowing genetic transcription to occur.However, acetyl group removal by histone deacetylases condenses DNA structure, preventing transcription [30].Furthermore, some data suggests that acetyl-L-carnitine, which has the acetyl group, may be more efficient than L-carnitine in specific applications [31].Resveratrol acetylation holds promise as one of the first anti-radiation drugs for human populations [32].
Carbonic anhydrases (CAs) are a superfamily of metalloenzymes and metabolize acid-base concentrations and they also play a role fluid balance in parts of the body such as the eyes, kidneys, and stomach [33,34].CA isoenzymes are CA is the second most plentiful protein after hemoglobin in erythrocytes and effectively interconnect and carbon dioxide (CO 2 ) and water to bicarbonate (HCO 3 − ) and protons (H + ) [35,36].It is well-known that CO 2 , HCO 3 − and H + are essential molecules and ions in a moat of crucial physiologic processes in life kingdoms.The family of human CA (hCAs) is divided into many isoforms, depending on the location of origin such as saliva, mitochondria and cytosol, etc. [37][38][39].The discovery and characterization of human CA isoforms, of which 16 are known today, has led to many new applications of inhibitors.They are widely used clinically as antiepileptic, anticonvulsant, antiglaucoma, and antiobesity agents, antitumor drugs in clinical development, as well as for the treatment of diseases such as idiopathic intracranial hypertension and acute mountain sickness [40][41][42].Also, the inhibition of CA isoenzymes has been fully elucidated.The inhibition of most classical inhibitory occurs by binding to the metal center in the active site of enzymes [43,44].Especially, increased levels of several isoforms of hCAs have been linked to a variety of diseases such as obesity, glaucoma and cancer [45,46].CA inhibitors (CAIs) are used clinically for many years as antiepilepsy, antimetastatic, antiglaucoma, diuretics, and antitumor.To that end, the development of new CAIs has been extremely important [47,48].
The cholinergic hypothesis is known that the degeneration of cholinergic neurons and the consequent loss of cholinergic neurotransmission in the cerebral cortex are responsible for the deterioration of cognitive function observed in the brain of AD patients [49][50][51].In the cholinergic hypothesis, acetylcholine (ACh) is a key neurotransmitter and it is decreased both in function and concentration in brains with AD [52,53].It should be noted that many other symptoms such as cognitive impairment, depression and psychosis occur simultaneously with AD.In AD brains, ACh is hydrolyzed by acetylcholinesterase (AChE), which regulates the amount of ACh in the body [54,55].Regarding the hydrolysis of ACh to choline and acetate by AChE, the concentration of this neurotransmitter in the central nervous system is insufficient to keep the brain functioning properly [56,57].AChE inhibitors are a type of drug used to treat AD.These drugs, on the other hand, do not stop the disease from progressing; they just hide the symptoms.Some AChE inhibitors including Tacrine as a reversible and potent AChE inhibitor have been used in the treatment of AD [58,59].There is evidence to suggest that tacrine has additional properties as well as an effect on the reduction of amyloid-β peptide-induced apoptosis in cortical neurons [60].Despite its inhibitory power, it has been withdrawn from use due to its toxicity and side effects such as hepatotoxicity and gastrointestinal discomfort [61,62].While clinical treatment has a variety of adverse effects, these medications can effectively reduce the symptoms of AD, for example, transaminase elevation, nausea, emesis and flatulence [63,64].Hence, there is an urgent need for developing potent AChE inhibitors to treat AD without adverse effects.
Recently, there are few studies on the enzyme inhibition activities of imidazolium salts in the literature [65].Recently, our workgroup described the synthesis, characterization, and enzyme inhibitory activities of different alkyl/ aryl-substituted benzimidazolium salts on certain metabolic enzymes [66,67].The new imidazolium salts had an acetylphenyl substituent on a nitrogen atom and an alkyl (bearing trifluoromethyl)/aryl group on the other.This work involved the synthesis of 1-(4-acetylphenyl)-3-alkylimidazolium salts containing electron-donating (2a-g) and electron-withdrawing (3a-f) groups, and the spectroscopic analysis of their structures.The inhibitory effects of 4′-(imidazol-1-yl)acetophenone (1) and new 1-(4-acetylphenyl)-3-alkylimidazolium salts (2a-g, 3a-f) against acetylcholinesterase and carbonic anhydrase as cholinergic enzymes were investigated.Also, their inhibition profiles and molecular docking were compared to the standard compounds like Tacrine and Acetazolamide as clinical inhibitors.Many computational approaches have been developed to research and develop robust for different targets.It has been widely applied in modern drug discovery, including virtual scanning, molecular docking, in silico absorption, distribution, metabolism, excretion, and toxicity (ADMET), and so on.In addition, in this study, by performing computational studies on the basis of the experimental data, the potential first three synthesized imidazolium salts provide the elucidation and support of the interaction mechanisms with the target enzymes (hCA I, hCA II and AChE).

Synthesis
4-(1-H-Imidazol-1-yl)acetophenone was reacted with various alkyl halides containing electron-donating groups (such as methyl and methoxy) and electron-withdrawing groups (such as trifluoromethyl, fluorine, and chlorine) on the benzene group in acetonitrile at 80 °C for 24 h (Scheme 1 and Scheme 2).New 1-(4-acetyphenyl)-alkylimidazolium salts were obtained in yields of 56% to 89%.4-acetylphenyl-substituted imidazolium salts (2a-g and 3a-g), which are stable to air and moisture, were soluble in polar organic solvents such as ethyl alcohol, dimethylformamide, and dimethylsulfoxide as well as water.However, imidazolium salts were also soluble in halogenated solvents such as dichloromethane and chloroform.But, none of these salts are soluble in polar organic solvents such as diethyl ether and nonpolar organic solvents such as pentane, hexane, and toluene.The chemical structures of all synthesized compounds were confirmed using 1 H NMR, 13 C NMR, 19 F NMR, and FTIR spectroscopic methods and elemental analysis techniques.The observation of characteristic acidic proton signals at the second carbon (2-CH) for the imidazole ring between 11.12 and 11.84 ppm in 1 H NMR spectra indicated the formation of imidazolium salts (2a-g and 3a-g).While characteristic ethylene (-CH = CH-) peaks for the imidazole ring were observed as doublet peaks in compounds 2d, 3a, and Scheme 1 Synthesis of imidazolium chloride/bromide salts containing an ethyl group and methyl/methoxy substituted benzyl group (2a-g) Scheme 2 Synthesis of imidazolium bromide salts containing trifluoromethyl, trifluoromethoxy, chloride, and fluorine substituted benzyl group (3a-f) 3b, other compounds were observed as a singlet.However, aromatic protons directly attached to the nitrogen atom in the imidazolium ring appeared between 6.93 and 8.13 ppm as doublets.The characteristic peaks of the benzylic CH 2 group attached to the nitrogen atom of the imidazolium ring were observed between 5.62 and 5.92 ppm as singlets.Protons of the methyl and methoxy groups at the ortho, meta and para positions on benzene gave sharp singlets between 2.17 and 3.82 ppm.In addition, the methyl protons of the acetyl group gave sharp singlets between 2.51 and 2.57 ppm.When the 13 C NMR spectra of all imidazolium salts were examined, the observation of characteristic salt peaks at the second carbon (2-CH) for the imidazole ring between 137.8 and 139.8 ppm in 13 C NMR spectra indicated the formation of imidazolium salts.The peaks of the carbonyl carbons in the 4-acetylphenyl group were observed between 196.2 and 196.5 ppm.The peaks of benzylic carbons were observed between 49.9 and 54.1 ppm.Peaks of methyl carbon in the 4-acetylphenyl group were observed between 26.4 and 26.8 ppm.The peaks of the methyl carbon in the ortho, meta and para positions of the benzene attached to the nitrogen atom of the imidazolium ring were observed between 19.4 and 21.3 ppm, while the methoxy carbons in the 2g compound were observed between 56.7 and 60.8 ppm.The carbon peaks of the CF 3 group in 3a, 3b and 3c compounds were found at 126.6, 126.2, and 126.4 ppm, respectively.The carbon peak of the -OCF 3 group in compound 3d was observed at 150.1 ppm.In compound 3e, the benzene carbon peak to which the F atom is attached was observed at 162.1 and 164.6 ppm.In the 3f compound, the peak of the carbon to which the F atom is attached was observed at 164.6 ppm, while the peak of the carbon to which the Cl atom is attached was observed at 162.0 ppm.When the 19 F NMR spectra of imidazolium salts (3a-f) containing fluorine, trifluoromethyl and trifluoromethoxy groups were examined, fluorine peaks were observed as singlet.The fluorine peaks of the 3a, 3b, 3c, and 3d compounds containing the CF 3 group in the ortho, meta and para position of the benzene ring were observed at -58.38, -60.97, -61.97, and -56.79 ppm, respectively.Fluorine peaks of 3a and 3e compounds containing F atom in the para position of the benzene ring were observed at -112.96 and -110.06 ppm, respectively.The FTIR spectral data of all imidazolium salts revealed a characteristic ν(C-N) band 1552, 1552, 1546, 1552, 1545, 1556, 1556, 1554, 1552, 1552, 1553, 1552, and 1555 cm − 1, respectively for 3a-f.When the elemental analysis results were examined, it was seen that the values found were very close to the calculated values.Elemental analysis results and all spectroscopic data are compatible with the literature [68-70].

Enzyme inhibition results
The 1-(4-acetylphenyl)imidazole ( 1) and 4-acetylphenylsubstituted imidazolium salts (2a-g, 3a-f) were researched in vitro for their ability to inhibit hCA I, hCA II and AChE enzymes.Acetazolamide (AZA) and Tacrine (TAC) were used as positive control for these enzymes.The inhibitory The exchange of substituents demonstrated a substantial influence on the inhibitory effect of the compounds.For instance, the inhibition strength was greatly affected by the addition of the trifluoromethyl group instead of the methyl group.Looking at the position of the groups of the trifluoromethyl group, the inhibitor effects of studied compounds were decreased in the following order: 4 th position > 3 rd > position > 2 nd position.The chlorine binding at position 2 to the 4-fluorobenzyl structure was almost twice as effective in inhibition (3f: K i : 8.30 ± 1.71 nM).

In silico studies
Our in silico study consists of two stages as molecular docking and ADMET analysis.All the computational operations performed in this section are to explain the relationship between the three compounds that exhibit the highest activity against the three target enzymes discussed as a result of in vitro analyzes, both in terms of structural and biological activity.The binding energies (Table 2) and binding types (Table S1) obtained as a result of the calculations were compared with the biological results and evaluated.First, compounds 2c, 2g, and 2e, which show high enzyme inhibition tendency against hCA I target, were investigated within the scope of the molecular docking study.Then, the status of possible compounds showing activity of compounds 2b, 2c, and 2f for hCA II and compounds 2g, 2f, and 2e against AChE enzyme, respectively, will be evaluated.Similarly, a second group (imidazolium bromide salts) of compounds with the same targets, compounds 3f, 3c, and 3a for hCA I, compounds 3b, 3e, and 3f for hCA II, and compounds 3f, 3d, and 3e towards the AChE target will be examined in terms of their visual orientation and interaction.
As shown in Fig. 1, with the binding energy value of -6.83 kcal/mol, compound 2c shows the best binding affinity with the target enzyme hCA I.Then, with the energy value of − 6.72 kcal/mol, the compound 2g and finally − 6.65 kcal/mol, compound 2e tend to interact with the hCA I. Considering these conditions at the atomic level, evaluations were made on the basis of the Acetazolamide (AZA) status of the target enzyme, which was accepted as the control compound.Compared to the hydrogen bonding (His200, Thr199, and Gln92), π-sulfur (His96) and hydrophobic interactions (His94, Ala121 and Leu198) with the current target, of the control compound in Figure S1; it is seen that 2c, 2g, and 2e compounds contribute to their biological activities by forming electrostatic interactions as well as other non-bonding interactions.They also have salt forms and their surface area is larger than the control compound.
In Fig. 2, the biological activity of the first three potential compounds 2b, 2c, and 2f against hCA II was examined by molecular docking study.According to the findings, compound 2b shows the best binding affinity with the target enzyme with a binding energy of − 7.73 kcal/mol.Then, with the binding energy value of − 7.03 kcal/mol, the second compound 2c and finally the compound 2f showed a tendency to bind with the target enzyme to -6.68 kcal/mol.When this situation is compared with the control compound AZA, it is seen that it is biologically active with the hCA II enzyme in a situation where hydrophobic and hydrophobic interactions take place at certain rates compared to hydrophilic interactions.When we computationally evaluate the first three compounds 2g, 2f, and 2e, which show the best inhibition tendency against the AChE target in Fig. 3; the compound 2g creates the best biological activity with its binding energy value of -10.38 kcal/mol.target enzyme.Because the compound 2g makes hydrogen bonds with Gly122, Ser203, Ser293, His447, Glu292 and Tyr124, and hydrophobic interactions with Phe338, Phe297, Trp86, Trp236, Phe295, Phe297, Tyr337 and His447 residues of the target enzyme.
In addition, the same target protein models and 2nd group compounds were investigated by molecular docking method.The poses and three-dimensional interactions of the hCA I, hCA II and AChE enzymes and the potential first three 2nd group compounds in the active site of each enzyme, respectively, are shown in Figs. 4, 5 and 6.
In Fig. 4, compounds showing activity against the hCA I enzyme are 3f, 3c and 3a.According to the calculation results, the binding energy values of the related compounds were -6.81 kcal/mol, − 6.47 kcal/mol and − 6.36 kcal/mol, respectively.The compound 3f forms hydrogen bonds with Thr199, His67, Leu198, and His200; and also hydrophobic interactions with His200, Leu198, and Pro202 amino acids in target enzyme.
The orientation of 3f compound in the binding site of the target enzyme, and the presence of fluorine and chlorine atoms in the ortho and para positions of the phenyl ring in the structure of 3f compound against the control compound AZA and the other two potent compounds 3c and 3a increased its biological efficiency.This state is revealed in Fig. 4 and details were given in Table S1.At the same time, the orientations and interactions of three potential compounds against the positive compound in the active site of the same target were compared both visually and in tables.
On the other hand, we evaluated the orientation and interactions in the visual active region for the first three compounds 3b, 3e, and 3f, which showed the best interaction According to these findings, compound 3b stands out as the most effective structure by forming hydrogen bonds with Asn67, halogen bonds with Glu69, Ile91, hydrophobic interactions with Phe131, Ile91, Val121 and Leu198 as given in Fig. 5.
Finally, the most active compound against the AChE target is 3f.Then, compounds 3d and 3e, respectively, exhibit the best inhibition behavior with the respective target.Considering this situation at the atomic level, it appears that fluorine and chlorine atoms in compound 3f have a more dominant biological activity than trifluoromethoxy in compound 3d and fluorine atoms in compound 3e, as seen in Fig. 6.
As a result of molecular calculations, it is seen that the 1st group compounds show a better binding tendency with three targets than the 2nd group compounds.Especially the 1st groups and 2nd groups show the best binding with the AChE enzyme, which is supported by both their binding energies and their three-dimensional orientation and interactions.
Besides docking studies, in silico ADMET analyzes of both groups of compounds were evaluated separately, and their properties in biological systems were analyzed by estimating their pharmacokinetic properties as well as their pharmacodynamics interactions.These are given in Fig. 7 for both group compounds and details data are tabulated in Tables 3, 4.
As a result of the in vitro analyzes of the 1st and 2nd group compounds, the drug similarity and ADMET analysis results of the first three active compounds according to the activity results against three types of enzymes are within the desired limits and are seen as potential drug candidates for future studies.

Conclusions
This work includes the synthesis of two new series of acetylphenyl substituted imidazolium salts (2a-g, 3a-f).All synthesized compounds have been characterized using 1 H NMR, 19 F NMR, 13 C NMR, and FTIR spectroscopy techniques.We think that 1-(4-acetylphenyl)imidazole (1) and acetylphenyl-substituted imidazolium salts (2a-g, 3a-f) were identified as potent AChE and both CA isoenzymes inhibitors.In this study, low nanomolar level of K i values were observed for each acetylphenyl-substituted compounds (1, 2a-g, 3a-f) and these compounds can be selective inhibitor of both cytosolic CA isoenzymes and AChE enzyme and can be used as potent medicals for treatment of Alzheimer's disease, glaucoma, intracranial hypertension, idiopathic epileptic seizure, altitude sickness, cystinuria, central sleep apnea, periodic paralysis, and dural ectasia after some further investigations.In molecular docking and ADMET applications, imidazolium chloride salts containing a methyl 2c or methoxy 2g substituted benzyl group in the 1st group compounds; and among the second group compounds, imidazolium bromide salts containing a trifluoromethyl 3b or fluorinated and chlorinated 3f benzyl group appear to be favored against three target enzymes.

Synthesis of 1-(4-acetylphenyl)-3-ethylimidazolium bromide (2a)
The method described in the literature was used to synthesize compound 2a.1-(4-acetylphenyl)imidazole (745 mg, 4 mmol) and ethyl bromide (436 mg, 4 mmol) were dissolved in acetonitrile (4 mL) and stirred for 24 h at 80 °C.The white solid that formed at the end of the reaction was filtered off, the solvent was removed, and the product was washed with diethyl ether.The crude product was crystallized from a mixture of ethyl alcohol/diethyl ether

hCAs inhibition assay
Commercial sources usually isolate both CA isoenzymes from fresh human erythrocytes and typically produce these isoenzymes by recombinant technology from E. coli [85].In this study, both hCA isoenzymes were purified via Sepharose-4B-L-Tyrosine-sulfanilamide affinity chromatography [86].CA isoenzymes were purified by Sepharose-4B-L-Tirozyne-sulfanylamide affinity column chromatography [87].The protein content during the purification steps was determined by Bradford method [88].Also, bovine serum albumin was used as standard protein [89].The purity of both hCA isoenzymes was controlled by SDS-PAGE as described in prior studies [90].During the isoenzyme's purification and inhibition process, esterase activity was performed [91].Both hCA isoenzyme activities were determined by following the change in absorbance at 348 nm according to the assay by Verpoorte et al. [92] as described in detail [93].

AChE and hCAs kinetic assay
To investigate the in vitro inhibitory mechanisms of acetylphenyl-substituted imidazolium salts (2a-g, 3a-f) and 4-(1-H-imidazol-1-yl)acetophenone (1) kinetic studies were made with the variable compound and substrate concentrations [94,95].From the observed data, IC 50 and K i values for these derivatives were computed, and the types of inhibition of AChE and hCAs were determined as in previous studies [96].

In silico studies
The 3D structures of carbonic anhydrases (hCA I, hCA II) and acetylcholinesterase (AChE) were obtained from the RCSB Protein Data Bank (PDB) having identifiers 1AZM (2.00 Å), 3HS4 (1.10 Å), and 4EY6 (2.40 Å), respectively.The 3D structures of proteins were evaluated in Discovery Studio 3.5 [97], and missing residue(s) and polar hydrogen atoms were added, and optimized by CHARMM force field [98] of DS 3.5 software.The data on ligand-binding sites in all three enzyme proteins were obtained from the literatures and with help of the "define and edit binding site" sub-protocol of DS software.Alsothe potential first three synthesized imidazolium salts as ligands were sketched and minimized at DFT/B3LYP/SDD level in Gaussian 09 (G09) [99].Lastly, the current ligands were docked into the related ligand-binding sites of each target using AutoDock 4.2 software [100].Intermolecular interactions among enzymes and ligands were assessed and 3D images were rendered with help of DS 3.5 software.
As control compounds, molecular docking calculations were also applied the drugs AZA and TAC for among hCA I, hCA II and AChE, respectively.The data of the control compounds were also utilized to compare and analyze the selected ligands.
Besides these, the pharmacokinetics features of dockingbased prioritized molecules as ligands ADMET were examined to define their activity within the human body via were calculated using DS 3.5 [97].The Lipinski [101] and Veber Rules [102] were used to estimate the drug-like qualities of the ligands.These rules are generally used and important rules in the pharmaceutical industry as a first step in describing the optimal compound for a medicine.So that, the bioavailability of the compounds can be forecasted [103].After then, ADMET descriptors [Aqueous solubility, intestinal absorption (HIA), blood brain barrier penetration (BBB), and cytochrome P450 2D6 binding (CYP2D6), hepatotoxicity and plasma protein binding (PPB)] were predicted with sub-protocol of DS 3.5 to be suitable drug properties or not of the current compounds.The impact of hydroquinone on acetylcholine esterase and

Fig. 1
Fig. 1 Three-dimensional representation and best pose view indicating the interaction of the top three ligands and, AZA as control compound: compound 2c, 2g, and 2e docked in the hCA I protein

Fig. 2
Fig. 2 Three-dimensional representation and best pose view indicating the interaction of the top three ligands and, AZA as control compound: compound 2b, 2c, and 2f docked in the hCA II protein

Fig. 4
Fig. 4 Three-dimensional representation and best pose view indicating the interaction of the top three ligands and, AZA as control compound: compound 3f, 3c, and 3a docked in the hCA I protein

Fig. 5 Fig. 6 3 -
Fig. 5 Three-dimensional representation and best pose view indicating the interaction of the top three ligands and, AZA as control compound: compound 3b, 3e, and 3f docked in the hCA II protein

Fig. 7 3 126. 4 ,
Fig. 7 ADMET plots for the first group (upper side) and the second group (down side) potential compounds and control compounds (AZA for hCA I and hCA II; Tacrine for AChE)

Table 1
Inhibition data of novel synthesized acetylphenyl-substituted imidazolium salts (2a-g and 3a-f) against AChE, hCA I and hCA II *Acetazolamide (AZA) was used as a positive control for both hCA I and II isoforms *Tacrine (TAC) was used as a positive control for acetylcholinesterase

Table 1 .
When the results are examined, the following structure-activity relationship can be easily conveyed:1.hCA I isoenzyme is expressed in erythrocytes and physiologically linked to the retina and cerebral edema.

Table 2
Free energy of binding energy values for first and second group compounds by using molecular docking studies