An Overview on Biological Importance of Pyrrolone and Pyrrolidinone Derivatives as Promising Scaffolds

Abstract

Pyrrolones and pyrrolidinones are five-membered heterocycles and are versatile lead compounds for designing powerful bioactive agents. Pyrrolone and pyrrolidinone moieties are among the most essential heterocyclic pharmacophores inducing prominent pharmaceutical effects. Therefore, researchers paid attention to synthesize various pyrrolone and pyrrolidinone derivatives. Numerous methods for the synthesis of pyrrolones and pyrrolidinones offer a great scope in the field of medicinal chemistry. This attractive group of compounds has diverse biological activities like antimicrobial, anti-inflammatory, anticancer, antidepressant, anticonvulsant, etc. The purpose of this review is to classify broad information on the chemistry and pharma­ceutical effects of pyrrolones and pyrrolidinones to open a new perspective for future studies. It is clear that a wide spectrum of pyrrolones and pyrrolidinone derivatives have been synthesized and that most of them have various significant biological activities. Thus, these derivatives can be used for the future development of novel compounds active against different infections and diseases.

1. Introduction

2. Pyrrolone and Pyrrolidinone Derivatives and Their Biological Uses

3. Biological Properties

3.1. Antimicrobial Activity

3.2. Anticancer Activity

3.3. Anti-inflammatory Activity

3.4. Antidepressant Activity

3.5. Anti-HCV Activity

4. Industrial Applications

5. Conclusions

1. INTRODUCTION

Rising concern has been paid to the synthesis of N-heterocyclic compounds due to their useful biologi­cal activities and their role as intermediates in medici­nal and organic chemistry [1]. Heterocyclic compounds are the most essential in the discovery of novel drugs. Various compounds such as alkaloids, amino acids, hemoglobin, vitamins, hormones, most synthetic drugs, and dyes contain heterocyclic ring systems. Nitrogen-containing heterocyclic compounds have been the topic of ample research due to their diverse and prominent biological, agrochemical, and synthetic applications. Pyrrolidin-2-one is a five-membered lactam present in both natural and synthetic compounds [2]. The pres­ence of a pyrrol-2-one fragment in drugs and natural compounds has gained significant attention in the development of novel methods of their synthesis [3]. Pyrrolidin-2-ones have been used in the synthesis of various alkaloids [4] and unusual β-amino acids such as statin and its derivatives [5].

1,3-Dihydro-2H-pyrrol-2-one (pyrrolone) deriva­tives exhibit diverse biological activities such as anti-inflammatory, analgesic [6], antibacterial [7] cardio­tonic [8], antimycobacterial [9], antidepressant [10], antiviral [11], antitumor [12], and other activities [13–18]. Pyrrolones can be synthesized by nucleophilic substitution from the corresponding furanones [6], as well as by different methods based on heterocycliza­tion of various Schiff bases with maleic anhydride [19, 20] and the reaction of furanone derivatives with amines [21–23].

2. PYRROLONE AND PYRROLIDINONE DERIVATIVES AND THEIR BIOLOGICAL USES

Compounds containing a pyrrolone moiety have wide clinical applications. For instance, althiomycin is a naturally occurring alkaloid produced by Strepto­myces althioticus and is used as an antibiotic which inhibits protein synthesis [7]. The pyrrolinone system is also present in natural compounds such as vitamin B₁₂, prodigiosin, bile pigments, and some antibiotics like distamycin [24]. Various pyrrolone and pyrrolidi­none derivatives are structural fragments of plentiful natural compounds such as holomycin, thiolutin [25], bilirubin [26], ypaoamide [27], lactacystin [28], indolocarbazole alkaloids (staurosporine) [29], otero­mycin [30], pyrrocidines A and B [31], thiomarinol A4 [32], quinolactacin C [33], salinosporamide A [34], (–)-azaspirene (angiogenesis inhibitor isolated from the fungus Neosartorya sp.) [35]. Oteromycin is the ET_B receptor antagonist (IC₅₀ = 2.5 pM) [30] (Scheme 1).

Scheme

1.

2-Oxodihydropyrrole ring is present in some alka­loids possessing diverse pharmaceutical activities. Pyr­rolone derivatives are used as optoelectronic materials [36], PI-091 is a platelet aggregation inhibitor [37], and thiomarinol A4 is a potent antibiotic. Inhibitors of HIV integrase [38], cardiac cyclic AMP phosphodiesterase (PDE) [39], and vascular endothelial growth factor receptor [40], neuritogenic [41], pesticidal [42], anti­bacterial, antifungal, and nootropic agents [43], pep­tido­mimetics [44], synthetic intermediates [45], DNA polymerase inhibitors [46], caspase-3 inhibitors [47], anticancer and cytotoxic agents [48], human cyto­megalo­virus (HCMV) protease inhibitors [49], human cytosolic carbonic anhydrase isozyme inhibitors [50], antibiotics [51], and annexin A2–S100A10 protein interaction inhibitors [52] were found among pyrrolone derivatives. Cotinine is an alkaloid present in tobacco and the main metabolite of nicotine [53]. Ethosuximide is a succinimide anticonvulsant used mainly in the treat­ment of the absence of seizures [54].

Despite their diverse usages, existing ways for their synthesis are limited mainly to multicomponent reac­tions (MCRs) [55]. N-Alkyl-5-methylpyrrolidin-2-ones can be synthesized by reductive amination of levulinic acid or its esters. They are widely used as surfactants, solvents, intermediates for pharmaceuticals and agro­chemicals [56]. N-Vinylpyrrolidone (NVP) has been studied for its usages in various fields [57] due to its good biocompatibility, hydrophilic character, and low cytotoxicity [58].

Pyrrolidinone cognition enhancers like piracetam and oxiracetam (Scheme 2) constitute a separate group due to their unique selectivity for brain areas involved in the procedures of acquiring knowledge and memory processes and safe profile [59]. These features make them suitable for chronic therapy in aged patients. Poly(vinylpyrrolidone) (PVP) is an important water-soluble polymer having diverse applications ranging from pharmacology (as a binder in tablets) to nano­particles and membranes for water purification [60]. Blending with PVP improves the anti-fouling prop­erties of biomedical membrane materials used in plasma separation and hemodialysis [61]. The R enan­tiomer of the marine natural product (S)-ypaoamide (Scheme 1) was obtained by asymmetric synthesis. The 3-pyrrolin-2-one moiety is the most important fragment responsible for the immunosuppressive effect [62]. One-pot multicomponent synthesis of substituted 3-pyr­rolin-2-ones 1 using citric acid as a green catalyst in a green solvent under ultrasound irradiation has been reported [63].

Scheme

2.

Optically pure forms (98%) of 1-(2-tert-butyl­phenyl)-5-(methoxymethyl)pyrrolidin-2-one (2) and 1-{2-[tert-butyl(diphenyl)siloxy]phenyl}-5-(methoxy­methyl)pyrrolidin-2-one (3) (including atropisomerism) were prepared from (S)-5-(methoxymethyl)butyrolac­tone in a stereoselective fashion [64]. Monocarbonyl analogs of cyclic imides, N-phenylpyrrolidin-2-ones and N-phenyldihydro-1H-pyrrol-2-ones 4–6, acted as potential protoporphyrinogen oxidase (PPO) inhibitors. The in vitro assay showed that most of the synthesized compounds have good to excellent PPO inhibition activ­ity and significant herbicidal activity [65] (Scheme 2).

Homochiral 5-methylidene-1,5-dihydro-2H-pyrrol-2-one derivatives 7 and 8 were synthesized from amino acid esters, amino alcohols, and chiral amines via photo­oxygenation [51] (Scheme 3). These compounds are useful precursors to various bioactive compounds like alkaloids and unusual amino acids. The multifunc­tional character of these derivatives can contribute to multiple stereoselective reactions like conjugate addi­tions, allylic substitutions, and cycloadditions [66].

Scheme

3.

Kawasuji et al. [38] reported the synthesis of a series of HIV inhibitors 9 containing a 3-hydroxy-1,5-dihydro-pyrrol-2-one moiety as a developmental derivative of 2-hydroxy-3-heteroaryl acrylic acid in­hibi­tors (HHAAs). The cyclic modification of the chelating entity of HHAA provided a favorable con­figuration for the coordination of two metal ions in HIV, which improved not only enzymatic evaluation but also antiviral cell-based assays in many cases [38]. Peptidomimetic analogs 10 were prepared from amino acid-derived tetramic acids as the key starting materials [44] (Scheme 4).

Scheme

4.

Tetra- and pentasubstituted polyfunctional dihydro­pyrrole derivatives 14 and 15 were synthesized by the reaction of but-2-ynedioates, aldehydes, and amines at room temperature or 70°C. Their in vitro pharmaco­logical evaluation against HIV-1 showed a considerable effect with IC₅₀ values in the micromolar range (38– 58 µM) [67]. Dihydropyrrole derivatives 16 and 17 exhibited inhibitory activity against caspase-3 with IC₅₀ values ranging from 5 to 20 µM; one compound (IC₅₀ = 5.27 µM) can be regarded as a superior caspase-3 inhibitor [47]. The synthesis of polyfunc­tional 2-oxodihydropyrrole derivatives 18 by one-pot four-component domino reaction of dialkyl acetylene­di­car­boxylate, amine, and formaldehyde at room tem­perature was reported [68]. N-Substituted 5-methylpyr­rolidin-2-one derivatives 19 were synthesized by one-pot reaction of ethyl levulinate and nitro compounds in presence of nanosized platinum catalyst [69] (Scheme 5).

Scheme

5.

1H-Pyrrol-2(5H)-ones 20 were synthesized from α,β-unsaturated ketones and ethyl nitroacetate under Paal–Knorr conditions [70] (Scheme 6).

Scheme

6.

N-Acyl-5-oxopyrrolidine-2-carbonitriles 21 were prepared by reacting 5-oxopyrrolidine-5-carboxamide (pyroglutamide) with trimethylchlorosilane in presence of zinc chloride as a catalyst [71]. Compounds 22 and 23 were claimed as potentially useful in the treatment of a wide range of diseases like schizophrenia, Alzheimer’s disease, Parkinson’s disease, anxiety, de­pres­sion, stroke, down syndrome, traumatic brain injury, and normal aging. The neurogenic features of the compounds were tested on the proliferation of human embryonic stem cells. The compound efficacy was measured by the increase in cells based on ATP levels. Among the compounds tested, 22 showed the strongest neurogenic features [72]. Six derivatives of 3,3-diphenylpyrrolid-2-one were synthesized and tested for anticonvulsant activity. Among them, 2-imino-1,5-dimethyl-3,3-diphenylpyrrolidine hydro­chloride 24 was effective in mice against maximal electroshock-induced seizures [73]. The anticonvulsant effects of these derivatives depended on the substituent at the 3-position, and the presence of an asymmetric center generally increased the anticonvulsant activity [74]. N-Aryl-3-amino-2-oxo-1,5-dihydropyrrole-4-car­boxylates 25 were synthesized by vitamin B₁₂-cata­lyzed condensation between formaldehyde, dialkyl acetylenedicarboxylates, and amines at ambient tem­perature in ethanol [75]. Pyrrolidinone derivatives 26 were regioselectively synthesized by a one-pot inter­molecular reductive coupling of acrylamides and nitriles in the presence of a cobalt catalyst [76] (Scheme 7).

Scheme

7.

The synthesis and hybridization activities of four stereoisomeric adenine pyrrolidinone PNA analogs toward DNA, RNA, and PNA (peptide nucleic acid) were reported [77] (Scheme 8). A special asymmetric synthesis of pyrrolidinone derivatives 27 starting from 3-acylpropionic acids and N-substituted pyrrolidinone was accomplished by reduction of chiral bicyclic lactams 28 which were prepared from (R)-phenyl­glycinol using triethylsilane and titanium tetrachloride [78]. A series of dihydro-1H-pyrrolo[1,2-a]imidazole-2,5(3H,6H)-diones 29 were prepared and were found to exhibit anti-amnesic activity. The unsubstituted com­pound (29, R¹ = R² = R³ = H, n = 1, dimiracetam) is 10–30 times stronger than oxiracetam [59] (Scheme 9). N-Arenesulfonyl-5-oxopyrrole-2,3-dicarboxylates 30 were synthesized by the reaction of dialkyl acetylene­di­carboxylates, ethyl chlorooxoacetate, and arenesul­fon­amides in the presence of Et₃N and Ph₃P under mild conditions [79] (Scheme 9).

Scheme

8.

Scheme

9.

The synthesis of thiolutin (Scheme 1) and its deriv­atives was achieved by reacting methoxycarbonylacetyl chloride and N-methyl-1-ethoxycarbonyl-2-diethoxy­ethylamine [80]. Holomycin (Scheme 1) and its deriv­atives were synthesized using S-benzyl-L-cysteine ethyl ester as a starting material [81]. Epolactaene (31), a neurogenic substance in human neuroblastoma cells, and its derivatives 32–34 (Scheme 10) showed DNA polymerase activities on mammalian and human DNA topoisomerase II with IC₅₀ values of 25, 94, and 10 µM, respectively [46].

Scheme

10.

A series of substituted 6-amino-4H-[1,2]dithiolo­[4,3-b]pyrrol-5-ones 35 exhibited cytotoxicity effect [48]. An effective synthetic route to functionalized dihydropyrrol-2-one derivatives 36 via domino reac­tion of ethyl glyoxylate with acetylenedicarboxylate and 2 equiv of aromatic amines in the presence of benzoic acid was described [82] (Scheme 11).

Scheme

11.

2-Oxo-2,5-dihydro-1H-pyrrole-4-carboxylic acid alkyl esters 37 were prepared by a novel, facile, and general approach involving multicomponent reaction of aldehyde, amine, and dialkyl acetylenedicarboxylate in the presence of reusable TiO₂ nanopowder [83]. Lactic acid was used as a more valuable and greener additive for the one-pot synthesis of pyrrole derivatives 38 in ethanol at ambient temperature [84] (Scheme 12).

Scheme

12.

Donohoe et al. [85] reported the asymmetric synthesis of the fully elaborated pyrrolidinone core of the β-lactone/γ-lactam antibiotic oxazolomycin A. The procedure included the Birch reduction of an aromatic pyrrole nucleus, RuO₄-catalyzed pyrrolidine oxidation, and diastereoselective organocerium addition to an al­de­hyde (Scheme 13).

Scheme

13.

3. BIOLOGICAL PROPERTIES

Various pyrrol-2-one derivatives exhibited diverse types of pharmacological activities against different types of diseases or disorders.

3.1. Antimicrobial Activity

Pyrrole-2-one derivative 39 exhibited significant activity against S. aureus with a minimum inhibitory concentration (MIC) of 6.5 μg/mL and good activity against E. coli (MIC 15 μg/mL) [86]. 2(3H)-Pyrrolone derivatives were evaluated as antibacterial agents. Compound 40 showed significant antibacterial activ­ity against S. aureus, E. coli, and P. aeruginosa at a level comparable to ciprofloxacin (MIC 6.25 µg/mL) [87]. A series of indolylpyrrolones displayed antibac­terial activity. For instance, compound 41 was equi­potent to chloramphenicol against E. coli with a MIC value of 2.5 µg/mL [88]. A series of pyrrolone and N-benzylpyrrolone derivatives were evaluated for anti­bacterial activity, and compound 42 exhibited the strongest antibacterial effect against E.coli and P. aeruginosa (MIC 6.25 µg/mL) and S. aureus (MIC 12.5 µg/mL) compared to ciprofloxacin (MIC 6.5 µg/mL) [89]. Among the quinolinyl pyrrolone series, compound 43 showed the highest antibacterial activity against E. coli and P. aeruginosa (MIC 12.5 µg/mL) and S. aureus (6.25 µg/mL) [90]. N-Benzylpyrrolone derivative 44 displayed remarkable antibacterial activity against S. aureus and E. coli with inhibition zone diameters of 5 and 7 mm, respectively, compared to penicillin (32 and 15 mm, respectively) [91]. 5-Phenoxyphenylpyrrol-2-one derivatives 45 and 46 showed antimicrobial activity against S. aureus (MIC 20 and 15 µg/mL, respectively) and C. albicans (MIC 10 µg/mL) [92]. Compound 47 showed the most promising antimycobacterial activity with IC₅₀ of 11.34 µg/mL [93] (Scheme 14).

Scheme

14.

Pyrrolidin-2-ones possess both antibacterial and antifungal activity. Aqueous Lutrol® F127 system comprising N-methylpyrrolidin-2-one (NMP) showed antimicrobial effect against S. aureus, E. coli, and C. albicans in a dose-dependent manner with respect to NMP [94]. 2-[1,3-Diphenyl-1H-pyrazol-4-yl]-5-oxo­pyr­rolidine-3-carboxylic acids 48 containing a ben­zenesulfonamide moiety exhibited similar or better antibacterial activity than those of ampicillin, tetra­cycline, gentamycin, and chloramphenicol against B. subtillis, S. aureus, E. coli, and P. aeruginosa [95]. N-Vinylpyrrolidone (NVP)–acrylic acid (AA) co-polymer 49 was synthesized and grafted with N,N-di­ethylaminoethanol through the carboxylic acid group to form an ester. The resulting copolymer showed antibacterial activity against gram-negative Klebsiella aerogenes NCIM-2098, Pseudomonas desmolyticum NCIM-2028, and E. coli NCIM-5051, as well as gram-positive S. aureus NCIM-5022. A significant antibac­te­rial effect was observed at a copolymer dose of 150 µg in all bacterial pathogens tested [96] (Scheme 15).

Scheme

15.

A series of amphiphilic poly(N-vinylpyrrolidone)(PNVP)-b-poly(D,L-lactide)-b-PNVP triblock copoly­mers 50 have been synthesized, and doxorubicin (DOX) was loaded into the block copolymer micelles with a loading efficiency of 37.5%. The antibacterial properties of DOX-loaded micelles were found to be significantly more effective with respect to free DOX [97]. Poly(vinyl alcohol)/poly(vinyl pyrrolidone) (PVA/PVP) hydrogel was obtained by using γ-irradia­tion method. The antimicrobial effect of PVA/PVP hydrogels was tested against S. aureus, P. aeruginosa, B. subtilis, and E. coli, as well as against the fungi Aspergillus fumigatus, Penicillium italicum, Syncepha­lastrum racemosum, and C. albicans [98]. 3,3-Di­fluoropyrrolidin-2-one derivatives 51 were synthesized by the reaction of ethyl 2,2-difluoro-4-iodo-4-(tri­methyl­silyl)butanoate with amines and were found to be biologically significant [99] (Scheme 16).

Scheme

16.

Pyrrocidines A and B, the two antibiotics including 13-membered macrocycles, were isolated from the fermentation broth of a fungus, LL-Cyan426; pyr­rocidine A showed a stronger effect against gram-positive bacteria than that of pyrrocidine B. It was also effective against C. albicans [31]. The pyrrolidinone moiety was found in other antifungal agents such as talaro­convolutin A and the novel platelet-activat­ing fac­tor acetyltransferase inhibitor ZG-1494 (Scheme 17), but the 13-membered macrocycle includ­ing phenyl, ether, pyrrolidinone, and ketone moieties as in talaro­convolutin A is the prime instance discovered in natural products [100, 101].

Scheme

17.

A series of GEQ (Genz-10850) analogs were syn­thesized in a few steps to afford pyrrolidinone and pyrrolidine derivatives 52. These compounds were tested against InhA, an essential target for Mycobac­terium tuberculosis (M.tb) survival. Compounds 52 were found to be quite active with MIC values of 1.4 and 2.8 µM respectively [102]. Photo-cross-linked quaternized chitosan analogs 53 (Scheme 18) prepared by electrospinning exhibited a strong antibacterial effect against gram-positive S. aureus and gram-nega­tive E. coli. These materials can be used for wound dressing. Poly(vinyl pyrrolidone) (PVP) has numerous applications in the biomedical field due to its useful features such as non-toxicity, high hydrophilicity, biocompatibility, excellent complexation features, and film-forming ability [103].

Scheme

18.

3.2. Anticancer Activity

3-Hydroxy-1-(4-methylphenyl)-5-(4-nitrophenyl)-4-pivaloyl-2,5-dihydro-1H-pyrrol-2-one (54) exhibited antitumor activity against lung cancer with growth inhibition of 55% and CNS cancer with growth inhibi­tion of 67% [104]. A series of 5-aryl-5-hydroxypyrrol-2-ones like 55 inhibited the growth of colon and pancreatic cancer models and acted as cholecysto­kinin-1 receptor antagonists with IC₅₀ of 0.008 and 0.4 μM against CCK-A and CCK-B, respectively; this compound was more effective than lorglumide (IC₅₀ 0.17 and >10 µM, respectively) [105]. A series of pyrrolone derivatives showed anticancer activity against HePG2, HCT116, and PC3 cancer cell lines. Compound 56 exhibited comparable activity to doxoru­bicin against Hep-G2 cancer cell line. Compounds 57 and 58 showed good cytotoxic activity against Hep-G2 cancer cell line with IC₅₀ of 11.47 and 7.11 μM, respectively, compared to paclitaxel (IC₅₀ 0.73 μM). These two compounds displayed promising inhibition for tubulin polymerase [106]. A series of indolyl-pyrrolone derivatives were tested as PIM1 kinase in­hibitors, and compound 59 showed the highest activity with ID₅₀ of 4.5 μM [107] (Scheme 19).

Scheme

19.

A series of helicid–pyrrolidone derivatives 60 (Scheme 20) were tested for their anticancer effect against human SKOV3 cells. Two derivatives showed a high anticancer effect against this cell line with an IC₅₀ range of 0.22 to 6.5 μM, respectively, and were more potent than 17AAG, the heat shock protein 90 (Hsp90) inhibitor [62]. 1-Substituted 4-aroyl-3-hydroxy-5-phenyl-1H-pyrrol-2(5H)-one derivatives 61 (Scheme 20) were synthesized as Annexin A2-S100A10 protein inhibitors. Selected analogs inter­rupted the complex structure of Annexin A2 and S100A10 both in broken cell preparation and inside MDA-MB-231 breast cancer cells [52]. The toxic effect of NEP (N-ethylpyrrolidone) was exhibited when used by gavage to Sprague-Dawley rats at doses of 5, 50, and 250 mg/kg/day for four weeks. Finally, 28 days of repeated oral exposure to NEP at doses of up to 250 mg/kg/day resulted in mild renal and hepatic effects in rats. The adverse effects consisted of a re­vers­ible reduction in body heaviness gain and a growth in urine volume [108]. Dithiolopyrrolone derivatives 62 constitute a class of strong natural antibiotics effective against both gram-negative and gram-positive bacteria. They include a 4H-[1,2]dithiolo[4,3-b]pyrrol-5-one chromophore, and have recently attracted growing attention in synthetic and biological studies as antiproliferative factors [109]. Compound 63 was selected for its anticancer effect tested on human SKMEL-28 V+ xenografts both in monotherapy and in combination with Taxol or Cisplatin, where potent effectiveness was found [48] (Scheme 20).

Scheme

20.

More than 300 nitrogen-containing natural products have been isolated and identified from marine cyano­bacteria [110]. Among these, microcolins A and B isolated from a Venezuelan sample of the blue-green algae Lyngbya majuscule [111] showed very effective immunosuppressive and antiproliferative effects [112]. Jamaicamides A–C belong to a class of strong neuro­toxins isolated from the Jamaican strain of L. majuscule [48, 113] (Scheme 21).

Scheme

21.

3.3. Anti-inflammatory Activity

A series of pyrrol-2-one exhibited anti-inflammatory activity, and compound 64 has comparable activity to diclofenac [86]. Quinolinylpyrrolone derivatives were tested as anti-inflammatory agents using carrageenan-induced paw edema. Compounds 65 and 66 produced 53% and 63% inhibition, respectively. The results indicated that the conversion of secondary NH group into tertiary moiety by introducing a benzyl substituent increased the anti-inflammatory activity [90]. Com­pounds 67 and 68 showed an edema inhibition percent­age comparable to that of diclofenac (71.47, 76.22, and 80.98%), respectively. These compounds suppressed the TNF-a level by 60.90 and 65.03%, respectively, compared to indomethacin (68.40%) [114]. A series of furan-2(3H)-ones and their 1-benzylpyrrol-2(3H)-one analogs, in particular compounds 69 and 70 displayed comparable anti-inflammatory activity to ibuprofen with inhibition % of 88.88, 89.50, and 89.50, respec­tively. These two compounds also showed superior gastric safety with protection % of 57.83 and 59.03 compared to ibuprofen (65.06%) and reduced lipid peroxidation to a greater extent than did the reference drug [9, 115]. Pyrrolone derivatives 71 and 72 exhibited significant anti-inflammatory activity which was comparable to that of diclofenac and a twice as high safety profile as that of diclofenac (1.3, 1.3, and 2.6, respectively) [116] (Scheme 22).

Scheme

22.

3.4. Antidepressant Activity

Pyrrolone 73 exhibited significant antidepressant potency, selectivity, and pharmacokinetic profile and showed nanomolar affinity to 5-HT2C receptor [117] (Scheme 23).

Scheme

23.

3.5. Anti-HCV Activity

A series of pyrrolone derivatives were tested for their antiviral activity against the hepatitis C virus (HCV). Compound 74 showed moderate interference with the helicase unwinding activity with IC₅₀ of 438 μM and proved to be less potent than primuline (IC₅₀ 10 µM) [11]. A series of bicyclic octahydrocyclo­hepta[b]pyrrol-4(1H) one derivatives exhibited anti­viral activity against HCV. For example, N-tosyl deriv­ative 75 was characterized by EC₅₀ values of 1.8 and 4.5 µM in genotypes 1b and 2a, respectively. This compound did not affect HCV NS5B, IRES, and NS3 helicase [118] (Scheme 24).

Scheme

24.

4. INDUSTRIAL APPLICATIONS

The main features of 1-vinylpyrrolidin-2-one (76) are its polarity characteristics and polymerizability to form soluble poly(vinylpyrrolidone) (PVP) or insoluble polyvinylpolypyrrolidone (PVPP, a highly cross-linked modification of PVP). PVP-based products are used in various fields are produced on large scale. PVP is used as an excipient in pharmacological formulations like tablets, food additive, and UV-durable inks. 1-Vinyl­pyr­rolidin-2-one is capable of permeating skin [57, 58]. An analytical procedure has been developed for the determination of 1-vinyl-2-pyrrolidone–mercapturic acid (VPMA) in urine using electrospray liquid chro­matography–tandem mass spectrometry (ESI-LC/MS) column switching approach [119].

N-Ethyl-2-pyrrolidone (NEP, 77) is an industrial chemical used as a solvent, catalyst, and surfactant. It was proposed as a substitute for its analog, N-methyl-2-pyrrolidone (NMP, 78), in many areas of usage, including coatings industry and cleaning of metals, glass, and plastics [108]. N-Methyl-2-pyrrolidone (NMP) is the 4-methylaminobutyric acid lactam. It is a colorless thermally stable liquid with low viscosity, low toxicity, and good biocompatibility. The dissolving power of NMP is similar to those of ethanol and dimethyl sulfoxide (DMSO). NMP increases trans­dermal sorption of some drugs like ibuprofen, flurbi­profen, phenolsulfonphthalein, and estradiol. It is isolated from a marine sponge for biosynthesis [120]. NMP can be used in the parenteral preparation of drugs since its increased solubilizing potency and low viscosity are the main factors for fine-gauge needles or microcatheters [121]. It is an important solvent used in extraction, purification, and crystallization of drugs [122]. NMP is used in nanoemulsions for the trans­dermal delivery of granisetron hydrochloride [123]. Many drugs contain NMP in their topical formulations as an absorption improver, in particular fluoxetine hydrochloride [124], lidocaine, granisetron hydro­chloride [122], griseofulvin, [125] insulin [126], estradiol [125–127], bupranolol [128], spantide II [129], levonorgestrel [127], luteinizing hormone-releasing hormone [130], ibuprofen, flurbiprofen [131], and morphine hydrochloride. An additional syringe wash with NMP can improve the stability of injections using gas chromatography syringes by getting better peak symmetry and reproducibility [132].

5. CONCLUSIONS

Pyrrolidinone derivatives are regularly investigated, and this review mainly focused on different significant biological activities of pyrrolidinone derivatives such as anti-inflammatory, antibacterial, antimicrobial, anti­coagulant, antihypertensive, antimycobacterial, and most importantly their anticancer activities [133, 134]. Medicinal chemists from all over the world have synthesized different substituted pyrrolone derivatives to explore their biological activity and their drug target. Despite the known biological activities of these scaffolds, there is a direction in the future toward the use of this nucleus in the design of novel molecules with effective biological activities.