Synthesis and Anticonvulsant activity of new 5-((1-(2-(4-substituted phenacyl bromide)-2-oxoethyl)-2-phenyl-1H-indol-3yl) methylene) pyrimidine-2, 4, 6(1H, 3H, 5H)-trione Derivatives

 

Surendra K Gautam*, Sujeet K Gupta, Bhumika Yogi

Department of Pharmaceutical Chemistry, Hygia Institute of Pharmaceutical Education and Research,

Ghaila Road, Gazipur Balram Rd, Lucknow, Uttar Pradesh 226021.

*Corresponding Author E-mail: surendra_bkt95@yahoo.in

 

ABSTRACT:

In the current scenario we have plant to study to synthesize novel indole derivatives (4a-d) and (5a-b) which have the target activity like anti-convulsion and anti microbial etc. In the primary phase, we synthesized 2-phenyl-1H-indole reacted with Phosphorus oxychloride and N, N’-dimethylformamide by using vilsmeier reagent formylation of a new compound 2-phenylindole-3-carbaldehyde (2). The 2-phenylindole-3-carbaldehyde was reacted with substituted phenacyl bromide, K2CO3 and TBAB (Tetra butyl ammonium bromide) into the presence of N, N’-dimethylformamide to gives [1-(2-(4-substituted phenacyl bromide)-2-oxoethyl)-2-phenylindole-3-carbaldehyde (3a-d). The compound [1-(2-(4- substituted phenacyl bromide)-2-oxo-ethyl)-2-phenylindole-3-carbaldehyde was permitted to mixed with various substituted phenacyl bromide gives corresponding indole derivatives. The indole derivatives (3a-d) were reacted with barbituric acid and thiobarbituric acid dissolved into the methanol at reflux for 4h to gives afforded compounds (4a-d) and (5a-b). The final indole barbituric derivatives (4a-d) and (5a-b) were synthesized from substituted phenacyl bromide by the react with methanol and recrystalized from ethanol. The last compound has been completed on the basis of spectra FT-IR and 1H NMR. All the value of FT-IR, 1H NMR, Solubility and TLC were considered to be prominent. The pharmacological screening through ear electrode induced current 50mA for 0.2 seconds in electro-convulsiometer for anticonvulsant activity. The synthesize compounds were establish to be 4b, 4c, 4d, and 5a. The compound 4c and 5a were established to be the most potent compound through compare to standard drugs phenytoin sodium.

 

KEYWORDS: Anticonvulsant activity, Indole, MES method, Phenytoin sodium, substituted phenacyl bromide.

 

 


INTRODUCTION:

Epilepsy is common neurological disorders distinguish with paroxysmal cerebral dysrhythmia, manifesting as concise seizure of failure or mental distress, through or excessive of belong to body convulsions, sensory and psychiatric phenomena1. Even though it was perceived by 2000 BC, new ideas about the pathogenesis, etiologic, and conduct are brought out approximately every year2.  It’s a set of a neurological issues influencing about 0.5-1% of the population all over the world3.

 

Anticonvulsants are often called anti-seizure drugs. Various groups of pharmaceuticals used in the healing of epileptic seizures. It is also used in the treatment of increased bipolar disorder. An anticonvulsant activity is to suppress the express, too much firing of neurons that start an epileptic. Anticonvulsant would visualise the spread of the seizure inside the consciousness and offer security against achievable excitotoxic impacts that result in the cerebrum hurt4. Nowadays there are intemperate of 40 diverse anti-epileptic medications (AEMs) exploratory use, at the same time, around 30% of patients keep on practice out of control seizure, and they are pharmaco-repellents to the accessible treatment5.

 

In the wonderful quantity of drugs presented for processing of epileptic, it’s required for the best antiepileptic agent accompanied to its properties i.e. broad-spectrum activity quickly beginning of the action and atleast therapeutic effects their good and low cost of the bioavailability6. Additionally, the treatment for seizure requires constant medicated for a remarkable to the period, which is associated with many adverse effects, such as CNS (ataxia, drowsiness), gastrointestinal (gingival, nausea, vomiting, hepatic dysfunction), and dermatological (rash, Stevens-Johnson syndrome) disorders6,7,8. Many antiepileptic agents exert their anticonvulsant effect via a variety of mechanisms. Inhibition of ion channels such as sodium channels (phenytoin and carbamazepine), calcium channels (ethosuximide), and potassium channels as well as GABAs receptors (benzodiazepines, barbituric acid) are common mechanisms of conventional antiepileptic drugs9. Anticonvulsant development is commonly seen the proximity of aryl restricting site with aryl/alkyl hydrophobic gathering, hydrogen holding space and electron supporter gathering, which the basic necessities for the particles are to indicates potential action10.

 

Indole is the most helpful heterocyclic nucleus which has gained quality in therapeutic science because it’s diverse biological activities such as anticonvulsant11,12,13,14,15,16, anti-inflammatory17 antipsychotic18, Antifungal19,20 Antibacterial21 Antiviral22 activities, Anti HIV23 and antioxidant24.  The present work highlights to synthesize of new 5-((1-(2-(4-subsitituted phenyl bromide)-2-oxoethyl)-2-phenylindol-3yl) methylene) pyrimidine-2, 4, 6 (1H, 3H, 5H)-trione. In vivo the synthesize indole derivatives were screened for the anticonvulsant activity by the MES method by using the standard drug of phenytoin sodium.

 

MATERIALS AND METHODS:

Experimental:

Chemicals required for the experimental procedure was procured form Spectrochem Pvt. Ltd., “SDFCL Mumbai and CDH (P) Ltd.”, New Delhi25. The liquefaction point are to be check synthesize compounds. The synthesized compounds were controlled and are uncorrected by open a narrow capillary glass tube method. Thin Layer Chromatography was prepared to silica gel G (E. Mark) plates utilizing to the reactions and to check purity of the synthesized compounds on the elemental analyzer. The λmax were synthesized compound scanned on UV- Visible spectrophotometer 60 F 254. Infrared spectra of the synthesize compounds in KBr pellets was recorded on an FTIR- PerkinElmer Spectrum Version 10.03.06 by using the KBr disc26.

 

The NMR proton spectra were recorded by means of Bruker Advance DX 300 MHz spectrometer via DMSO-d6 as a solvent and DMSO as internal standard respectively. The results are represented as following:

1.     Chemical shift δ (ppm),

2.     Multiplicity,

3.     Coupling constant (Ј) values in Hertz (Hz),

4.     Number of protons, and

5.     Proton’s position.


 

Synthesis of 2-phenyl-1H-indole (1):

Prepare a mixture of 20g of acetophenone and 18g of phenyl hydrazine with 60 ml of ethanol and few drops of glacial acetic acid. The reaction mixture was cold and filtered and washed with dil. HCl solution and ethanol and recrystalized of the ethanol. The crude drug was taken 28g in a beaker containing 180g polyphosphoric acid and heat on a boiling water bath sir with maintained temperature at 100-120˚C for 10 minutes. Added 450 ml of cold water was complete solution of the polyphosphoric acid. Filtered and wash with water. The crude drug was boiled under the reflux with 300 ml of ethanol and little charcoal added to it, was with the hot ethanol. Cool and filtrate to room temperature, filter off the 2-phenylindole and washed three times of ethanol. Dry the vacuum desiccators over anhydrous CaCO3. (Yield 68%; M.P. 176-178˚C)27.  

 

Synthesis of 2-phenylindole-3-carbaldehyde (2):

Prepare vilsmeier reagent a mixture of Phosphorus oxychloride (21.45ml, 0.14mol) were drop wise to N, N’-dimethylformamide (10.21 ml, 0.14mol) under cooled with ice bath and the reaction mixture was stirring for two hours on magnetic stirrer. The compound (1) (19.57gm, 0.072mol) in DMF (20ml) were added drop wise into the vilsmeier reagent and stir continuously, kept at ambient temperature for 2h then stand overnight of the compound. The mixture was added cold water, and then maintain neutralized with weak ammonia solution till the give rise to occur. The formed precipitate was gathered by filtrate and recrystalized from ethanol. (Yield 70%; M.P. 170˚C)

 

General method for “synthesis of 1-(2-oxo-2-phenylethyl)-2-phenylindole-3-carbaldehyde” (3a-d):

The compound of 2-phenylindole-3-carbaldehyde (5g) derivatives of substituted phenacyl bromide (5g), K2CO3, TBAB was quintet with DMF for irradiation. The whole mixture was heated for 200˚C on heating mantle at 1h.The monitoring of the reaction time to time by TLC. The chemical reaction was cooled at room temperature by using ice- water. Filtered the obtained compound were recrystalized for purity in ethanol.

 

All purpose procedure for the “synthesis of substituted phenacyl bromide indole derivatives” (4a-4d)

The compounds of 1-(2-oxo-2-phenylethyl)-2-phenyl-1H–indole-3-carbaldehyde (5g)  and barbituric acid (1 mol) was added and dissolved in methanol, the mixture was heated under reflux for 4 h at 100-170˚C. On cooling, the trustworthy was creating to separate. The rash was filtered and washed with cold methanol and recrystalized from the ethanol. The characterization data of compounds (4a-4d) is given below.

 

All purpose procedure for the synthesis of substituted phenacyl bromide indole derivatives (5a-5b)

1-(2-oxo-2-phenylethyl)-2-phenyl-1H–indole-3-carbaldehyde (5g) derivatives were dissolved in methanol and thiobarbituric acid was added. Then the reaction mixture was heating under the reflux for time duration at 4h.  After completion reaction, the filtrate and washed with chilled water then recrystalized from ethanol. The characterization data of compounds (5a-5b) is given below.

 

SPECTRAL ANALYSIS:

5-((1-[{{(2-(4-methoxy phenacyl bromide)}-2-oxoethyl)}-2-phenyl-1H-indol-3yl)}] methylene)]-2, 4, 6-trione pyrimidine derivative (4a)

 

Solid, Brown; melting point 175-177˚C; Yield: 60%; FTIR (KBr):  3386 (N-H), 3021 (Ar CH3 Stretch), 2443 (C-H Stretch), 1621 (C=O), 1570 (=C-H bend), 1457 (CH3, C-H Bend), 1H NMR (DMSO-d6 ppm): 2.50 ( 3H, OCH3), 3.66 (d, 2H, CH2), 7.63-8.13 (m, 1H, Ar C-H), 8.19-8.69( s, 1H, CH=), 11.68 (s, 1H, NH). Anal.calc.for: C28H21N3O5; C, 71.04; H, 5.41; N, 8.76: Found: C, 70.12; H, 4.39; N, 8.69%.

 

5-[{((1-{(2-(4-chloro phenacyl bromide)}-2-oxoethyl)-2-phenyl-1H-indol-3-yl)}]-methylene)]-2, 4, 6-trione pyrimidine derivative (4b)

Solid Yellow; M.P. 168-175˚C; Yield: 78%; FTIR (KBr):  3744 (NH stretch), 3285 (Ar C-H Stretch), 1651 (C=O stretch), 1539 (N-H bend), 763 (C-Cl stretch), 665 (=C-H bend). 1H NMR (DMSO-d6 ppm): 2.49-2.51 (d, 1H, RH), 3.32 (d, 1H, Ar CH), 6.23-6.75(m, 1H, Ar C-H), 7.23 (s, 1H, CH), 11.02(s, 1H, NH); Anal.calc.For: C27H18ClN3O4; C, 67.02; H, 4.75; N, 8.68: Found: C, 66.88; H, 3.71; N, 8.65%.

 

5-[{((1-(2-(3,4-dichloro phenacyl bromide)-2-oxoethyl)}-2-phenylindol-3-yl)}methylene)]-2, 4, 6-trione pyrimidine derivative (4c):

White solid; M.P. 170-175˚C; Yield: 80%; FTIR (KBr):  3436 (N-H stretch), 3021 (Ar C-H stretch), 1652 (C=O stretch), 1526 (N-H bend), 1215 (C-O stretch), 932 (=C-H stretch), 860 (C-Cl stretch).1H NMR (DMSO-d6 ppm): 2.48-2.51 (d,1H, RH), 4.92-4.94 (s, 2H, CH2), 10.71-11.11(s,1H,NH); Anal.calc.for: C27H17Cl2N3O4; C, 62.56; H, 3.31; N, 8.11: Found: C, 62.54; H, 3.29; N, 8.09%.

 

5-[{((1-(2-(4-fluoro phenacyl bromide)-2-oxoethyl)]-2-phenyl-1H-indol-3-yl})-methylene)}-2, 4, 6-trione pyrimidine derivative (4d)

 Melting point 127-130˚C; solid white; Yield: 42%; FTIR (KBr):  3443 (N-H stretch), 3020 (Ar C-H stretch), 1652 (C=O stretch), 1541 (N-H bend), 1455 (C-H bend), 1216 (C-F stretch), 932 (=C-H stretch). 1H NMR (DMSO-d6 ppm): 2.48-2.50 (d, 1H, RH), 3.34-3.38(s, 1H, CH2), 7.35-7.54 (d, 1H, Ar C-H), 8.09-8.12(s,1H, CH=), 11.52( s, 1H, NH); Anal.calc for: C27H18FN3O4, C, 70.37; H, 3.88; N, 8.99; Found: C, 69.35; H, 3.79; N, 8.97%.

 

(z) 5-{1-(2-(4-methoxyphenacyl bromide)-2-oxo-ethyl]-2-phenylindol-3-ylmethylene} pyrimidine-6-thioxodihyropyrimidine-2, 4-dione (5a)

Melting point 135-138˚C; Brown solid; Yield: 70%; FTIR (KBr):  3440 (N-H stretch), 1659 (C=O stretch), 1455 (C-H bend), 1450 (Ali C-H stretch), 1216 (C-F stretch), 932 (=C-H stretch). 1H NMR (DMSO-d6 ppm): 2.48-2.51 (s, 3H, OH3), 3.31-3.85(s, 2H, CH2), 6.99-7.28 (d, 1H, Ar C-H), 7.85-7.97(s,1H, CH=), 8.02(s, 1H, SH), 11.52( s, 1H, NH); Anal.calc for: C28H21N3O4S, C, 68.86; H, 4.27; N, 8.48; Found: C, 67.73; H, 3.25; N, 8.36%.

 

(z) 5-{1-(2-(4-chlorophenacyl bromide)-2-oxo-ethyl]-2-phenylindol-3-ylmethylene} pyrimidine-6-thioxodihyropyrimidine-2, 4-dione (5b)

Melting point 117-120˚C; Brown solid; Yield: 78%; FTIR (KBr):  3483 (N-H stretch), 1589 (C-H bend), 1448 (Ali C-H stretch), 1223 (C=O stretch), 932 (=C-H stretch), 797 (C-Cl stretch). 1H NMR (DMSO-d6 ppm): 2.47-2.50 (s, 3H, OH3), 3.33-3.88(s, 2H, CH2), 7.10-7.26 (d, 1H, Ar C-H), 7.88-7.95(s,1H, CH=), 8.02(s, 1H, SH), 11.02( s, 1H, NH); Anal.calc for: C27H18ClN3O3S; C, 64.86; H, 3.63; N, 8.40; Found: C, 64.84; H, 3.61; N, 8.38%.

 

ANTICONVULSANT ACTIVITY:

The synthesize derivatives of barbituric indole having in an exceedingly potent nature and it show anticonvulsant activity by Maximal electroshock method. The strategy has been approval by the “Institutional Animal Ethical Committee” at “Hygia Institute of Pharmaceutical Education and Research, Lucknow” (reference. no. HIPER/IAEC/30/18/10). Within the MES method, the rats (Wister strain) weighing 150-200 g28. The rat was divided into three major groups (control, standard, and test) and each group comparing three rats.  Group I (Control) No drug was administered in one group. Group II (Standard) the opposite group was administered with achieved of phenytoin sodium administered orally at dose of 30mg/kg and was kept as standard.  Group III (Test) the last group was administered with the compound of 0.5% aq. CMC suspension at dose of 15mg/kg. After 30 min by use of electrical shock the activity was observed. The present flow was given of ‘150mA for duration of 0.2 sec’. The method was assessed for around 30 min of interval for response produce by experimental animal. By this method the potency drug was observed out29, 30. The term of varied times of epilepsy, as an example, the tonic flexion (towards the furthest points), tonic extensor stage (expansion of the lower limits), clonic seizure (transitional of snapping of appendages), trance (obviousness) and recuperation or demise were watched31, 32. (Information appeared in table). The recently incorporated mixes were surveyed by the nonattendance or decrease of the rear appendage tonic extensor stage.

 

RESULTS AND DISCUSSION:

All currently synthesize compounds were characterized at the concept in their m.p., Rf, FT-IR, 1H NMR, mass spectra and elemental evaluation.

 

Anticonvulsant activity of the compounds turned into accomplished via the maximal electroshock method in albino rats of either sex. This technique claimed to come across compounds owning acidity in opposition to generalized tonic-clonic seizures. The MES check can be a percentage of an antiepileptic to abolish or reduce the season of the tonic extensor factor of the limb inside the maximal seizure brought on by means of 150 mA of modern-day added for 0.2 seconds.

 

inside the number one MES screening compound 4c, 4d and 5a afforded protection in opposition to seizure confirming their pastime statistics reveal that all compounds confirmed of limb tonic extensor section while given within the dose of 30 mg/kg orally and compound 4c and 5a have been found to be the foremost  compounds within the collection. The anticonvulsant activity of the other examined compounds became found to be lots much less powerful than phenytoin used as a regular antiepileptic constant with the results acquired plainly the presence of the chloro group is potency.

 

Table 1: Characterisation data of the synthesized compound (4a-d)

Compound

R

m.p. (˚C)

Yield (%)

Rf value

4a

4-OCH3

175-177

60

0.56

4b

4-Cl

172-175

78

0.82

4c

3,4-Cl

170-172

80

0.41

4d

4-F

128-130

42

0.57

5a

4-OCH3

136-138

70

0.76

5b

4-Cl

118-120

78

0.52

Solvent system: ethyl acetate: n-Hexane (2:8) for TLC

 

CONCLUSION:

The structures of all new synthesize compounds are established on the idea of their analytical and spectral data. All of the synthesized compounds were evaluated for his or her anticonvulsant activity using electro-convulsiometer induced ear electrode 150mA “current for 0.2 second” and phenytoin sodium because the standard drug. within the MES screening compound 4c, 4d and 5a afforded protection against seizure confirming their activity. The synthesize compounds are 4c and 5a most potent drug of chloro group.

 

Table 2: anticonvulsant activity of titled compounds

15 mg/kg (Dose)

Code

Flexion

(Mean± SEM)

Extensor

(Mean± SEM)

Clonic

(Mean± SEM)

Stupor

(Mean± SEM)

Recovery/

Death

4a

4.52±0.4

10.32±0.6

11.34±0.9

111.86±0.6

R

4b

4.91±0.1

7.10±0.9

10.62±0.6

111.23±0.9

R

4c

4.31±0.4

7.12±0.9

10.69±0.7

106.43±0.5*

R

4d

4.55±0.5

8.84±0.9

8.92±0.9

109.35±0.6*

R

5a

3.97±0.3

7.25±0.8

8.21±0.6

105.47±0.9*

R

5b

3.98±0.4

7.29±0.8

8.19±0.6

112.48±0.8

R

Control

4.14±0.4

8.91±0.7

11.86±0.9

114.41±0.6

R

Phenytoin sodium

2.51±0.7

5.71±0.9

3.73±0.8

103.36±0.9

R

 


 

ACKNOWLEDGEMENT:

Authors would like to think management of Hygia Institute of Pharmaceutical Education and Research, Lucknow for providing research facilities CSIR-Central Drug Research Institute, Lucknow is acknowledged for providing the spectral data of the synthesized compounds.

 

 

 

CONFLICT OF INTEREST:

All authors declare that they have no conflicts of interest.

 

 

ABBREVIATIONS

Sec

Second

CDH

Central drug House

Ltd

Limited

FT-IR

Fourier Transform Infrared Spectroscopy

mol

Mole

UV

Ultraviolet

TLC

Thin Layer Chromatography

MES

Maximal Electroshock Method

p

Private

MHz

Megahertz

g

Gram

h

Hours

DMF

Dimethyl formamide

mp

Melting Point

 

 

 

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Received on 23.04.2020           Modified on 08.06.2020

Accepted on 16.07.2020         © RJPT All right reserved

Research J. Pharm. and Tech. 2021; 14(5):2681-2685.

DOI: 10.52711/0974-360X.2021.00473