2(3H)Pyrrolone – a Biologically Active Scaffold (A Review)

Introduction

Pyrrolones are the five-membered heterocyclic lactams which are either Δ³ (1) or Δ⁴ (2) derivatives described by several authors^1,2.

 

Scheme 1 Click here to View Scheme

 

These are also known as pyrrolin-2-ones. The γ-lactone ring present in butenolide (3) derivatives possess significant reactivity and has been utilized in the synthesis of pyyrolone derivatives with potent biological acitivity^3,4. Pyrrolone and N-benzyl pyrrolone derivatives were reported to have good antifungal, antibacterial and anti-inflammatory activities⁵. Pyrrolones have been proved important as chiral synthons used in the preparation of a variety of bioactive compounds⁶. The frequent use of these compounds as chiral intermediates provides a fast universal method for the determination of absolute configuration.⁷ The chemistry of these versatile building blocks has been explored by a number of groups. Because of their multifunctional nature, these heterocycles can take part in several stereo selective transformations like conjugate additions ^8,9, cycloadditions^10,11, acyliminium ion chemistry¹² and allylic substitution¹³.

Cycloadditions

 

Scheme 2:  Cycloadditions Click here to View figure

 

Conjugate additions

 

Conjugate additions Click here to View figure

 

Acyliminium ion 

 

Acyliminium ion   Click here to View figure

 

The interest concerning these pyrrolinones is in part due to the presence of pyrrolic systems, which are also present in the natural products¹⁴ viz vitamin B₁₂¹⁵, prodigiosin¹⁶, bile-pigments¹⁷ and some antibiotics like distamycin.¹⁸

 

Figure Click here to View figure

 

Synthetic methodology of pyrrolinones:

Synthesis of pyrrolones & N-benzylpyrrolones from 3-arylidene-5-biphenyl-2(3H) furanones :

 

Synthesis of pyrrolones & N-benzylpyrrolones from 3-arylidene-5-biphenyl-2(3H) furanones  Click here to View figure

 

3-Arylidene-5-biphenyl-2(3H) pyrrolones (7) have been prepared by treating 3-arylidene-5-biphenyl-2(3H) furanones with dry ammonia gas in absolute ethanol. 3-Arylidene-5-biphenyl-1-benzyl-2(3H) pyrrolones (8) have been reported to be synthesized by reacting appropriate furanones with benzylamine in dry benzene to give γ-ketobenzylamides which on lacatamization in 6N HCl give N-benzyl-pyrrolones⁵.

 

Synthesis of 1-substituted-5-aryl-4-aroyl-3-hydroxy-3-pyrrolin-2-ones: From ester of pyruvic acid derivatives Click here to View figure

 

Synthesis of 1-substituted-5-aryl-4-aroyl-3-hydroxy-3-pyrrolin-2-ones:

From ester of pyruvic acid derivatives

The reaction between equimolar amounts of esters of  pyruvic acid with a mixture of aromatic aldehydes and amines gives 1-substituted-5-aryl-4-aroyl-3-hydroxy-3-pyrrolin-2-ones (9) ^{7, 19,-21}.

 

Figure Click here to View figure

 

Instead of ester of pyruvic acid derivatives, esters of 4-aryl-2,4-dioxobutanoic acids²² with aliphatic amines like 2-(N,N-diethylamino)ethylamine and aldehydes in ethanol at room temperature gives good yield.

 

Figure Click here to View figure

 

Reactions conducted in aqueous alcohol mixtures with short time heating gives good yield⁷.

 

Figure Click here to View figure

 

Pyrrolinones so obtained appear as light-yellow crystalline substances insoluble in water and soluble in ethanol, chloroform and DMSO.^20-22All these compounds develop a characteristic intense cherry-red colour on reacting with an alcoholic solution of iron chloride³⁷. 

 

Figure Click here to View figure

 

The interaction of benzoylpyruvic acid with mixture of aromatic aldehydes and amines involves several competing reactions. For this reason, the products include both substituted 4-benzoyl-3-hydroxy-2,5-dihydro-2-pyrrolones, benzoylpyruvic acid amides.²³ 1-(4-Antipyryl)-5-aryl-4-aroyl-3-hydroxy-3-pyrrolin-2-ones (16) have been synthesized by reacting esters of 4-aryl-2,4-dioxobutanoic acids with Schiff bases (15), which are obtained by the condensation of aromatic aldehydes with 4-amino antipyrine²². To a solution of 0.001 mole of a methyl ester of 4-aryl-2,4-dioxobutanoic acid in ethanol, a mixture of ethanolic solutions of benzaldehyde (0.001 mole) and 4-amino antipyrine (0.001 mole) was added at room temperature. The excess of solvent is distilled off and the product is crystallized from ethyl acetate²².

 

Figure   Click here to View figure

 

 Synthesis of unsaturated hydroxy-butyrolactones under phase transfer conditions

Unsaturated hydroxy-butyrolactones or 2-alkylidene-3-ketocarbocyclic acids (17) can be synthesized by carbonylation of α-ketoalkynes in the presence of Ni(CN)₂ under phase-transfer conditions²⁴. 

 

Figure Click here to View figure

 

By changing the reaction conditions it is possible to obtain hydroxyl-butyrolactams (18) in good yields²⁵.

 

Figure   Click here to View figure

 

However the formation of hydroxylactams by hydrocyanation of α-ketoalkynes in water under mild conditions, it is possible to obtain hydroxyl butyrolactams (19) and (20)²⁶

 

Figure Click here to View figure

 

Synthesis of Δ³ and Δ⁴-pyrrolinones by oxidation of pyrrole:

Using sulfoxide electrophillic sulfenylation:

Δ³ Pyrrolinones with very small amounts of Δ⁴ isomer can be obtained by the oxidation of pyrrole²⁵ during sulfoxide electrophilic sulfenylation (SES). Sulfoxide electrophilic sulfenylation (SES) is a useful technique for the synthesis of heterocycles. Pyrrole-containing sulfoxides have been exploited for intramolecular sulfenylation to form a wide variety of N,S-heterocycles.

 

Figure Click here to View figure

 

Typical (SES) reaction conditions via two possible reaction pathways accounts for pyrrolinones formation during SES cyclization.^27-29 Upon treatment with trifluro acetic acid (TFAA) (DMF, room temperature) compound (21) produced the expected SES product only as minor product(23) and the major product was the pyrrolinones (22). Similarly compound (24) produced a mixture of pyrrolinones (25) and (26) SES cyclization product^30-32.

 

Figure Click here to View figure

 

Synthesis of an enantioselective enzymatic transesterification:

N-Methyl derivatives of Δ³-pyrrolinones have been synthesized from pyrroles using an enantioselective enzymatic transesterification³³. N-Methyl pyrrolinone (28) have been synthesized by photo-oxidation of N-methylpyrrole (27) followed by esterification. Subsequent enzymatic resolution by Candida antarctica mediated transesterification has been reported.

 

Figure   Click here to View figure

 

Synthesis of N-acyl derivatives of Δ³-pyrrolinones from methoxy furanones:

N-Acyl derivatives of Δ³-pyrrolinones (30) have been reported to be  synthesized from 5-methoxy-3-furan-2-one (29) using an enantioselective enzymatic transesterification.³³

 

Figure Click here to View figure

 

Synthesis of C-5 substituted –δ³-pyrrolin-2-ones:

From nitrone:

C-5 substituted-δ³-pyyrollinones (31)have been synthesized from nitrones¹⁷.

 

Figure  Click here to View figure

 

The addition of lithium propiolate (33) to nitrone (32) takes place with complete syn selectivity and in quantitative yield to afford the prop-2-ynyl hydroxylamine.^34,35

 

Figure   Click here to View figure

 

The selective hydrogenation of the triple bond was achieved in 1 hr at ambient temperature and 1 atm pressure using the lindlar catalyst. The corresponding allylhydroxylamine was obtained in quantitative yields³⁶. Further deoxygenation of hydroxylamine was accomplished with Zn-Cu catalyst in acetic acid as a solvent. Under these conditions, resulting allylamine could not be isolated since it cyclized spontaneously to the pyrrolin-2-one (34) which was obtained in 84% yield after purification by column chromatography³⁷. This is a straight forward method of preparing enantiomerically pure δ³-pyrrolin-2-ones which can serve as templates for the construction of a number of highly functionalized 2-pyrrolidones and pyrrolidines. The latter has attracted much attention due to their ability to act as selective glycosidase inhibitors with a variety of therapeutic effects.^38-40

From N-boc protected amino acids:

N-boc protected 5-methyl-δ³-pyrrolinone (37) has been synthesized from N-boc protected amino acids (35) by Jouin⁴¹ and further improved by Ma⁴². (5S)-N-tert-butoxycarbonyl-4-hydroxy-5-methyl-3-pyrroli-2-one (36) was synthesized from N-boc protected L-alanine and meldrum’s acid which was then reduced with NaBH₄⁴² and hydroxyl group of resulting compound was eliminated to get N-boc protected 5-methyl-pyrrolinone^43,44.

 

Figure   Click here to View figure

 

From (S)-malic acid:

5-Isopropoxy-δ₃-pyrrolin-2-ones (39) can be obtained via stereo-selective synthetic route starting  from (S)-malic acid (38)^43,45.

 

Figure   Click here to View figure

 

Synthesis of isomeric pyrrolones by flash vacuum pyrrolysis of bis aminomethylene derivatives of meldrum’s acid:

Under flash vacuum pyrrolysis^46,47 (FVP) conditions (600°C, 0.005 Torr) bis-amino methylene derivatives of meldrum’s acid (40) were transformed into mixtures of the pyrrolones (41). FVP  provides a simple and direct synthetic route to 1-substituted-3-hydroxypyrroles and their tautomers i.e. 1H-pyrrol-3-(2H)-ones. Its mechanism was investigated by Brown and Eastwood⁵⁷ and more recently by Wentrum et al.⁴⁸.

 

Figure  Click here to View figure

 

Spectral Properties:

Circular dichroism (CD) spectra:

In case of the simple 3-pyrrolin-2-ones bearing no substituents on the olefinic bond, the maximum of the π-π* cotton effect is observed at λ_max 200 nm. The maximum of the π-π * cotton effect is seen at longer wavelength, around 230 nm, where the UV spectrum displays a broad shoulder. The 3-pyrrolin-2-ones with an oxygen substituent at C (5) generally display much stronger cotton effects than those containing alkyl group. A methoxy substituent at C(3) shifts the positions of the π-π * band to λ_max 230 nm, as does tosyl substitution at N¹. 3-Pyrrolin-2-ones with an imide-type group (R² = acyl) display an additional cotton effect at 280 nm, presumably due to a second π-π * transition. Such double π-π * cotton effects are observed at 250 nm in a saturated imides⁴³ and result from the transitions involving combinations of the carbonyl n  orbitals of opposite symmetry. This cotton effect however is much smaller than the n-π* cotton effects caused primarily by the α,β-unsaturated lactam chromophore^49-52.

Spectral data of representative compounds: 

 

Figure  Click here to View figure

¹H NMR: In structure A, the chemical shift (δ) value at 6.44-6.95 ppm confirmed the presence of proton at C-4 of pyrrolone ring.  Also, the chemical shift ranging between 7.39- 7.68 showed the presence of olefinic proton at C-3 position. Both these peaks appeared as singlet which further evidenced that these are not aromatic protons. The proton attached to N of pyrrolone ring generally appeared at δ = 7.92-8.10.  The formation of benzyl pyrrolones (structure B) could be confirmed by disappearance of -NH proton and appearance of a sharp singlet at δ = 4.74-4.88. (methylene proton). IR: The IR spectra of structure A showed the absorption bands at 1680-1710 cm^-1 due to the stretching vibrations of the lactam carbonyl groups²¹. MS: Generally, the mass spectra 3(H)-pyyrolin-2-ones showed peaks at M⁺ and M⁺– Ar with high intensities²⁶.

Biological Action:

Various types of pharmacological activities shown by pyrrolinones are as follows:

Antimicrobial activity:

A series of 5-aryl-4-acyl-1-(N,N-dimethylaminoethyl)-3-hydroxy-3-pyrrolin-2ones were found to show weak  bacteriostatic activity⁵⁵. Also various compounds of type 1-substituted-5-aryl-4-aroyl-3-hydroxy-3-pyrrolin-2-ones and derivatives were found to be bacteriostatic against Staphylococcus aureus and Escherichia coli³⁹.  3-Arylidene-4-(biphenyl)- 2(3H)-pyrrolones ⁵, 3-Arylidene-5-(substituted)- 2(3H)-pyrrolones ⁵⁶, 3-Arylidene-5-(4-phenoxy phenyl)-2(3H)-pyrrolones⁵⁷ and 3-Arylidene-5-(4-Methyl)- 2(3H)-pyrrolones⁵⁸were found to have good antimicrobial activity.

List of compounds showing anti microbial activity 

 

List of compounds showing anti microbial activity  Click here to View figure

 

Antiviral activity:

A number of synthesized pyrrolinones has shown antiviral activity. N-methylated-3,5-linked bis-pyrrolin-4-ones derivatives have been found to be orally bioavailable inhibitors of the HIV-1 protease^59-62.

 

Figure Click here to View figure

 

Antitumour activity:

The compound 3-hydroxy-5-nitrophenyl-4-pivaroyl-2,5-dihydro-2-pyrrolone (43) exhibits antitumour activity¹⁹and  inhibited the growth of lung cancer (Tumour Growth = 45%) and CNS cancer (Tumour Growth = 33%)¹⁹.

 

Figure   Click here to View figure

 

Nootropic / Antiamnesic activity:

The compounds 3-hydroxy-5-nitro phenyl-4-pivaroyl-2,5-dihydro-2-pyrrolones (44)¹⁹ and 4-Acetyl-5-(3,4-dimethoxy-phenyl)-3-hydroxy-1-1(2-piperidin-1-ylethyl)-2,5-dihydro-2-pyrrolones (45)⁶³ were found to have antiamnesic activity. The drugs were characterized by the ability to eliminate amnesia, increase the latent period and change the number of animals in the test group visiting a dark compartment of the experimental box. The time of stay in the light and  dark compartments was determined three minutes after drug injection¹⁹. All synthesized compounds favored recovery of the memory trace in the test rats, as evidence by a drop in the number of animals visiting the dark compartment and the time of stay there⁶⁴.

 

Figure   Click here to View figure

 

Anti-inflammatory activity:

2-Arylidene-4-biphenyl-but-3-en-4-olides and their corresponding pyrrolones and N-benzyl-pyrrolones⁴ (Table 1), 2-Arylidene-4-(4-phenoxy-phenyl) but-3-en-4-olides and their corresponding pyrrolones and N-benzyl-pyrrolones⁵⁷ (Table 2) were found to exhibit anti-inflammatory activity. A series of 3-Arylidene-5-(substituted aryl)-1-benzyl-2(3H)-pyrrolones  were also  found to have promising anti-inflammatory activity⁵⁶ (Table 3). But the anti-inflammatory activity decreased by the substitution of oxygen atom of butenolide ring with NH (pyrrolones), while substitution of oxygen atom with benzylamine moiety (N-benzyl-pyrrolones) markedly increased the activity. A series of 3-arylidene-5-(4-chloro-phenyl)-2(3H)-benzyl pyrrolones  were  found to show promising anti-inflammatory activity⁶⁵. (Table4).

 

Table 1. Anti-inflammatory activity of 2-Arylidene-4-biphenyl-but-3-en-4-olides and their corresponding pyrrolones and N-benzyl-pyrrolones.  Click here to View table

 

 

Table 2. Anti-inflammatory activity of 2-Arylidene-4-(4-phenoxy-phenyl)but-3-en-4-olides and their corresponding pyrrolones and N-benzyl-pyrrolones.  Click here to View table

 

 

Table 3. Anti-inflammatory activity of  3-Arylidene-5-(substituted aryl)-1-benzyl-2(3H)-pyrrolones.  Click here to View table

 

 

Table 4. Anti-inflammatory activity of 3-arylidene-5-(4-chloro-phenyl)-2(3H)-benzyl  pyrrolones.  Click here to View table

 

Analgesic activity:

A series of 3-Arylidene-4-(4-phenoxy-phenyl)1-benzyl-2-(3H) pyrrolones ⁵⁷ and 3-Arylidene-4-(4-chloro -phenyl)1-benzyl-2-(3H) pyrrolones⁶⁵ were found to have promising analgesic activity. The compounds of type 3-hydroxy-1,5-diaryl-4-pivaloyl-2,5-dihydro-2-pyrrolones and their derivatives were found to have potent analgesic activity⁶³.

 

Figure   Click here to View figure

 

Some compounds showing good analgesic activity are shown in Table 5.

 

Table 5. Analgesic activity of pyrrolones.  Click here to View table

 

A series of disubstituted-1-(2-amino ethyl)- 3-hydroxy-3-pyrroline-2-ones and their derivatives have been reported to posses showed analgesic activity.⁶⁶

 

Figure Click here to View figure

 

Conclusion

It may be concluded that pyrrolones and N benzyl pyrrolones exhibit a broad spectrum of biological activities like anti-inflammatory, anticancer, antibacterial, antifungal, antiviral, analalegic and anti-HIV activities. Thus the pyrrolone scaffold still remains as therapeutic target for the development of new leads in the modern medicinal chemistry. The physical, chemical and the pharmacokinetic properties of pyrrolones still maintains the importance of this moiety inspite of the rising levels of drug resistance in today’s era.

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