A Green Route Approach of α, β-Unsaturated Ketone Having a Benzimidazole Tail and Their Virtual Screening on the Molecular Descriptors for Predicting the CNS-Druglikeness.

 

Bijo Mathew*, Githa Elizebeth Mathew, Shafeer V.P., Mohammed  Musthafa C. and Femina P.

Grace College of Pharmacy, Palakkad 678004.Kerala, India.

*Corresponding Author E-mail: bijovilaventgu@gmail.com

ABSTRACT:

Synthetic derivatives of α, β-unsaturated ketone bearing a benzimidazole moiety in the molecule has been prepared via microwave assisted method. The structures of the synthesized compounds were confirmed by IR, ¹HNMR data. Parameters related to druglikeness of the derivatives were established on the basis of Lipinski’s Rule of 5.The molecular properties were calculated from suitable computational tools. All the derivatives showed a zero violations of the Rule of 5, which indicates good bioavailability. Druglikeness was determined by the methods of Actelion, Molsoft and Molinspiration software programmes. Blood-brain barrier prediction of the set of compounds was calculated by DEC-1 model. It has been found that good correlation between Total polar surface area and predicted logBB of the synthesized derivatives (r²=0.873).Our research found that the above titled compounds have a favourable druglikeness scores and the values of the logBB of the synthesized derivatives indicates their ability of penetrating blood-brain barrier.

 

 

 

INTRODUCTION:

Benzimidazoles are considered as a promising class of bioactive heterocyclic compounds that exhibit a wide range of biological activities¹. A, β-unsaturated carbonyl system are versatile substrates, which can be prepared by simple nucleophilic addition of a methyl ketone to an aldehydes in presence of a base and alcohol. Druglikeness is a measure of similarity of a proposed drug compound to general population of drugs in use². Drug like molecule exhibits a favorable blood-brain adsorption, distribution, metaboloism, excretion and toxicological parameters. The most promising ADME parameters for CNS research are blood-brain distribution. It is defined as the ratio of concentrations measured in blood and brain. Measuring BB distribution, quantified as log BB. Polar surface area(PSA) based quantitative structure activity relationship approach are most popular methods used to predict the brain penetration.PSA area is defined as the surface area occupied by nitrogen atom and polar hydrogen connected to these atoms³. The purpose of this research work was to analyze the CNS acting drug like property of α, β-unsaturated ketone having a benzimidazole tail.

 

The synthesis done with microwave assisted by the use of a domestic microwave oven. O-phenyelenediamine reacts with lactic acid gave 2(α-hydroxyethyl) benzimidazole (2a) which on subjected with oxidation in presence of potassium dichromate produced 2- acetyl benzimidazole (3a).The chalcones (4a–g) were prepared by reacting 2-acetyl benzimidazole with appropriate aldehydes in the presence of a base by Claisen-Schmidt condensation⁴.

 

MATERIALS AND METHODS:

All the chemicals and reagents used were of AR grade. Melting points were determined by using melting point apparatus MP-DS TID 2000 V and the values were uncorrected. Reactions were monitored by thin layer chromatography (TLC) on pre coated silica gel G plates using iodine vapour as visualizing agent.IR spectra were recorded on JASCO FT/IR-140 spectrophotometer by using KBr pellets technique.PMR spectra were recorded using BRUCKER FT-NMR-500MHz spectrophotometer by using DMSO as solvent and TMS as internal standard. The chemical shift was expressed in δ ppm. Molecular properties like CLogP, Total Polar surface area (TPSA), Rule of Five of the proposed candidates were determined by Chemsketch, Molinspiration and Actelion computer software programmes.

 

General method for the Synthesis of 2(α hydroxyethyl) Benzimidazole. (2a):

O-Phenylenediamine (0.25mol) was mixed with lactic acid (0.35 mol) in a RBF and refluxed for 3hours. The reaction mixture was cooled added with 10% NaOH until bacisity to litmus paper. The crude pink colured product obtained was dissolved in 100 ml of boiling water. To this add 2 gm of decolourising carbon was added and heated for 15 minutes. The mixture was filtered rapidly at the pump through a preheated Buchner funnel. The product obtained was further filtered and washed with (25 X3) ml cold water and dried at 100^oC.The yield was found to be 78%.

 

Micro wave assisted Synthesis of 2(α-hydroxyethyl) Benzimidazole. (2a):

O-Phenyelenediamine (0.25 mol) was mixed with lactic acid (0.35 mol) in a beaker and subjected to microwave oven at 40% power over a period of 4 minutes. The reaction mixture was cooled added with 10% NaOH until bacisity to litmus paper. The crude pink colured product obtained was thoroughly washed with water until it free from the added base in the product. The product obtained was dried over a hot air oven and recrystallized with hot water. The yield was found to be 88%⁵.

 

Synthesis of 2- acetyl benzimidazole. (3a):

To a solution of 2-(α-hydroxy) ethyl benzimidazole 2a (0.01 mol) in dil. H₂SO₄ (5%, 40 ml) was drop wise added the solution of K₂Cr₂O₇ (0.15 mol) and H₂SO₄ (25%, 80 ml) with constant stirring at room temperature over a period of 20 min. Further the reaction mixture was stirred at room temperature for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was neutralized with aqueous NH₃ solution (1:1) and resultant orange solid was filtered, washed with water and dried, recrystallized from ethyl acetate⁶

 

General Synthesis of (2E)-1-(1H-benzimidazol-2-yl)-3-phenylprop-2-en-1-one (4a-h):

2-Acetyl benzimidazole (0.01 mol) and appropriately substituted aromatic aldehydes (0.012 mol) were mixed in ethanol (20 ml) containing 10% aq. KOH (8 ml) and magnetically stirred the solution constantly at room temperature for 10 h.The whole mixture was transferred in to 100 ml ice cold water and acidified with dil.HCl. The solid formed was washed, filtered and dried, recrystallized from absolute ethanol⁷.The physical data of the derivatives were shown in table no:1.

Micro wave assisted Synthesis of (2E)-1-(1H-benzimidazol-2-yl)-3-phenylprop-2-en-1-one (4a-h):

2-Acetyl benzimidazole (0.01 mol) is taken in 10ml of ethanol in a beaker and stir well. To this add 4ml of 10% KOH with aldehydes (0.012) .The whole mixture stirs vigorously for 20 minutes. Then it becomes viscous and that subjected to microwave oven at 60% power over a period of 2-3minutes.The resultant product cooled and diluted with cold water and neutralized with dil.HCl.

 

Characterization of the synthesized derivatives:

4a:IR(KBr):3230(N-H str),1693(C=O),1587(C=N).¹H NMR (DMSO-d6 +CDCl₃) in δ ppm:8.9 (1H,s,NH benzimidazole), 7.2-7.9 (9H,m ArH),5.2-5.8( 2H,d,=CH-).

4b:IR(KBr):3232(N-H str),1678(C=O),1581(C=N),771(Ar-Cl).¹H NMR (DMSO-d6 +CDCl₃) in δ ppm:8.7 (1H,s,NH benzimidazole), 7.1-7.8(8H,m ArH),5.3-5.8( 2H,d,=CH-).

4c:IR(KBr):3238(N-H str),1673(C=O),1577(C=N).¹H NMR (DMSO-d6 +CDCl₃) in δ ppm:8.9 (1H,s,NH benzimidazole), 7.3-7.8 (8H,m ArH),5.2-5.8( 2H,d,=CH-),3.3(3H,s,OCH₃)

4d:IR(KBr):3252(N-H str),1680(C=O),1592(C=N).¹H NMR (DMSO-d6 +CDCl₃) in δ ppm:8.8 (1H,s,NH benzimidazole), (8H,m ArH),5.2-5.8( 2H,d,=CH-)3.1(6H,s N(CH₃)₂

4e:IR(KBr):3244(N-H str),1678(C=O),1567(C=N).¹H NMR (DMSO-d6 +CDCl₃) in δ ppm:8.9 (1H,s,NH benzimidazole), (8H,m ArH),5.4-6.1( 2H,d,=CH-).

 

Table 1-Physical Data of the Synthesized Derivatives.

Compound	Colour	MW	MP(0C)	% Yield
4a 4b 4c 4d 4e 4f 4g	Pale Brown Pale yellow Pale green Red Brown Pale yellow Brick red	248 282 278 291 293 264 274	246 227 230 140 262 271 138	83 92 90 81 79 69 82

 

Insilico screening

These parameters are essential for the determination of calculated logBB by using DEC-I equation⁸. Blood brain barrier prediction of a molecule is usually by log [C_brain/C_blood], which is represented as LogBB. The positive value indicates an increase in lipophilic nature and increased solubility in lipid membranes⁹.

 

 

Table 2-Determination of LogBB

Compound	ACDLogP	CLogP	miLogP	TPSA	LogBB	Drug likeness
						Molsoft	Actelion
4a 4b 4c 4d 4e 4f 4g	3.27 4.05 3.32 3.88 2.85 3.01 3.82	3.04 3.65 2.93 3.03 3.04 2.74 3.61	3.40 4.08 3.46 3.51 3.34 3.16 3.92	45.75 45.75 54.98 48.99 91.57 65.98 45.75	-0.07 0.017 -0.11 -0.12 -0.15 -0.42 0.01	0.39 0.63 0.29 -0.49 -0.86 0.06 -0.38	-2.47 1.82 1.09 -3.19 0.07 0.99 -4.07

ACDLogP              -Calculated by Chemsketch.;                                   CLogP                   -Calculated by Actelion

miLogP andTPSA    - Calculated by Molinspiration;                           LogBB = -0.0148(miPSA) +0.152(ClogP) +0.139

Scheme of synthesis

 

 

Figure 1

 

Table 3-Determination Lipinski’s Rule of 5

Compound	H –bond donors	H-bond acceptors	Rotatable bond	No. of violation
4a 4b 4c 4d 4e 4f 4g	1 1 1 1 1 2 1	2 3 3 3 5 2 2	3 3 4 4 4 3 4	0 0 0 0 0 0 0

 

The calculated bioactivity of the synthesized model as the sum of the activity contributions of the fragments present in the molecule. This will give an ‘activity score’ for the individual compound. This score represents the probability that the particular molecule will have the desired biological activity. The higher this score, the higher the probability that compound will active¹⁰. The Molinspiration virtual screening was selected as the base methodology for predicting the bioactivity of the synthesized compounds.

 

Table 4-Determination of Bioactivity score

Comp ound	GCPR	KI	NRC	Protease IN	Enzyme inhibitor
4a 4b 4c 4d 4e 4f 4g	0.05 0.08 0.06 0.14 -0.05 0.09 0.16	0.01 0.00 -0.09 -0.03 -0.08 -0.01 -0.08	-0.29 -0.25 -0.19 -0.13 -0.27 -0.12 -0.21	-0.21 -0.21 -0.18 -0.11 -0.25 -0.16 -0.04	0.16 0.12 0.10 0.12 0.00 0.19 0.25

 

RESULT AND DISCUSSION:

In the present study the CNS drug-likeness of the derivatives were found by DEC-I equation. All the 1-(1H-benzimidazol-2-yl)-3-phenylprop-2-en-1-one derivatives showed a good predicted logBB value which indicates their ability to cross the blood brain barrier. It has been noted that the better brain penetration is predicted for compounds have high calculated log P and low TPSA.Polar surface area being an indication of compound’s capacity to form hydrogen bonds. Compound 4b and 4g having a good positive log BB value than the other derivatives. The drug likeness also gave a favourable range in the proposed model. It has been found that good correlation between Total polar surface area and predicted logBB of the synthesized derivatives (r²=0.847).This can be shown in figure 1.

CONCLUSION:

The electron withdrawing group in the aromatic nucleus of the model reduces the predicted logBB. The presence of lipophilic methyl group in the derivatives is also not favoured for the CNS drug-likeness. All the derivatives showed a zero violation of Lipinski’s Rule of 5, which indicates good bioavailabilty.The positive bioactivity score of the derivative were also agreement with their probability of drug likeness. Our research suggests that the benzimidazole chalcone derivatives have good logBB values that will focused on their CNS activity.

 

REFERENCES:

1.       Ansari KF , Lal C. Synthesis, physicochemical properties and antimicrobial activity of some new benzimidazole derivatives. Eur. J. Med. Chem 2009; 44:4028–4033.

2.       Bartzatt R, Cirillo SLG ,Cirillo JD. Molecular properties and antibacterial activity of methyl and ethyl ester derivatives of Ampicillin. Physiol. Chem. Phys. and Med.NMR 2004;36:85-94.

3.       Lobell M, Molnar L, Keseru GM. Recent advance in the prediction of blood- brain partitioning from molecular structure. J .Pharm. Sci 2003; 92(2): 360-362

4.       Dubey PK, Ravikumar C, Balaji Babu. Solid phase synthesis of Benzimidazole ketone and chalcones under solvent free conditions. Indian. J. Chem 2003;42B(12): 268-270.

5.       Kalirajan R . Leela Rathore, Jubie S , Gowramma B, Gomathy S, Sankar S .Elango K .Microwave Assisted Synthesis and Biological Evaluation of Pyrazole Derivatives of Benzimidazoles. Indian J. Pharm. Educ. Res. 2010; 44(4): 358-361.

6.       Vanga M R ,Kunduru R R. Synthesis and Antimicrobial Activity of Some Novel 4-(1H-Benz[d]imidazol- 2yl)-1,3-thiazol-2-amines. Chem. Pharm. Bull 2010; 58(7):953-956.

7.       Mohammad Shaharyar, Bakht M.A, Jaseela Majeed. Pyrazoline bearing benzimidazoles: Search for anticancer agent Eur. J. Med. Chem 2010; 45:114-119.

8.       David  E C .Rapid Calculation of Polar Molecular Surface Area and Its Application to the Prediction of Transport Phenomena.-Prediction of Blood-Brain Barrier Penetration. J. Pharm. Sci. 1999; 88:815-820.

9.       Abraham, M H, Takacs Novak K, Mitchell RC. On the Partition of Ampholytes: Application to Blood-Brain Distribution. J. Pharm. Sci. 1997; 86:310-315.

10.     Pineiro RP, Burgos A, Jones DC, Andrew LC, Wishart DS. Development of a novel virtual screening cascade protocol to identify potential Trypanothione reductase inhibitors. J.Med. Chem 2009;52:1670-1680.

 

 

Received on 21.12.2011         Modified on 02.01.2012

Accepted on 10.01.2012         © AJRC All right reserved