Journal of Applied Pharmaceutical Science Vol. 6 (03), pp. 159-171, March, 2016 Available online at http://www.japsonline.com DOI: 10.7324/JAPS.2016.60330 ISSN 2231-3354 Recent Advances and Future Prospects of Phthalimide Derivatives Neelottama Kushwahaa*, Darpan Kaushikb aPranveer Singh Institute of Technology, Kanpur, India. bPrasad Institute of Technology, Jaunpur, India. ABSTRACT ARTICLE INFO Article history: Among bicyclic non-aromatic nitrogen heterocycles, phthalimides are an interesting class of compounds with a Received on: 21/05/2015 large range of applications. Phthalimide contains an imide functional group and may be considered as nitrogen Revised on: 13/09/2015 analogues of anhydrides or as diacyl derivatives of ammonia. They are lipophilic and neutral compounds and can Accepted on: 02/11/2015 therefore easily cross biological membranes in vivo and showing different pharmacological activities. In the Available online: 10/03/2016 present work compounds containing phthalimide subunit have been described as a scaffold to design new prototypes drug candidates with different biological activities and are used in different diseases as, for example Key words: AIDS, tumor, diabetes, multiple myeloma, convulsion, inflammation, pain, bacterial infection among others. Phthalimide derivatives, imide, biological activity. INTRODUCTION have served as starting materials and intermediates for the synthesis of many types of alkaloids and pharmacophores. Phthalimides possess a structural feature –CO-N(R)- CO- and an imide ring which help them to be biologically active Structure of Phthalimide and pharmaceutically useful. Phthalimides have received attention due to their androgen receptor antagonists (Sharma et Phthalimide is an imido derivative of phthalic acid. In al., 2012), anticonvulsant (Kathuria and Pathak, 2012), organic chemistry, imide is a functional group consisting of two antimicrobial (Khidre et al., 2011), hypoglycaemic (Mbarki and carbonyl groups bound to nitrogen. They are hydrophobic and Elhallaoui, 2012), anti-inflammatory (Lima et al., 2002), neutral, and can therefore cross biological membranes in vivo. antitumour (Noguchi et al., 2005), anxiolytic (Yosuva and These compounds are structurally related to acid anhydrides Sabastiyan, 2012) and anti HIV-1 activities (Sharma et al., 2010). (Azzawi and Razzak, 2011). Several reports demonstrated the antimicrobial In N-Benzyl phthalimide the benzene and imide groups potential of phthalimide derivatives (Santos et al., 2009). are planar and make a dihedral angle of 74.2 (1)° with one another. Phthalimide derivatives of amino acid analogues possess There are three weak C-H O hydrogen bonds, forming a two- anthelmintic activity (Srinivasan et al., 2010). There is a dimensional network structure. Most of the imides are cyclic growing interest in the usefulness of phthalimides and its compounds derived from dicarboxylic acids and their names reflect derivatives. They have found relevance as inhibitors of tumor the parent acid. necrosis factor production (Okunrobo et al., 2006). Phthalimides Examples are succinimide derived from succinic acid and phthalimide derived from phthalic acid. As imide has the formula * Corresponding Author NH, being highly polar, imides exhibit good solubility in polar Neelottama Kushwaha, Assistant Professor, Department of Pharmacy, media. The N-H centre for imides derived from ammonia is acidic Pranveer Singh Institute of Technology, Kanpur, India. Tel: +91, 9452166918; E-mail: [email protected] and can participate in hydrogen bonding. © 2016 Neelottama Kushwaha and Darpan Kaushik. This is an open access article distributed under the terms of the Creative Commons Attribution License - NonCommercial-ShareAlikeUnported License (http://creativecommons.org/licenses/by-nc-sa/3.0/). 160 Kushwaha and Kaushik. / Journal of Applied Pharmaceutical Science 6 (03); 2016: 159-171 Effect of neighboring carbonyl groups on acidity of N-Bond ordination of aliphatic tertiary amino nitrogen is not sterically Imides such as phthalimide readily dissolve in aqueous favored, the high electron density available on the tertiary amino NaOH as water-soluble salts. Imides are more acidic than amides. nitrogen favors its coordination to a metal ion where there is a The order of acidity N- bond given in figure 1: possibility for chelation (Ramesh and Sabastiyan, 2012). The phthalimide moiety serves as a ‘protected’ form of amine amide imide ammonia. The phthalimide carbonyls increase the acidity of the O O nitrogen (thus allowing formation of its conjugate base). Most importantly, the phthalimide carbonyls protect the nitrogen from NH 2 ‘over alkylation’ thus preventing the formation of quaternary NH2 NH ammonium salts. N-benzoyl phthalimide resembles both classical benzodiazepines and barbituric acid structure. It consists of tricyclic hydrophobic structure comparable to that of O benzodiazepines and possesses a conjugated ureid functional pKa = 38 < pKa = 15 - 17 < pKa = 8 - 10 group as can be found in barbiturates. Size and tridimentional Fig. 1: increasing order of N-H acidity. structure of benzodiazepines and phthalimide backbones are Figure 1: Increasing Order Of N-H acidity similar (Hassanzadeh et al., 2011). Phthalimide is highly acidic in nature due to it easily donate the Phthalimide and N-substituted phthalimides are an proton and form water soluble salts with stronger bases. Reaction important class of compounds because they possess important for salt formation is given in figure 2: biological activities the identifiable structural features for their activity are as: hydrophobic aryl ring, a hydrogen bonding domain, an electron-donor group, another distal hydrophobic site Bhat and Al-Omar (2011). 4-(phthalimide)-substituted phenoxy propanolamines also possessed cardioselective β-adrenergic receptor binding affinity (Jindal et al., 2005). Some marketed pharmaceutical products of phthalimide derivatives are reported in table 1. Fig. 2: Phthalimide salt formation with strong base. Table 1: List for biological active some reported phthalimide derivatives. Imides are more acidic than amides because: S. N. Structure Name Use O 1. The electron-withdrawing inductive of the two adjacent C=O Folpet Fungicide 1. N SCCl groups weakens the N-H bond 3 EFSA (2014) 2. More resonance delocalization of the negative charge. O O Phthalimide have resonance stabilized structures which are shown Capton in figure 3: N SCCl EFSA (2014) 2. 3 Fungicide O O O O O Thalidomide N O Antineoplastic N N 3. Wu et al., N NH Antileprotic O O (2005) O S O O O H2 Phosmet Pesticide, N C S P O 4. EFSA (2013) insecticide and Fig. 3: A Resonance-stabilized anion. O Figure 3: A Resonanance- stabilized anion acaricide. O Phosphodiesterase OMe Often, Phthalimides are oxidative stable, heat retardant, -4 inhibitors solvent resistant, and have superior mechanical properties. The O OEt (PDE-4) for the Apremilast treatment of specific reactivity of imides is a result of the relative acidity of the N CH O Schett et al., asthma and 5. S O (2010) NH group, a direct consequence of the presence of the two O CH H3C NH 3 chronic carbonyl groups. obstructive O It is also observed that the metal complexes are more pulmonary disease Phosphodiesterase active than the free organic ligand. Chelation reduces the polarity -4 inhibitor, anti- O of the metal ion and enhances the lipophilicity or hydrophobicity O inflammatory. It is of metal chelate which favours its permeation through microbial N S O LASSBio-468 a useful lead to 6. N Barbosa et al., therapy of cell wall. The metal chelates may also disturb the respiration O (2012) rheumatoid S process of the microbial cells and thus protein synthesis and arthritis & shock septic syndrome. further growth of the microorganism is hindered. Though the co- Kushwaha and Kaushik. / Journal of Applied Pharmaceutical Science 6 (03); 2016: 159-171 161 Preparation of phthalimide moiety nucleophilic attack of amino group to a anhydride moiety, by Some synthetic reactions for preparation of phthalimide mechanism presented in figure 4: moity summarized in scheme 1: O O O O O H-NH OH OH C 2 C NH OH O NH2 2 O OH P2O5 C C O O O O O phthalic anhydride NH4OH NH 3 2 q. H a N O O C O H OH NH2 2 O O NH O O C O NH C C H C N CH NH2 NH NH O O C C phthalimide C OH O O O FigFig.ure 4:4: MechanismMechanism ofo fimideimid eformationformatio byn b directy dire condensation.ct condensati on O C NH -HCOOH A general and interesting synthetic pathway for the C synthesis of imides by direct condensation using cyclic anhydrides O O or their corresponding dicarboxylic acids and form amide which is C a simple affordable reagent. This approach has the advantage that NH this specific reagent can also serve as solvent, especially for C aliphatic imides. For aromatic cyclic imides with lower solubility O Scheme. 1: Reactions for preparation of phthalimide moity. in formamide, another appropriate solvent can be supplementary used in order to maintain a homogeneous reaction medium and to Mathews Reaction allow the main product to be obtained in high yields. Synthesis of The Mathews’ reaction, a ‘dry’ hydrolysis procedure of phthalimide in presence of formamide reagent given in scheme 3: nitriles by phthalic acid or amides by phthalic anhydride to give the corresponding carboxylic acid and phthalimide. Mathews’ O O O H-CONH O reaction is given in scheme 2: 2 H H N CHO N CH O O O NH COOH OH C C C O OH O R O R C N phthalic anhydride OH OH -HCOOH C C O O O NH O O C O O C R NH2 N C R -H O C phthalimide 2 O C O Schem. 3: Synthesis of imides in the presence of formamide as reagent. C Scheme 3: Synthesis of imides in the presence of formamide as reagent O O BIOLOGICAL ACTIVITY OF PTHALIMIDE H2O DERIVATIVES ALONG WITH SAR STUDY O Cytotoxic Activity C Stanton et al., (2008) demonstrated that presence of NH RCOOH benzothiazole unit attached to nitrogen of phthalimide, exhibits C cytotoxic activity (compound 1) carried out ‘one pot’ condensation O Scheme.