New 2-Methyl Benzimidazole Derivatives bearing 4-Thiazolidinone Heterocyclic Rings: Synthesis, Preliminary Pharmacological Assessment and Docking Studies

 

Abdul Muhaimen Amjed Adnan1, Monther Faisal Mahdi2, Ayad Kareem Khan2

1Department of Pharmacy, Baghdad College of Medical Science, Baghdad, Iraq.

2Department of Pharmaceutical Chemistry, College of Pharmacy, Mustansiriyah University, Baghdad-Iraq.

*Corresponding Author E-mail: ayad@uomustansiriyah.edu.iq

 

ABSTRACT:

New 2-methyl benzimidazole derivatives were prepared and evaluated as possible inhibitor agents for cyclooxygenase-2 (COX-2). The synthesized derivatives structures have been recognized according to their spectral FT-IR, 1H-NMR data and physical properties. The newly synthesized compounds were inspected in vivo for their anti-inflammation efficiency using egg-white stimulated edema of paw method regarding the effect of propylene glycol 50%v/v as a control group. Ibuprofen (10mg/kg i.p.) was chosen as a reference ligand. New compounds exhibit a significant in vivo anti-inflammatory efficacy approached with ibuprofen as a reference drug. Selective evaluation of cyclooxygenase-2 by stimulating molecular cohesion through (GOLD suite v.5.6.2). All the investigated compounds via molecular docking showed significant more activities comparable with diclofenac and ibuprofen as referenced drugs. ADME studies were performed to estimate site of absorption, bioavailability, topological polar surface area and drug-likeness and it appeared that all synthesized compounds absorbed from GIT.

 

KEYWORDS: 2-methyl benzimidazole, 4-thiazolidinone, synthesis, pharmacological assessment, docking.

 

 


1. INTRODUCTION:

Inflammation defines as the complex biological reception of vascular tissues to harmful stimuli, such as pathogenic agents, damaged cells or irritants. Inflammation is a preventive attempt by the living body to eliminate the harmful catalysts injurious as well as initiate the healing process of the tissue.1 Inflammation can be categorized as either chronic or acute. Acute inflammations describe the rapid reply of innate immune components to a challenge. Acute inflammation begins fastly and converts severe like: acute bronchitis, severe appendicitis, severe dermatitis, sore throat from a cold or flu, severe tonsillitis and acute sinusitis.

 

While chronic inflammation may arise because of susceptibility in the individual to continue the inflammatory response, failure to eradicate the agents or factors triggering inflammation (e.g. foreign body embedded in injured tissue), persistent microbial infection (e.g. TB, or continuing tissue damage) and pro-inflammatory stimuli, such as those encountered in the atherosclerotic plaque.2-3 Nonsteroidal anti-inflammatory drugs (NSAIDs) are devilishly applied for the preference treating in several inflammatory maladies such as arthritis, rheumatisms as well as to relax the pain of daily life. NSAIDs usually block the activity of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) which is responsible for prostaglandin synthesis and synthesis of thromboxane. It was believed that blocking cyclooxygenase-2 will lead to the antipyretic, analgesic and anti-inflammatory results and in addition NSAIDs blocks COX1 that lead to side effect.4 Aspect effects base on the specified drug, but broadly contain a raised danger of bleeding and gastrointestinal ulcers, heart and kidney failure.5 Benzimidazole is an aromatic heterocycles which synthesized depend on poly heterocyclic draw the notice of pharmacists since few decades as it features as a main pharmacophore in pharmaceutical chemistry.

 

Essentially, benzimidazole is a bicyclic ring involving of the fusion of imidazole with benzene which finally gives a special structure. Many pharmacological properties depend on this unusual moiety. Most prominent benzimidazole moiety is naturally occurring N-ribosyl-dimethylbenzimidazole it sit on the axial ligand for cobalt in vitamin B12.6 Many living effectiveness of benzimidazole derivatives are reported recently such as antimicrobial,7 anti-fungus,8 anti-histaminic,9 anti-inflammatory,10 antiviral agents,11 Anti-oxidant12 and anticancer activities.13 On the other hand 4-thiazolidinone derivatives are multilateral and have special uses a many clinically drugs. They have numerous uses as antibacterials,14 anti-tubercular,15 anti-inflammatory16 and effective against viruses particularly as anti-HIV agents.17 This research is presented to develop a new method for design and syntheses a series of 2-methyl benzimidazole derivatives attached with 4-thiazolidinone heterocyclic rings and evaluated as potential anti-inflammatory activities with expected selective inhibition role against COX-2 enzyme.

 

2. EXPERIMENTAL:

2.1. Material and methods:

All chemicals used without further purification were purchased by commercial suppliers. 2-methyl benzimidazole was supplied by the Merck Company, China. Melting points were determined by

 

Melting points were set on capillary tubes by the digital (STUART ScientificSMP30) apparatus and have not been corrected. The Fourier Transform Infrared FT-IR spectra were determined on Shimadzu (8400, Kyoto, Japan) spectrophotometer using KBr discs in the spectral range (400-4000) cm-1. Proton nuclear magnetic resonance was recorded on 1H-NMR (400MHz) spectrophotometer in dimethyl sulfoxide DMSO-d6 as solvent and tetramethyl silane used as internal reference standard.

 

2.2. Synthesis of Ethyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl) acetate (I):

To a stirred suspension of 2-methyl benzimidazole (0.01mol, 1.32g.) potassium carbonate anhydrous (0.015mol, 2g.) in dry acetone, ethyl chloroacetate (0.01mol, 1.2mL) was added gently at room temperature for about (30min.). Mixture of reaction was stirred for further (12hrs.) at room temperature. The formed precipitate was filtered off and the filtrate was concentrated under rotatory evaporator and recrystallized from (1:1) benzene: diethylether.18

 

 

Ethyl 2-(2-methyl-1H-benzo[d]imidazol-1-yl)acetate(I):

Physical properties: Yellowish crystals (94% yield); m.p. 105°C;

 

FT-IR: 3055cm-1 ν (C-H aromatic), 1734cm-1 ν (C=O of ester) and 1111cm-1 ν(C-O).

1H-NMR: 1.24ppm (t,3H, CH3), 2.56 ppm (s,3H, CH3) 4.21ppm (q,2H, CH2), 5.2ppm (s,2H, CH2) and 7.17-7.60ppm (m,4H, Ar-H).

 

2.3. Synthesis of Benzimidazole acetyl hydrazide (II):

Hydrazine hydrate (99.5%) (0.02mol, 1mL) was added to compound (I) (0.01mol, 2.18g.) in absolute ethanol (15mL). This mixture refluxed for (3hrs.). The reaction mixture was iced; the solid gained was filtered and recrystallized from ethanol.19

 

2-(2-methyl-1H-benzo[d]imidazol-1-yl)acetohydrazide (II):

Physical properties: white powder (72% yield); m.p. 228°C;

FT-IR: 3305-3211cm-1 ν(NH2), 3151cm-1 ν(N-H) and 1660cm-1 ν (C=O amide).

1H-NMR: 2.48ppm (s,3H, CH3), 4.34ppm (s,2H, NH2), 4.80ppm (s,2H, CH2), 7.07-7.52ppm (m,4H, Ar-H) and 9.52ppm (s,1H, NH).

 

2.4. Synthesis of 2-Methyl benzimidazole acetyl hydrazide (IIIa-d):

Compound (II) (0.001mol, 0.22g.) and appropriate aromatic aldehydes (0.0011mol) in absolute ethanol (25mL) were heated under reflux on a water bath for (4hrs.) at 80°C, during the refluxing period (2-3) drops of glacial acetic acid were added. Reduced pressure was used to remove of solvent. The residue was poured into the chilled water with ice to get the product. The disred products was filtered, washed with cold water, dried and recrystallized from ethanol.20

 

N'-(4-methoxybenzylidene)-2-(2-methyl-1H-benzo[d]imidazol-1yl) acetohydrazide (IIIa):

Physical properties: White fluffy powder (68% yield); m.p.238°C;

 

FT-IR: 3291cm-1 ν(N-H),1687cm-1 ν (C=O amide) and 1267cm-1 ν(C-O-CH3).

1H-NMR: 2.5ppm (s,3H, CH3), 3.81ppm (s,3H, CH3), 5.48ppm (s,1H, CH2), 7.01-7.21ppm (m,4H, CH aromatic of benzimidazole), 7.46-7.78ppm (m,4H, Ar-H), 8.26ppm (s,1H, CH) and 11.73ppm (s,1H, NH).

 

2-(2-methyl-1H-benzo[d]imidazol-1-yl)-N'-(4-nitrobenzylidene) acetohydrazide (IIIb).

Physical properties: Yellow fluffy powder (69% yield); m.p. 261°C;

FT-IR: 3438cm-1 ν(N-H), 1697cm-1 ν (C=O amide) 1595-1342 cm-1 ν(NO2).

 

1H-NMR: 2.48ppm (s,3H, CH3), 5.07ppm (s,1H, CH2), 7.18-7.56ppm (m,4H, CH aromatic of benzimidazole), 7.98-8.31ppm (m,4H, Ar-H), 8.41ppm (s,1H, CH) and 12.12ppm (s,1H, NH).

 

N'-(4-chlorobenzylidene)-2-(2-methyl-1H-benzo[d]imidazol-1-yl) acetohydrazide (IIIc).

Physical properties: White fluffy powder (73% yield); m.p. 267°C;

 

FT-IR: 3402cm-1 ν(N-H), 1684cm-1 ν (C=O amide) and 741cm-1 ν(C-Cl).

1H-NMR: 2.45ppm (s,3H, CH3), 5.4ppm (s,2H, CH2), 7.11-7.41ppm (m,4H, CH aromatic of benzimidazole), 7.49-7.82ppm (m,4H, Ar-H) ,8.25ppm (s,1H, CH) and 11.85ppm (s,1H, NH).

 

N'-(4-(dimethylamino) benzylidene)-2-(2-methyl-1H-benzo[d]imidazol-1-yl) acetohydrazide (IIId).

Physical properties: Yellow fluffy powder (65% yield); m.p. 311°C;

 

FT-IR: 3190cm-1 ν(N-H), 1687 cm-1 ν (C=O of amide) and 1363 cm-1 ν(C-N(CH3)2).

1H-NMR: 2.37ppm (s,3H, CH3), 3.14ppm (s,3H, CH3), 5.44ppm (s,2H, CH2), 7-7.80ppm (m,4H, CH aromatic of benzimidazole), 6.77-7.17ppm (m,4H, Ar-H),7.98ppm (s,1H, CH) and 11.54ppm (s,1H, NH).

 

2.5. Synthesis of thiazolidin-4-one derivatives (IVa-d):

A mixture of 2-mercaptoacetic acid (0.0145mol, 1mL) and either compound (IIIa-d) (0.001mol) were heated at (60°C.) until complete of reaction about (3hrs.) then (5mL) of ethyl acetate was added to the reaction mixture. The organic layer was rinsed with saturated solution of sodium bicarbonate (20mL) three times and distilled water (10mL). Anhydrous sodium sulfate was used to drying the organic layer and then concentrated to give oil by rotatory evaporator. Finally diethyl ether utilized to triturate the oil to give the thiazolidin-4-one            derivatives. 21

 

N-(2-(4-methoxyphenyl)-4-oxothiazolidin-3-yl)-2-(2-methyl-1H-benzo[d]imidazol-1-yl) acetamide (IVa).

Physical properties: White powder (67% yield); m.p. 250°C;

FT-IR: 3481cm-1 ν(N-H), 1722cm-1 ν (C=O of thiazolidinone ring), 1685cm-1 ν (C=O amide) and 1250cm-1 ν(C-O-C).

1H-NMR: 2.40ppm (s,3H, CH3), 3.69-3.96ppm (d,2H, CH2), 3.91ppm (s,3H, CH3), 4.87ppm (s,2H, CH2), 5.78ppm (s,1H, CH).7.01-7.23ppm (m,4H,Ar-H),7.34-7.49ppm (m,4H, CH aromatic of benzimidazole), 10.72 ppm (s,1H,NH).

 

2-(2-methyl-1H-benzo[d]imidazol-1-yl)-N-(2-(4-nitrophenyl)-4-oxothiazolidin-3-yl) acetamide (IVb).

Physical properties: White powder (72% yield); m.p. 262°C;

 

FT-IR: 3469cm-1 ν(N-H), 1732cm-1ν(C=O thiazolidinone ring), 1697cm-1 ν(C=O amide) and 1522-1344cm-1 ν(NO2).

1H-NMR: 2.37ppm (3H,s, CH3), 3.70-3.90ppm (d,2H, CH2), 4.80ppm (s,2H,CH2), 5.96ppm (s,1H,CH), 7.03-7.21ppm (m,4H,CH aromatic of benzimidazole), 7.48-8.25ppm (m,4H,Ar-H), 10.88ppm (s,1H,NH).

 

N-(2-(4-chlorophenyl)-4-oxothiazolidin-3-yl)-2-(2-methyl-1H-benzo[d]imidazol-1-yl) acetamide (IVc)

Physical properties: White powder (66% yield); m.p. 265°C;

 

FT-IR: 3419cm-1 ν(N-H),1716cm-1 ν (C=O of thiazolidinone ring), 1678cm-1 ν (C=O amide) and 762 cm-1 ν(C-Cl).

 

1H-NMR: 2.36ppm (s,3H, CH3), 3.89-3.97ppm (d,2H, CH2), 4.8ppm (s,2H, CH2), 5.80ppm (s,1H, CH), 7.07-7.14ppm (m,4H, CH aromatic of benzimidazole), 7.20-7.50ppm (m,4H, CH), 10.78ppm (s,1H, NH).

 

N-(2-(4-(dimethylamino) phenyl)-4oxothiazolidin-3-yl)-2-(2-methyl-1H-benzo[d]imidazol-1-yl) acetamide (IVd)

Physical properties: Yellow powder (60% yield); m.p. 247°C;

 

FT-IR: 3448cm-1 ν(N-H), 1726cm-1 ν (C=O of thiazolidinone ring), 1689cm-1 ν(C=O amide), 1346 cm-1 ν(C-N(CH3)2).

1H-NMR: 2.37ppm (s,3H, CH3), 3.11ppm (s,3H, CH3), 3.69-3.84ppm (d,2H, CH2), 4.40ppm (s,2H, CH2), 5.66ppm (s,1H, CH), 6.72-7.14ppm (m,4H, Ar-H),7.23-7.51ppm (m,4H, CH aromatic of benzimidazole), 10,64ppm (s,1H, NH).

 

3. RESULTS AND DISCUSSION:

3.1. Chemistry:

Newly synthesized benzimidazole derivatives bearing thiazolidinone moieties (IVa-d) it was achieved by the following procedures described in scheme (1).

 


Scheme (1)

 


2-methyl benzimidazole and ethyl 2-chloroacetate in the existence of anhydrous potassium carbonate in dried acetone were used as raw materials for the formation of ethyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl) acetate (I), which on treating with hydrazine hydrate resulted in the forming of 2-(2-methyl-1H-benzo[d]imidazol-1-yl) acetohydrazide (II). Imine intermediates (IIIa-d) were prepared by condensation of compound (II) with various aryl aldehydes in absolute ethanol. The cyclization method of Schiff bases (IIIa-d) well-done with 2-mercaptoacetic acid in free solvent conditions to give thiazolidin-4-one analogues of 2-methyl benzimidazole (IVa-d)

 

3.2. Anti-inflammatory assessment:

In vivo, the acute anti-inflammatory effects of final compounds (IVa-d) in egg white induced paw edema were evaluated. The results of anti-inflammatory activity depend on measuring the decreases in paw thickness.

 

3.3. Animals Methods:

Albino rats weighing (170±10gm) were housed in Mustansiriyah University/College of Pharmacy under standard conditions for ten days to acclimate. Animals were fed commercial chaw and had free access to water. The animals were transported to the laboratory, one hour before the experiment, and were divided into six groups (each group consists of six rats) as follows:

 

Group A: six rats served as a control and treated with the vehicle (propylene glycol 50% v/v).

Group B: six rats treated with ibuprofen as a reference substance in a dose of 10mg/kg suspended in propylene glycol22.

Group C-F: six rats per each group treated with the final compounds (IVa-d) respectively in doses that determined below, also suspended in propylene glycol.

 

3.4. Calculations for dose determination:

Molecular weight (M.Wt.) of ibuprofen = 206.29g/mol.

10mg/kg/206.29 = Dose/molecular weight of the tested compound23.

 

Table (1): Final compounds with their molecular weight and dose.

Compounds

Molecular weight

Dose mg/ kg

Ibuprofen

206.29

10

IVa

396.47

19.6

IVb

411.44

20.3

IVc

400.08

19.7

IVd

409.51

20.2

 

3.5 Experimental design:

The acute anti-inflammatory activity of the final compounds (IVa-d) was done by using the egg-white induced edema method. The thickness of the rat's paw was measured by vernier at seven-time intervals (0, 30, 60, 120, 180, 240, and 300 min) after taking the drug. Subcutaneous injection of 0.05ml of undiluted egg white into the plantar side of the left-hand paw of the rats was induced acute inflammation; 30 min after intraperitoneal [i.p.] administration of the drugs or their vehicle.

 

3.6. Statistical analysis:

The data were expressed as the mean ± SEM. The results were analyzed for statistical significance using student t test (Two Sample Assuming Equal Variances) to compare mean values. While comparisons between different groups were made using ANOVA: Two factors without repetition. The probability value [P] was considered to be less than 0.05 significant. The anti-inflammatory activity of the final compounds has been done in comparison with propylene glycol 50%v/v (control group) and ibuprofen. The tested compounds and the reference drug produced a significant reduction of paw edema with respect to the effect of propylene glycol 50%v/v. All tested compounds significantly reduced the inflammation in paw edema, the onset of final compounds started at time 120 min and show higher anti-inflammatory activity than ibuprofen (10mg/kg, i.p.). However, the duration of action of all compounds continued till the end of the experiment with a statistically significant (P<0.05) reduction in paw thickness as shown in table (2) and Figure (1).


 

Figure (1): Effect of propylene glycol, ibuprofen, compounds (IVa-d) on egg white provoked paw edema in rats.

 

Table (2): Anti-inflammatory effect of control, ibuprofen, and compounds (IVa-d) on egg-white induced paw edema in rats.

 

Compounds

Time (min)

0

30

60

120

180

240

300

Paw

Thickness

(mm) / n=6

Control

2.33±0.05

5.58±0.02

6.55±0.05

6.92±0.02

6.70±0.02

6.26±0.03

5.20±0.04

Ibuprofen

2.31±0.02

5.51±0.02

6.49±0.03

5.89±0.02*a

5.12±0.06*a

4.20±0.05*a

2.90±0.02*a

IVa

2.26±0.03

5.45±0.03

6.31±0.04

5.55±0.04*b

3.99±0.03*b

3.53±0.03*b

2.36±0.04*b

IVb

2.22±0.04

5.47±0.04

6.35±0.02

5.68±0.02*a

4.33±0.04*c

3.74±0.04*c

2.39±0.02*b

IVc

2.27±0.03

5.46±0.03

6.39±0.05

5.73±0.04*a

4.49±0.03*c

3.89±0.02*c

2.41±0.02*b

IVd

2.25±0.03

5.52±0.01

6.42±0.03

5.79±0.02*a

4.54±0.05*c

3.89±0.02*c

2.46±0.02*b

 

Table (3): PLP fitness value and H bonding of the synthesized compounds.

Compounds

COX-2 Binding Energy (PLP Fitness)

Amino Acids Included in Hydrogen bonding

COX-1 Binding Energy (PLP Fitness)

2-Methyl benzimidazole

40.41

-

42.8

Ibuprofen

67.3

Arg120 and Tyr355

60.3

Diclofenac

71.8

Ser530 and Tyr385

60.1

IVa

81.1

Ser530 and Tyr 355

48.4

IVc

72.7

Ser530, Tyr385 and Tyr 355

45.8

IVd

73.6

Tyr 355

43.9

IVf

71.7

Tyr 355

40

 


3.7. Comparative analysis:

The comparison explains that at 0-30 min. there are no differences among all groups. Compounds IVa showed significantly higher activity than standard from time (120 to 300 min.) and higher than compounds IVb-d from time (120 to 240 min.). Compounds IVb, IVc and IVd showed significantly higher activities than standard from time (180 to 300 min.).

 

3.8. In silico analysis and molecular docking study:

The aim of this study was to analyze the inhibitory action of the newly synthesized compounds to COX-2 isoenzymes by computational docking studies. The crystallographic structure of molecular target COX-2 and COX-1 isoenzymes was obtained from protein data bank (PDB) database. Ibuprofen and diclofenac are classical NSAID were taken as the standards for comparative analysis. Computational docking analysis was performed using GOLD. The PLP fitness indicated that the COX-2 protein was successfully blocked with the newly synthesized compounds as shown in table (3). The docking of COX-2 target with the newly synthesized compounds using docking procedure revealed that all the computationally predicted lowest energy complexes of COX-2 are stabilized by intermolecular hydrogen bonds while COX-1 does not have any intermolecular hydrogen bonds with synthesized compounds.

 

Docking results showed that the newly synthesized compounds can enter the substrate-binding region of the active site and the compound (IVa) had shown the highest PLP fitness for COX-2. Finally, the results demonstrated clearly that there is a good correlation between in vivo and in silico study. The candidate (s) to be the safest and most likely to filter vehicles most likely to fail in later stages of drug development due to unfavorable ADME properties. We evaluated all ADME synthesized compounds.

 

3.9. ADME studies

The ADME studies for our synthesized compounds (IVa-d) were evaluated by the Swiss ADME server to predict the candidate (s) to be the safest and potential drug that filters out the compounds which are most likely to fail in later stages of drug development due to unfavorable ADME properties. We assessed all compounds' (IVa-d) by the ADME method. Also, the topological polar surface area (TPSA) was measured,


 

Table (4): the ADME properties for the synthesized com­pounds (IVa-d).

Compounds

M.Wt

hydrogen-bond acceptors

hydrogen-bond donors

MR

TPSA

GI Abs.

BBB permeant

Lipinski violations

IVa

396.46

4

1

111.66

101.76

high

No

0

IVb

411.43

5

1

113.99

138.35

high

No

0

IVc

400.88

3

1

110.18

92.53

high

No

0

IVd

407.53

2

1

123.51

78.70

high

No

0

 


since it is another important property that has been linked to the drug bioavailability. Thus, passively absorbed drugs with a TPSA less than 140 Aare thought to have low oral bioavailability 24. The results showed that all synthesized com­pounds have TPSA less than 140, which is in the range of (78.70-138.35) and the bioavailability for all ligands was 0.55 which means that all compounds reach the systemic circulation. All compounds fulfilled Lipinski rule. Also, it also satisfied with the topological descriptors and finger­prints of molecular drug-likeness structure keys as LogS and LogP as shown in table (4). The gastrointestinal absorption score is a measure of the extent of absorption of molecules from the intestine after oral administration. The absorption could be excellent if the result were high. In this study, the gastrointestinal absorption of all synthesized compounds was high predicting them to be well absorbed from the intestine.

 

4. CONCLUSIONS:

The designed compounds have been suc­cessfully achieved. Identification and characterization of the synthesized compounds were confirmed by determination of FT-IR, 1H NMR data and physical properties. The anti-inflammatory evaluation of the final products indicates that the incorporation of 4-thiazolidinone pharmacophore into 2-methyl benzimidazole improved its anti-inflammatory action. All compounds fulfilled the Lipinski rule as shown by the ADME studies, and all synthesized com­pounds absorbed from the gastrointestinal tract. Docking studies showed a perfect agreement with in vivo study. The study of anti-inflammatory activity showed that all compounds have significantly more anti-in­flammatory outcomes than ibuprofen.

 

5. ACKNOWLEDGMENTS:

The authors would like to thank Mustansiriyah University (www.uomustansiriyah.edu.iq) Baghdad–Iraq for its support in the present work.
 

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Received on 29.02.2020            Modified on 16.04.2020

Accepted on 13.05.2020           © RJPT All right reserved

Research J. Pharm. and Tech 2021; 14(3):1515-1520.

DOI: 10.5958/0974-360X.2021.00269.9