INTRODUCTION:

Thalidomide, a drug used to treat different inflammatory diseases is also an inhibitor of TNF-a expression. It has been approved by the Food and Drug Administration (FDA) in July 1998 for a treatment of Erythema nodosum leprosum. After that, the interest in this drug has been intensified because of its effective immunomodulatory and anti-inflammatory properties.

Phthalimides possess a structural features –CO-N(R)-CO- and an imide ring which help them to be biologically active and pharmaceutically useful. Thalidomide, first synthesized as antihistaminic drug in 1954, was introduced as a sedative hypnotic drug in 1956 but withdrawn from the marketbecause of its catastrophic teratogenicity. The teratogenic action of thalidomide was due to the (S)- enantiomer. In the early 1960s, a new use was found for thalidomide as a sedative in patients suffering from lepromatous leprosy (Erythema nodosum leprosum), an acute inflammatory manifestation of lepromatous leprosy.

In recent years, N4-phthalimide derivatives have emerged as structurally novel anticonvulsants. Phthalimide and N-substituted phthalimides are an important class of compounds because they possess important biological activities including anti-inflammatory activity, analgesic activity and hypolipidemic activity.

Acylation of amines by phthalic anhydride produce phthalamic acid derivatives, which are organic herbicides. Further cyclization results into the formation of N-substituted imides, which exhibit various biological activities such as analgesic, antimicrobial, antipsychotic, anti-inflammatory, tuberculosis, hypolipidemic and anxiolytic.

Among the bicyclic non-aromatic nitrogen heterocycles, phthalimides are an interesting class of compounds with a large range of applications. Phthalimides have served as starting materials and intermediates for the synthesis of many types of alkaloids and pharmacophores. Recently, phthalimide and some of its derivatives have proved to have important biological effects similar or even higher than known pharmacological molecules and so their biological activity is being a subject of biomedical research.

LITERATURE REVIEW:

Antimicrobial Activity

N-Phthilimido derivatives of amino acids (1) was designed and investigated for antimicrobial and fungal activity by Srinivasan et al; 2010. The chemical structures of the titled compound were confirmed by IR, ¹³C-NMR and elemental analysis. All the compounds are screened for antimicrobial activity against gram positive, gram negative bacteria (Escherichia coli, Klebsiella, Staphylococcus epidermitis, Bacillus cereus, Micrococcus leteus, Staphylococcus aureus) and fungal strains (Candida albicans, Aspergillus niger).¹

(1)

Some novel Schiff bases linked to phthalimide moiety (2) have been synthesized via multistep synthesis by Ahlam et al; 2011;. The first step involved reaction of phthalic anhydride with aniline producing N phenyl phthalamic acid which was subsequently dehydrated to the corresponding N-phenyl phthalimide via treatment with acetic anhydride and anhydrous sodium acetate. Structures of the prepared compounds were elucidated on the basis of FTIR, H-NMR and ¹³C-NMR spectral data which agreed with the proposed structures. The synthesized compounds were screened for their antibacterial activity against two microorganisms Staphylococcus aureus and EscherichiaColi and they were found to exhibit good to moderate antibacterial activity.²

(2)

Hitherto the various ligands have not been reacted with N-hydroxymethyl phthalimide. Hence the proposed work is the formation of phthalimide-ligand derivatives and to study their complexationproperties.The ligand was prepared by condensation of N-hydroxymethyl phthalimide and salicylicacid. formation of phthalimide-ligand derivatives and to study their complexation properties by Solanki et al;2012. The ligand designated as HL6 (3) were characterized by elemental analysis. ³

(3)

Anticonvulsant Activity

Synthetic heterocyclic compounds have been found to possess important biological properties including anticonvulsant effects in man and animals. This study was aimed at highlighting the anticonvulsant properties of two phthalimide derivatives (N cyclopentylphthalimide and N benzylphthalimide). N-Cyclopentylphthalimide (4a) and N-benzylphthalimide (4b) were synthesized by Iniaghe et al; 2010 and screened for anticonvulsant properties using adult Swiss mice. Convulsion was induced using maximum electroshock therapy. The compounds were found to be seizure protective and protection was observed even after forty eight hours. ⁴

(4a) (4b)

The phenyl (thio) semicarbazide derivatives of phthalimido pharmacophores were synthesized by Bharat et al;2003 and evaluated for their anticonvulsant activity. A series of N4-(4-Methyl Phthalimido) Substituted Phenyl (Thio) Semicarbazide were synthesized by reaction of substituted phenyl (thio) semicarbazide with 4-methyl phthalic anhydride. All the synthesized compounds were characterized on the basis of their IR,1HNMR and elemental analysis. These compounds exhibited highly significant and comparable anticonvulsant activity with respect to standard drug Phenytoin.

Two series of phthalimides-one possessing an N- phenoxyalkyle moity substituted at position 3 or 4 of the phenyl ring and the other of N- alkenyl or alkinyl phthalimide were synthesised by Magzorzata et al;2009. Evaluated for anticonvulsant activity and theire in silico lipophilicity estimatrd using computer programs. The anticonvulsant activity of phthalimide containing an unsaturated substituent at the phthalimide nitrogen was superior to that of the N- phenoxy alkye phthalimide. Alkinyl derivative emerged as the most active(in MES andsc met test) of all the compound tested. a correlation between anticonvulsant activity andin silico estimated lipophilicity was not observed. ⁵

A series of Schiff bases of phthalimide (5a-i) were prepared by Mashooq et al; 2011 in satisfactory yields and evaluated for their anticonvulsant and neurotoxicity activities. The structures of all the compounds were in good agreement with elemental analysis and spectral data. All the compounds were active in MES screen and less neurotoxic than phenytoin. Compound 5i having nitro substitution at ortho position of the distal aryl ring emerged as most promising anticonvulsant agent with low neurotoxicity. ⁶

(5a-i)

5a=R₁=H, R₂=4-OH

5b=R₁=H, R₂= 3,4(-OCH₃)

5c= R₁=H, R₂=3-NO₂

5d= R₁= CH₃, R₂= 2-OH

5e= R₁=CH₃, R₂= 4-OH

5f= R₁= CH₃, R₂= 4-CH₃

5g= R₁= CH₃, R₂= 4-Cl

5h= R₁= CH₃, R₂= 4-NO₂

5i= R₁= CH₃, R₂= 2-NO₂

A series of novel 1,3,4-oxadiazole derivatives of phthalimide were prepared in satisfactory yields and evaluated for their anticonvulsant and neurotoxicity studies. All the compounds were in good agreement with elemental analysis and spectral data. All the compounds were active in MES screen and less neurotoxic than phenytoin. Compound 4j having methoxy substitution at para position of the distal aryl ring emerged as most promising anticonvulsant agent with low neurotoxicity.

Anti-inflammatory Activity

This paper describes the synthesis and anti-inflammatory activity of new N-phenyl-phthalimide sulfonamides (6a) and the isosters N-phenyl-phthalimide amides (6b), designed by Lidia et al; 2002. as hybrids of thalidomide and aryl sulfonamide phosphodiesteraseinhibitor. In these series, compound (LASSBio 468), having a sulfonyl-thiomorpholine moiety, showed potent inhibitory activity on LPS-induced neutrophil recruitment with ED50=2.5mg kg_1, which was correlated with its inhibitory effect on TNF-a level. ⁷

(6a) (6b)

A new series of methyl-2-[substituted benzylidine]-4-[2-(phthalimide) ethoxy]acetoacetate (7a) have been synthesised by Kishor et al; 2010, from combination of methyl- [2(phthalimide)ethoxy] acetoacetate,3 and substituted benzaldehyde (7b) which result in both anti-inflammatory and aantimicrobial active compound by IR, 1H NMR,Mass spectal and elemental analysis. These compound have been subjected to preliminary anti-inflammatory screening using the carrageenan induced rat paw oedema model.

7(a) 7(b)

R= 4-Cl, -Br, 4-OCH₃, 2-OH, 3-NO₂ , 3,4,5-OCH₃, 6-methoxy napthalene

Analgesic Activity

Phthalimide derivatives synthesis (8) were carried out by Suvarna et al; 2012 eco-friendly microwave irradiation methods where, montmorillonite-KSF was used as the reusable clay catalyst. In the context of green chemistry, among the non-conventional methods of reaction activation in organic synthesis, microwave irradiation for reaction activation provides an alternative to the conventional heating for introducing energy into chemical reactions by using the ability of some liquids and solids to transform electromagnetic energy into heat. These compounds were characterized by TLC, melting point determination, and by IR and 1H NMR spectroscopy. The acute oral toxicity studies of the compounds were carried out using OECD guidelines. The compounds were than screened for analgesic activity using Aspirin as the standard and activity was correlated with FISA (Hydrophilic component of the totalaccessible surface area). The molecular modeling software, Maestro, from Schrodinger, USA, was used for QSAR studies. ⁸

(8)

Antifungal Activity

4-(1,3-dioxoisoindolin-2-yl)benzohydrazide undergoes facile condensation with aromatic aldehydes to afford the corresponding N'-arylidene-4-(1,3-dioxoisoindolin-2-yl) benzohydrazide (9a) in good yields. Cyclocondensation of compounds (9a) with chloro acetyl chloride yields N-(3-chloro-2-oxo-4- arylazetidin-1-yl)-4-(1,3-dioxoisoindolin-2-yl)benzamide (9b). The structures of these compounds were established on the basis of analytical and spectral data. The newly synthesized compounds by Gunvantsinh et al; 2011 were evaluated for their antibacterial and antifungal activities.⁹

(9a) (9b)

R= 4-OH, 2-OH, 4-OCH₃, 3-OCH₃

Anticancer Activity

To improve the therapeutic efficacy of 20(s)-camptothecin (CPT) polymeric drugs containing CPT have been designed. A new CPT-conjugate, 3,6-endo-methylene-1,2,3,6 tetrahydrophthalimidoacetamidoglycine camptothecin ester (ETPA-gly-CPT), was synthesized by Neung et al; 2004 linking its hydroxyl group to the phthalimido monomer through a glycine–glycine spacer. Its homo- and copolymer with acrylic acid (AA) were prepared by photopolymerization using 2,2-dimethoxy-2-phenylacetophenone (DMP) as a photoinitiator. The monomer and its polymers were characterized by IR, 1H- and 13CNMR spectra. The ETPA-gly-CPT content in poly(ETPA-gly-CPT-co-AA) obtained by elemental analysis was 40 wt.%. The number-average molecular weights of the polymers determined by gel permeation chromatography were as follows: Mn ¼ 15; 000 for poly(ETPA-gly-CPT), Mn ¼ 18; 700 for poly(ETPA-gly-CPT-co-AA) (10). The IC50 values of ETPA-gly-CPT and its polymers against cancer cells were much larger than that of CPT. ¹⁰

(10)

Attachment of anticancer agents to polymers has been demonstrated to improve their therapeutic A new monomer containing camptothecin, 5-norbonene-endo-2,3-dicarboxylimidoundecanoyl-camptothecin (NDUCPT) and its homopolymer and copolymer with acrylic acid (AA) were synthesized and spectroscopically characterized. The NDUCPT content in poly(NDUCPT-co-AA) obtained by elemental analysis was 51%. The average molecular weights of the polymers determined by gel permeation chromatography were as follows: Mn = 12 100, Mw = 23 400 gmol−1, Mw/Mn = 1.93 for poly(NDUCPT) (11), Mn = 15 400, Mw = 28 300 gmol−1, Mw/Mn = 1.83 for poly(NDUCPT-co-AA). The IC50 value of NDUCPT and its polymers against U937 cancer cells was larger than that of CPT. The in vivoantitumour activity of all polymers in Balb/C mice bearing the sarcoma 180 tumour cell line was greater than that of CPT at a dose of 100mgkg−1.

(11)

CONCLUSION:

Phthalimide moiety has shown valuable biological activities and can be used for an intermediate for synthesizing various heterocyclic compounds. Some compounds have shown encouraging activities and are needed to be investigated further to get better agents that can have strong future commitments.

REFERENCES:

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3. Solanki MR, Limbachiya MC. Synthesis and Antimicrobial Activity of Metal Complexes Containing Novel Phthalimide Ligands. Asian Journal of Biochemical and Pharmaceutical and Research. 1(2); 2010: 317-322.

4. Iniaghe LO and Usifoh CO. Biological and Chemical Sciences Anticonvulsant properties of N-cyclopentylphthalimide and N-benzylphthalimide. Research Journal of Pharmaceutical, Biological and Chemical Sciences. 1(4); 2010: 1068-1072.

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8. Gajare SP, Mahajan SS. Eco-friendly Synthesis of Phthalimide Derivatives, their Analgesic Activity and QSAR Studies. International Journal Pharmaceutical Phytopharmacological Research. 1(7); 2012: 357-362.

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10. Lee N, Lee S. Kim S, Kang Y, Moon S, Sohn H. Synthesis and in vitro antitumor activity of phthalimide- based polymers containing camtothecin. European Polymer Journal. 40; 2004: 1291-1296.

Received on 05.04.2013 Modified on 16.04.2013

Research J. Pharm. and Tech 6(7): July 2013; Page 711-714