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 Table of Contents  
ORIGINAL ARTICLE
Year : 2012  |  Volume : 1  |  Issue : 4  |  Page : 244-248

Synthesis and anti-Parkinson's screening of some novel 2-(naphthalen-1-yl)-N-[2-substituted (4-oxothiazolidin-3-yl)]acetamide derivatives


Department of Pharmaceutical Chemistry and Pharmacology, JSS College of Pharmacy, Ooty (A Constituent College of JSS University, Mysore), Rocklands, Ooty, The Nilgiris, Tamil Nadu, India

Date of Web Publication27-Feb-2013

Correspondence Address:
S Gomathy
Department of Pharmaceutical Chemistry, JSS College of Pharmacy, Ootacamund - 643 001
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2278-344X.107871

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  Abstract 

Context: The objective of this study is to synthesize some novel 2-(naphthalen-1-yl)-N-[2-substituted (4-oxothiazolidin-3-yl)] acetamide derivatives and to study their anti-Parkinson's activity. Materials and Methods: Ethyl (naphthalen-1-yl) acetate (1) was prepared from naphthalene-1-yl acetic acid in ethanol. Condensation of ethyl (naphthalen-1-yl) acetate (1) with an equimolar quantity of hydrazine hydrate in methanol afforded 2-(naphthalen-1-yl) acetohydrazide (2). Compound 2 which on condensation with different aromatic aldehydes yielded respective Schiff bases (3a-e). The Schiff bases are then cyclised with mercaptoacetic acid in dioxane to yield the corresponding naphthalene bearing 4-thiazolidinone derivatives (4a-e). The structures of the synthesized compounds have been established based on their analytical and spectral data such as FT-IR, Mass and NMR spectroscopy. Results: The synthesized compounds were evaluated for their anti-Parkinson's screening using in vitro free radical scavenging assay. Compounds 4c, 4d, and 4e showed potent free radical scavenging activity giving 82%, 74% and 76% respectively. Three compounds 4c, 4d and 4e were taken for in vivo anti-Parkinson's screening by 6-Hydroxydopamine lesioned rat's model (6-OHDA). Among these, one of the 4-thiazolidinone derivatives having a 3-nitro phenyl group at 2 nd position 4c exhibited maximum anti-Parkinson's activity. Conclusion: Thiazolidinone derivatives showed significant anti-Parkinson's activity in the 6-OHDA lesioned rat model. The estimated parameters were closely relevant to clinical parkinsonism, and the drug treatment protected the diseased brain of a rat. We appreciate further detailed studies with these drugs in anti-Parkinson's pharmacology and toxicology.

Keywords: 4-Thiazolidinone, anti-Parkinson′s activity, schiff bases


How to cite this article:
Gomathy S, Singh G, Gowramma B, Antony A S, Elango K. Synthesis and anti-Parkinson's screening of some novel 2-(naphthalen-1-yl)-N-[2-substituted (4-oxothiazolidin-3-yl)]acetamide derivatives. Int J Health Allied Sci 2012;1:244-8

How to cite this URL:
Gomathy S, Singh G, Gowramma B, Antony A S, Elango K. Synthesis and anti-Parkinson's screening of some novel 2-(naphthalen-1-yl)-N-[2-substituted (4-oxothiazolidin-3-yl)]acetamide derivatives. Int J Health Allied Sci [serial online] 2012 [cited 2021 Sep 27];1:244-8. Available from: https://www.ijhas.in/text.asp?2012/1/4/244/107871


  Introduction Top


Heterocycles bearing nitrogen, sulfur, and thiazole moieties constitute the core structure of a number of biological interesting compounds. The thioazolidin-4-one ring system is of considerable interest as it is a core structure in various synthetic pharmaceuticals, displaying a broad spectrum of biological activities. Thiazolidin-4-one derivatives are known to exhibit diverse bioactivities such as antidiarrheal, anticonvulsant, antimicrobial, antidiabetic, antihistaminic, anticancer, anti-HIV, psychotropic effects, potential analgesics, herbicidal activity, antiepileptic, antiinflammatory, antitumor, CNS activity, calcium channel blockers, PAF antagonist, anti-ischemic, cardioprotective, cyclooxygenase inhibitor, antiplatelet activating factor, nonpeptide thrombin receptor antagonist, and tumor necrosis factor alpha antagonist activities. [1],[2],[3] Synthesis and anti-Parkinson's screening of some novel 3-[2-(naphthalen-1-yl) acetyl]-2-substituted thiazolidin-4-one derivatives serve as the pathfinder for the design of novel molecule for anti- Parkinsonism More Details. The discovery of this class of drugs provides an outstanding case history of modern drugs development and also points out the unpredictability of biological activity from structural modification of a prototype drug molecule. Led by these considerations, it appeared of interest to synthesize some novel-4-thiazolidinone derivatives bearing the naphthalene moiety and to screen in vitro and in vivo for their anti-Parkinson's activity.


  Materials and Methods Top


Melting points were determined in an open capillary tube using a Veego VMP-1 apparatus and are uncorrected. The IR spectra (4000-400 cm -1 ) of synthesized compounds were recorded on a Shimadzu 8400-S FT-IR spectrophotometer with KBr pellets. Nuclear magnetic spectra ( 1 H-NMR) were obtained from a 400 MHz FT-NMR spectrophotometer using CDCl 3 as solvent with TMS as the internal standard. Mass spectra were obtained from GC-MS using EI+ as ionization mode. Thin layer chromatography was performed on glass slides coated with silica gel-G, using appropriate mobile phase system and spots were visualized under UV radiation.

Synthesis of ethyl naphthalen-1-ylacetate (1)

To a solution of naphthalene-1-yl acetic acid (18.6 g) in ethanol (50 mL) was added dropwise in conc. H 2 SO 4 (12 mL). The mixture was refluxed for 6 h. The resulting solution was made neutral by the addition of ammonia water. The precipitate was collected by filtration and then washed with water and subsequently dried to get ethyl naphthalene-1-yl acetate (1). [4]

Synthesis of 2-(naphthalene-1-yl) acetohydrazide (2)

2 mmol of Compound 1 (0.428 g) was dissolved in methanol (10 mL) and to this hydrazine hydrate (0.05 g) was added and shaken well. A clear solution was obtained and this reaction mixture was refluxed for 5 h. TLC was checked using 5% methanol: chloroform solvent system (0.5:9.5). The precipitate was separated out, and the product was filtered, dried and recrystallized from ethanol. [5]

Synthesis of (E)-NͲ-benzylidene-2-(naphthalen-1-yl) acetohydrazide derivative (3a-e)

1 mmol of Compound 2 (0.2 g) was dissolved in methanol (10 mL). To this reaction mixture, equimolar quantity of formaldehyde and substituted aldehydes was added. The clear solution obtained was refluxed for 6 h. TLC was checked using 5% methanol: chloroform solvent system (0.5:9.5). The precipitate was collected by filtration and recrystallized with ethanol.

Synthesis of 2-(naphthalene-1-yl)-N-[2-substituted (4-oxothiazolidin-3-yl)] acetamide (4a-e)

To 1 mmol solution of Compound 3a-e (0.28 g) in dry dioxane (10 mL), a solution of 0.01 mol of mercapto acetic acid (1.042 mL) in dry dioxane (10 mL) was added and followed by addition of zinc chloride (0.15 g) and the reaction mixture was refluxed for 10 h. The reaction was monitored by TLC. The solvent was evaporated under reduced pressure and separated residue was neutralized by sodium bicarbonate to remove excess of mercaptoacetic acid. Solid product obtained was recrystallized from ethanol.

Biological studies

The synthesized thiazolidinone derivatives were evaluated for in vitro anti-Parkinson's activity by free radical scavenging assay and in vivo screening for their anti-Parkinson's activity by using the 6-OHDA rat model.

Compound 4a: 2-(naphthalen-1-yl)-N- (4-oxo-2-phenylthiazolidin-3-yl) acetamide

IR (KBr, cm -1 ): 3048 (Ar-CH), 2752 (C-H aliphatic), 1644 (C = O), 1489 (Ar C = C), 1420 (C-N), 722 (C-S-C). 1 H-NMR: 7.16-7.54 (m, 11H, Ar-H), 4.0 (s, 2H, CH 2 -CON), 5.94 (s, 1H, N-CH), 3.02 (s, 2H, CH 2 -S), 8.00 (s, 1H, NH). Mass m/z: 362 calculated for C 12 H 18 N 2 O 2 S, found 362.1.

Compound 4b: N-(2-(4-(dimethylamino) phenyl)-4-oxothiazolidin-3-yl)-2- (naphthalen-1-yl) acetamide

IR (KBr, cm -1 ): 3051 (Ar-CH), 2852 (C-H aliphatic), 1623 (C = O), 1446 (Ar C = C), 1418 (C-N), 715 (C-S-C). 1 H-NMR: 6.47-7.7 (m, 11H, Ar-H), 3.88 (s, 2H, CH 2 -CON), 5.92 (s, 1H, N-CH), 3.28 (s, 2H, CH 2 -S), 8.0 (s, 1H, NH), 2.85 (s, 6H, N-(CH 3 ) 2 . Mass m/z: 405 calculated for C 23 H 23 N 3 O 2 S, found 405.15.

Compound 4c: 2-(naphthalen-1-yl)-N-(2-(3-nitrophenyl)-4-oxothiazolidin-3-yl) acetamide

IR (KBr, cm -1 ): 3087 (Ar-CH), 2954 (C-H aliphatic), 1675 (C = O), 1566 (Ar C = C), 1501 (Ar-NO 2 ), 1430 (C-N), 785 (C-S-C). 1 H-NMR: 7.29-8.0 (m, 11H, Ar-H), 3.68 (s, 2H, CH 2 -CON), 5.92 (s, 1H, N-CH), 3.38 (s, 2H, CH 2 -S), 8.0 (s, 1H, NH). Mass m/z: 407 calculated for C 21 H 17 N 3 O 4 S, found 407.09.

Compound 4d: N-(2-(4-hydroxyphenyl)-4-oxothiazolidin-3-yl)-2-(naphthalen-1-yl) acetamide

IR (KBr, cm -1 ): 3126 (C-N), 3026 (Ar-CH), 2924 (C-H aliphatic), 1748 (Ar C = C), 1675 (C = O), 760 (C-S-C). 1 H-NMR: 6.6-7.7 (m, 11H, Ar-H), 3.88 (s, 2H, CH 2 -CON), 5.92 (s, 1H, N-CH), 3.46 (s, 2H, CH 2 -S), 8.8 (s, 1H, NH), 5.0 (s, 1H, OH). Mass m/z: 378 calculated for C 21 H 18 N 2 O 3 S, found 378.4.

Compound 4e: N-(2-(3-hydroxy-4-methoxyphenyl)-4-oxothiazolidin-3-yl)-2-(naphthalen-1-yl) acetamide

IR (KBr, cm -1 ): 3048 (Ar-CH), 2998 (C-H aliphatic), 1732 (Ar C = C), 1688 (C = O), 3174 (C-N), 718 (C-S-C). 1 H-NMR: 6.6-7.7 (m, 11H, Ar-H), 3.88 (s, 2H, CH 2 -CON), 5.92 (s, 1H, N-CH), 3.46 (s, 2H, CH 2 -S), 8.8 (s, 1H, NH), 3.86 (s, 3H, CH 3 ), 5.0 (s, 1H, OH). Mass m/z: 408 calculated for C 22 H 20 N 2 O 4 S, found 408.7.


  Results Top


We have synthesized five novel 4-thiazolidinone derivatives such as 2-(n aphthalene- 1-yl)-N-(4-oxo-2- phenylthiazolidin-3-yl) acetamide, N-(2-(4-(dimethyl amino) phenyl)-4-oxothiazolidin-3-yl)-2-(naphthalen- 1-yl) acetamide, 2-(naphthalene-1-yl)-N-(2- (3- nitrophenyl)-4-oxothiazolidin-3-yl) acetamide, N-(2-(4-hydroxyphenyl)-4-oxothiazolidin- 3-yl)-2- (naphthalen-1-yl) acetamide, and N-(2-(3-hydroxy- 4-methoxyphenyl)-4-oxothiazolidin-3-yl)- 2-(naphthalen- 1-yl) acetamide as illustrated in [Scheme 1[Additional file 1]]. Structures of all the compounds were established on the basis of IR, 1 H-NMR and mass spectral data. The physical parameters are presented in [Table 1].
Table 1: Physical parameters of synthesized compounds

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In vitro study

The synthesized thiazolidinone derivatives were evaluated for in vitro anti-Parkinson's activity by free radical scavenging assay. The results are presented in [Table 2].[6]
Table 2: Effect of thiazolidinone derivatives 4a, 4b, 4c, 4d and 4e on reactive oxygen species

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Based on in vitro study by free radical scavenging assay, it was found that Compounds 4c, 4d, and 4e showed potent free radical scavenging activity giving 82%, 74%, and 76% respectively. These three derivatives were subjected to in vivo screening for their anti-Parkinson's activity.

In vivo study

Compounds 4c, 4d, and 4e were taken for anti-Parkinson's screening. These were given orally after 48 h of induction for 45 days at the dose of 30 mg/kg to Wistar rats. The parameters such as circulating behavior, grip strength, catatonia and complex I activity are checked after 45 days of the treatment. The results were tested for its significance using one-way ANOVA followed by Dunnett's multiple comparisons test. The results are shown in [Table 3],[Table 4],[Table 5] and [Table 6]. [7],[8],[9],[10]
Table 3: Effect of thiazolidinone derivatives 4c, 4d and 4e on quantification of circling behavior in rats

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Table 4: Effect of thiazolidinone derivatives 4c, 4d and 4e of experimental groups by using the rotarod apparatus

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Table 5: Effect of thiazolidinone derivatives 4c, 4d and 4e on catatonia activity of experimental groups

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Table 6: Effect of thiazolidinone derivatives 4c, 4d and 4e on mitochondrial complex i activity in brain homogenate of treatment groups

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  Discussion Top


A series of thiazolidinone derivatives 4a-e were synthesized in the range of 40-50% yield using the synthetic route outlined in Scheme 1. The structures of all the synthesized compounds were established on the basis of IR, 1 H-NMR and mass spectral data analysis. The synthesized compounds were evaluated for their anti-Parkinson's activity. The final step compounds (thiazolidinone derivatives) were subjected for in vitro free radical scavenging assay. Based on the results of in vitro free radical scavenging assay, three potent compounds 4c, 4d and 4e were selected for in vivo 6-OHDA lesioned rat's model. Among these, Compound 4c has shown maximum anti-Parkinson's activity. The estimated parameters were closely relevant to clinical parkinsonism and the drug treatment protected the diseased brain of rat. We appreciate further detailed studies with these drugs in anti-Parkinson's pharmacology and toxicology. From these findings, we suggest that these drug molecules can be future drugs of choice for the treatment of clinical parkinsonism.

 
  References Top

1.Wadher SJ, Karande NA, Sonawane SD, Yeole PG. Synthesis and biological evaluation of schiff base and 4-thiazolidinones of aminosalicylic acid and their derivatives as an antimicrobial agent. Int J chem Tech Res 2009;1:1303-7.  Back to cited text no. 1
    
2.Mulay A, Mangesh G, Nikalje AP. Exploring potential of 4-Thiazolidinone: A brief review. Int J Pharm Sci 2009;1:44-9.  Back to cited text no. 2
    
3.Parekh HH, Parikh KA, Parikh AR. Synthesis of some 4-Thiazolidinone derivatives as antitubercular agents. Islam Repub Iran 2004;15:143-8.  Back to cited text no. 3
    
4.Prajapati A. Synthesis, antimicrobial and insecticidal activity studies of 5-Nitro-N-[arylidenhydrazidomethyl indole]-2-(substituted aryl)-3-(N-indolyl acetamidolyl)-4-oxothiazolidinone. Res J Recent Sci 2012;1:99-104.  Back to cited text no. 4
    
5.Viswajanani JS, Ajay S, Smita S, Seema K, Manisha P, Pragya B, et al. Synthesis and antimicrobial activity of novel thiazolidinones. Arkivoc 2005;2:46-59.  Back to cited text no. 5
    
6.Krishan S, Karnine SP, Michael RB, Vijayalaxmi R. Evidence for generation of oxidative stress in the brain by MPTP: In vitro and in vivo study in mice. Brain Res 1997;749:44-52.  Back to cited text no. 6
    
7.Heffi F, Mohamed E, Liutsuman EJ. Partial lesions of the dopaminergic system in rat brain: Biochemical characterization. Brain Res 1980;195:23-37.  Back to cited text no. 7
    
8.Oiwa Y, Yoshimuna R, Nakau K, Itakawa T. Dopaminergic neuroprotection and regeneration by neurturin assessed by using behavioural, biochemical and histochemical measurements in a model of progressive Parkinson's disease. Brain Res 2002;947:271-83.  Back to cited text no. 8
    
9.Maharaj H, Maharaj DS, Daya S. Acetylsalicylic acid and acetaminophen protect against MPP+-induced mitochondrial damage and superoxide anion generation. Life Sci 2006;78:2438-43.  Back to cited text no. 9
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10.Sunil KM, Chaudhari RY, Rupali SW. Synthesis, characterisation, antiparkinson and antioxidant evaluation of novel derivatives of resorcylic acid and gallic acid. J Pharm Res 2011;4:88-94.  Back to cited text no. 10
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]


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