Efficient synthesis of piperazine-2,6-dione and 4-(1H-indole-2-carbonyl)piperazine-2,6-dione derivatives and their evaluation for anticancer activity

Condensation of iminodiacetic acid 1 with various amines i.e., cyclohexanamine, 1-(3-aminopropyl)imidazole, pyridin-2-ylmethanamine, pyridin-3-ylmethanamine, pyridin-4-ylmethanamine, 2-morpholinoethanamine, thiophen-2-ylmethanamine, 2-(thiophen-2-yl)ethanamine, furan-2-ylmethanamine, 2-(pyrrolidin-1-yl)ethanamine, and 1-(3-aminopropyl) pyrrolidin-2-one 2a–k under microwave irradiation gave the corresponding piperazine-2,6-dione derivatives 3a–k in quantitative yields. Piperazine-2,6-dione derivatives 3a–k on condensation with 1H-indole-2-carboxylic acid under microwave irradiation gave the corresponding 4-(1H-indole-2-carbonyl)piperazine-2,6-dione derivatives 4a–k in quantitative yields. All the synthesized compounds (3a–k & 4a–k) were purified by crystallization and characterized by spectroscopic means. On screening at a concentration of 10 μM, compounds 3k, 4e, 4i breast (T47D), 4j lung (NCI H-522), 3i colon (HCT-15), 4e ovary (PA-1), and 4g liver (HepG-2) exhibited good anticancer activity.     

Synthesis and characterization of flurbiprofen hydrazide derivatives as potential anti-HCV, anticancer and antimicrobial agents

A novel series of new flurbiprofen hydrazide derivatives 2-(2-fluorobiphenyl-4-yl)-N′-[(substituted phenyl/5-nitro-2-furyl)methylene]propanehydrazide (3a–k), 2-(2-fluorobiphenyl-4-yl)-N-(2-substituted-4-oxo-1,3-thiazolidine-3-yl)propanamide (4a–b, 4d–k), 2-[2-(2-fluorobiphenyl-4-yl) propanoyl]-N-substituted hydrazinecarbothioamide (5a–h) and 2-(2-fluorobiphenyl-4-yl)-N′-[(3-methyl-4-oxo-1,3-thiazolidin-2-ylidene]propanehydrazide (6a–b, 6e and 6g) has been synthesized in this study. All synthesized compounds were screened for antimicrobial activity against various bacterial and fungal strains. Additionally, compounds were evaluated for the ability to inhibit Hepatitis C virus NS5B polymerase. The most active 4-thiazolidinone compound was 4k (SGK119) with 67.0 % and thiosemicarbazide compound was 5d (SGK123) with 69.50 % inhibition at 200 μM against hepatitis C virus NS5B RNA polymerase. Anticancer activity of the selected compounds (3i, 3j, 3h, 4d, 4i and 6b) was determined at a single dose towards the full panel of 60 human cancer cell lines by the National Cancer Institute (NCI). 2-(2-Fluoro-4-biphenylyl)-N-[2-[4-(trifluoromethyl)phenyl]-4-oxo-1,3-thiazolidine-3-yl]propanamide 4d, containing thiazolidinone ring, demonstrated the most marked effect with 20.80 % growth percent on leukaemia cancer cell line SR at 10^?5 M. The results demonstrated that none of the compounds tested have anticandidal and antifungal activities, but two of them (4a and 4i) showed antibacterial inhibition against Micrococcus luteus, and Staphylococcus cohnii and Staphylococcus aureus, respectively.     

Synthesis of some novel C-5 and N-3 substituted 2-(2-hydroxyphenylimino)thiazolidin-4-one derivatives with broad-spectrum antimicrobial activity

In the present article, compounds 5-((substituted-2-chloroquinolin-3-yl)methylene)-2-(2-hydroxyphenylimino)thiazolidin-4-ones (3a–k), 1-(2-(2-(2-hydroxyphenylimino)-4-oxothiazolidin-3-yl)-2-oxoethyl)pyrimidine-2,4,6(1H,3H,5H)-trione (6) and 1-(2-(5-((substituted-2-chloroquinolin-3-yl)methylene)-2-(2-hydroxyphenylimino)-4-oxothiazolidin-3-yl)-2-oxoethyl)pyrimidine-2,4,6(1H,3H,5H)-triones (8a–k) have been synthesized by substituting C-5 and N-3 position of parent compound 2-(2-hydroxyphenylimino)thiazolidin-4-one (1). Structures of the newly synthesized compounds were assigned on the basis of elemental analyses, IR, ¹H NMR, ¹³C NMR, and mass spectra. In vitro antimicrobial activity of target compounds (3a–k, 6 and 8a–k) was investigated against two Gram-positive, two Gram-negative bacteria and three fungal strains. Among the tested compounds (3e), (3f), and (3h) showed very good antifungal activity, while compound (6) showed very good antibacterial activity. Compounds (8e), (8f), and (8h) showed excellent antifungal and antibacterial activities.     

Synthesis and biological studies of a novel series of 4-(4-(1H-imidazol-1-yl)phenyl)-6-arylpyrimidin-2-amines

A novel series of eleven 4-(4-(1H-imidazol-1-yl)phenyl)-6-arylpyrimidin-2-amines has been prepared from synthesized 3-[4-(1H-imidazol-1-yl) phenyl]prop-2-en-1-ones and evaluated for phosphodiesterase (PDE) inhibition and antimicrobial activities. N-arylation of imidazole with 4-fluorobenzaldehyde using hexadecyltrimethylammonium bromide as catalyst gave 4-(1H-imidazol-1-yl) benzaldehyde which on treatment with substituted acetophenones yielded corresponding chalcones (1a–1k). Each chalcone on further reaction with guanidine hydrochloride resulted in title compounds (2a–2k). Pyrimidines thus synthesized were subjected to biological studies. Some compounds showed marked activities in PDE inhibition and anti-bacterial and anti-fungal bioassays.     

Synthesis of β-amino carbonyl derivatives of coumarin and benzofuran and evaluation of their biological activity

A series of β-amino carbonyl compounds containing coumarin (4a–h) and benzofuran (6a–i) moieties was synthesized by a three component Mannich reaction of 3-acetyl-2H-chromen-2-one (1) or 1-(1-benzofuran-2-yl) ethanone (5) with p-substituted aromatic aldehydes (2a–g) and aromatic amines (3a–b) in the presence of cerric ammonium nitrate as a catalyst. The newly synthesized compounds were screened for antimicrobial and antioxidant activities. Compounds 4b, 4e, 4f, 6f, 6g, and 6i showed microbial inhibition with minimal inhibition concentration ranging between 0.040 and 0.500 mg/mL, compounds 4b, 4c, 6c, 6e, and 6i showed promising free radical scavenging activity and compounds 4b, 4f, 6c, 6d, and 6h showed good chelating ability with Fe²⁺ ions. The synthesized compounds were studied for docking on the enzyme, glucosamine-6-phosphate synthase to predict the binding affinity and orientation at the active site of the receptor.     

Synthesis and antimicrobial screening of 4-thiazolidinone and 2-azetidinone derivatives of piperazine

The Schiff’s bases 3a–3h were synthesized by reacting substituted/unsubstituted aromatic aldehydes 2a–2h with 1-(2-aminoethyl)-piperazine 1. A series of novel aryl-3-(2-piperazin-1-ylethyl)-1,3-thiazolidin-4-one 4a–4h and 3-chloro-1-{2-[4-(chloroacetyl)piperazin-1-yl]ethyl}-4-arylazetidin-2-one 5a–5h were synthesized from the Schiff’s bases of 1-(2-aminoethyl)-piperazine 3a–3h. The structures of synthesized compounds were confirmed by analytical (C, H, and N) and spectral (FT-IR, ¹H NMR, ¹³C NMR, and Mass) data. The compounds 4a–4h and 5a–5h were screened for antimicrobial activity. The compounds 4a, 4d, 4f, 4g, 5a, 5d, 5f, and 5g exhibited substantially significant antibacterial as well as antifungal activity.     

Synthesis of some new indolo[2,3-c]isoquinolinyl pyrazoles, -1,3,4-oxadiazoles and their biological activities

A new series of novel compounds [10-substituted 6H, 7H-indolo[2,3-c]isoquinolin-5-one-6-yl]carbohydrazides (3a–c), 1-[10-substituted 6H, 7H-indolo[2,3-c]isoquinolin-5-one-6-yl]fomyl-, -3′,5′-dimethylpyrazoles (4a–c), -3′,5′-diphenylpyrazoles (5a–c), -3′-methylpyrazol-5′-ones (6a–c) and -1′,3′,4′-oxidiazole-2′-thiones (7a–c) linked to indoloisoquinoline at position-6 through formyl bridge was prepared. The structures of these newly synthesized compounds were confirmed by their spectral studies and elemental analysis. These compounds have been screened for their antimicrobial and antioxidant activities. Compounds 4a, 4b, 5a, 5b, 5c, 6b, 7a, and 7c exhibited the maximum zone of inhibition against A. niger, A. flavus, and A. fumigatus. Compounds 4a, 5a, 5c, 6b, 6c, 7a, and 7b showed good antibacterial activity. Compounds 4b, 4c, 5b, 5c, 6a, 6b, 7a, 7b, and 7c showed good radical scavenging activity compared with standards.     

Synthesis,antimicrobial, and antioxidant activity of benzofuran barbitone and benzofuran thiobarbitone derivatives

The synthesis of novel series of benzofuran derivatives, containing barbitone moiety, 5-[(2/4-substitutedphenyl)(5-substituted-1-benzofuran-2-yl) methylidene]pyrimidin-2,4,6(1H,3H,5H)-trione (4a–i) and thiobarbitone moiety, 5-[(2/4-substitutedphenyl)(5-substituted-1-benzofuran-2-yl)methylidene]-2-thioxodihydropyrimidin-4,6(1H, 5H)-dione (5a–i) have been reported. The target compounds (4a–i) and (5a–i) were synthesized by the Knoevenagel condensation of (5-substituted-1-benzofuran-2-yl)(2/4-substitutedphenyl) methanone (3a–i) with barbituric acid and thiobarbituric acid, respectively, in acid medium. These compounds were screened for the antimicrobial and antioxidant activities. From antimicrobial activity results it was found that compounds 4a, 5a, 4c, and 5c displayed good antibacterial and antifungal activity against all tested strains. Further, the synthesized compounds were studied for docking on the enzyme, Glucosamine-6-phosphate synthase and the compounds 4c and 5c have emerged has an active antimicrobial agent with least binding energy (?5.27 and ?4.85 kJ mol^?1). Compounds 4e, 4f, 5e, and 5f showed promising free radical scavenging activity and compounds 5a and 5b showed good chelating ability with Fe²⁺ ions.     

An efficient, solvent-free microwave-assisted synthesis and antimicrobial screening of 1,6-dihydropyrimidine analogues

A series of compounds 4-(4-(4-aminophenyl)-6-(aryl)-1,6-dihydropyrimidin-2-ylthio)butanenitriles 5a–l were synthesised by the reaction of allyl cyanide 4 with 3a–l. Compounds 3a–l were prepared from reaction between various chalcones 1a–l and thiourea in presence of catalytic amount of potassium hydroxide. Compounds 3a–l, and 5a–l were prepared by classical as well as MWI methods. Structures of the compounds were characterized by IR, ¹H NMR, ¹³C NMR and mass spectral data. The newly synthesized compounds 5a–l were screened for their antimicrobial activity against different strains of bacteria and fungi using serial broth dilution method. Compounds 5e, 5g and 5k were found to be most active with MIC of 25?μg/mL against selected bacterial strains, while compound 5d, 5f, 5j and 5k were found to be most active with MIC 50?μg/mL against selected fungal strains.     

Synthesis, characterization and antimicrobial studies of a few novel thiazole derivatives

A series of novel N-[4-(substituted)-1,3-thiazol-2-yl]-2-(substituted)acetamide (9a–m) and methyl 2-(2-(2-(substituted)acetamido)thiazol-4-yl)acetate (9n–o) derivatives have been synthesized and compounds were characterised by spectral and analytical studies. All compounds were screened for their in vitro antibacterial activity against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and Klebsiella pneumonia by disc diffusion method and for antifungal activity against Penicillium marneffei, Trichophyton mentagrophytes, Aspergillus flavus and Aspergillus fumigatus by serial plate dilution method. Compounds 9b, 9e, 9m and 9o exhibited growth inhibition against all the tested bacterial strains, with MIC values varying from 12.5 to 6.25 μg/ml. Among the compounds tested for antifungal activity, 9a, 9b, 9d, 9j, 9k, 9p and 9n showed wide range of activity against all the tested strains. Most of the newly synthesized compounds were effective against fungal strains rather than bacterial strains. However, some of the compounds like 9a, 9e, 9j, 9k and 9i showed selective sensitivity against some of the bacterial strains whereas they were unable to sustain the growth of other strains.     

Synthesis,antimicrobial, and cytotoxic activities of novel benzimidazole derivatives bearing cyanopyridine and 4-thiazolidinone motifs

A series of 6-(1H-benzo[d]imidazol-2-yl)-2-(2-(3-nitrophenyl)-4-oxothiazolidin-yl)-4-(aryl)nicotinonitriles 5a–l were synthesized and characterized by IR, ¹H NMR, ¹³C NMR, and mass spectrometry techniques. These novel compounds 5a–l were screened for their in vitro antimicrobial activity against different bacterial and fungal strains and in vitro cytotoxicity study (HeLa cell line) using MTT colorimetric assay. The results demonstrated that compounds 5c, 5e, and 5i–k exhibited excellent antibacterial activity, while compounds 5d, 5i, and 5k were found to be the most potent antifungal agents. From the standpoint of SAR studies, it was observed that the presence of electron donating groups remarkably enhanced the antimicrobial activity of newly synthesized compounds. Further, the results of preliminary MTT cytotoxicity studies on HeLa cells suggested that potent antimicrobial activity of 5c–e and 5i–k was accompanied by low cytotoxicity.     

Synthesis and pharmacological activities of some novel 5-chloro-N-(4-(1,5-(disubstituted)-4,5-dihydro-1H-pyrazol-3-yl)phenyl)-2-methoxybenzamide derivatives

A series of substituted pyrazole derivatives were prepared from N1-[4-(cinnamoyl) phenyl]-5-chloro-2-methoxybenzamides 2a–c, which were prepared from N-(4-acetylphenyl)-5-chloro-2-methoxybenzamide as starting material. Treating of compound 2a–c with methylhydrazine or phenylhydrazine afforded the corresponding N-substituted pyrazoline derivatives 3a–c and 4a–c, respectively. The acryloyl derivatives 2a–c were reacted with hydrazine hydrate in dioxane afforded a pyrazoline 5a–c, which was acetylated with acetyl chloride in dioxane to yield the N-acetyl analogue 6a–c. In addition, pyrazoline 5c was reacted with morpholine in the presence of paraformaldehyde to give the corresponding N-substituted pyrazoline derivative 7. The structure assignments of the new compounds are based on chemical and spectroscopic evidence. The pharmacological screening showed that many of these compounds have less toxicity and good anti-inflammatory activities.     

Synthesis and cytotoxicity of novel 4-(4-(substituted)-1H-1,2,3-triazol-1-yl)-N-phenethylbenzenesulfonamides

A new series of 4-(4-(substituted)-1H-1,2,3-triazol-1-yl)-N-phenethylbenzenesulfonamide derivatives 5 were synthesized through the Click approach and evaluated for their cytotoxic activity against four cancer cell lines (HuCCA-1, HepG2, A549, and MOLT-3). Most of the synthesized triazoles 5 displayed cytotoxicity against MOLT-3 cell line, except for analogs 5a–c and 5e. Significantly, 4-phenyltriazoles (5a and 5n), 4-(naphthalen-2-yloxy)methyltriazole 5d, as well as 4-((2-oxo-2H-chromen-7-yl)oxy)methyltriazole 5l showed higher cytotoxic activity against HepG2 cells than the reference drug, etoposide. Interestingly, the 4-phenyltriazole 5a was the most potent and promising compound with IC₅₀ value of 9.07 μM against HepG2 cell line. The analog 5a also exerted the highest cytotoxic activity against HuCCA-1 cells. This finding provides the novel lead molecules for further development.     

Synthesis of some benzoxazinyl pyrazolone arylidenes as potent antimicrobials and antioxidants

2-[2-(3-Methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl)-2-oxoethyl]-2H-1,4-benzoxazin-3(4H)-one (3) was obtained starting from methyl-(3,4-dihydro-3-oxo-2H-1,4-benzoxazin-2-yl) acetate (1) through the corresponding hydrazide (2). Condensation of (3) with different aromatic aldehydes under Knoevengel condensation afforded 2-{2-[3-methyl-4-(2-methylbenzylidine)-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]-2-oxoethyl}-2H-1,4-benzoxazin-3(4H)-ones (4a–k). The structures of the compounds were determined by FT-IR, ¹H NMR, ¹³C NMR, mass spectral data, and elemental analysis. All the synthesized compounds were screened for their in vitro antimicrobial and antioxidant studies.     

Synthesis and antimicrobial activities of some isoxazolyl thiazolyl pyrazoles

A series of isoxazolyl thiazolyl pyrazoles 5a–d was synthesized by multi-step process, starting from 3-acetyl-4-hydroxy-6-methyl-2H-pyran-2-one (dehydroacetic acid, DHAA) 1. DHAA 1 was easily converted to thiosemicarbazone 2 which on reaction with α-bromoketones yielded thiazolyl hydrazones 3. Refluxing 3 in ethanol-acetic acid furnished 1-(5-hydroxy-3-methyl-1-substituted pyrazol-4-yl)-1,3-butanediones 4. Finally, the title compounds 5a–d were synthesized from 4 on treatment with hydroxylamine. The in vitro antimicrobial activity of compounds 3a–d, 4a–d and 5a–d were tested. Most of the synthesized compounds exhibited significant antibacterial and antifungal activities.     

Type II diabetes-related enzyme inhibition and molecular modeling study of a novel series of pyrazolone derivatives

Inhibitors of alpha-amylase are targets for the development of novel drugs for the treatment of diabetes and obesity. Alpha amylase is an enzyme which increases the bio availability of glucose in the blood. Hence, the inhibition effects of alpha amylase of 2-[1-(4-isobutylphenyl)ethyl]-5-methyl-4-[2-(aryl-substituted)hydrazinylidene]-2,4-dihydro-3H-pyrazol-3-one (4a–l) were investigated, among them compounds 4d, 4f, 4a, and 4g have displayed good inhibitory activity. The compounds with significant results were further evaluated for their molecular modeling study using in silico method. The new series of compounds were synthesized by solvent-free microwave irradiation method and were characterized by spectral and analytical data.     

Synthesis of azabicyclo[4.2.0]octa-1,3,5-trien-8-one analogues of 1H-imidazo[4,5-c]quinoline and evaluation of their antimicrobial and anticancer activities

In search of new and efficient antimicrobial and anticancer agents based on the imidazoquinoline structural framework, a series of novel 7-(1-isobutyl-1H-imidazo[4,5-c]quinolin-4-yl)-7-azabicyclo[4.2.0]octa-1,3,5-trien-8-ones (8a–f) were synthesized from the corresponding 2,4-dihydroxoquinoline derivative through multistep reactions. The structures of these compounds were established by IR, ¹H NMR, ¹³C NMR and mass spectral studies. The 7-(1-isobutyl-1H-imidazo[4,5-c]quinolin-4-yl)-7-azabicyclo[4.2.0]octa-1,3,5-trien-8-one (8a–f) analogues were evaluated for their in vitro antimicrobial activity by serial dilution method minimum inhibitory concentration (MIC). The derivatives 8c, 8e and 8f exhibited excellent antibacterial activity comparable to the parent drug ampicillin with MIC value. Compounds 7a–f and 8a–f were also assessed for their cytotoxic activity (IC₅₀) against HeLa cells using the Trypan blue exclusion assay method. The compounds 7c and 8b displayed potential anticancer activity. In a molecular docking study, these compounds showed minimum binding energy and good affinity towards the active pocket. They are believed to be good inhibitors of β-tubulin. The results of these studies provided evidence that 7-(1-isobutyl-1H-imidazo[4,5-c]quinolin-4-yl)-7-azabicyclo[4.2.0]octa-1,3,5-trien-8-one (8a–f) derivatives are a promising class of antibacterial and anticancer agents.     

Antibacterial and free radical scavenging potential of synthesized 7-hydroxy-2-aryl-6-aryldiazenyl-4H-chromen-4-ones

A series of 7-hydroxy-2-aryl-6-aryldiazenyl-4H-chromen-4-one derivatives (6a–m) was synthesized in quantitative yields and their structures were corroborated on the basis of FT-IR, ¹H, ¹³C NMR, ESI–MS, and elemental analysis data. The synthesized compounds were screened for in vitro antibacterial activities against a representative panel of Gram-positive and Gram-negative bacteria, as well as to evaluate their antioxidant potential using DPPH assay method. Bio-evaluation studies revealed that compounds 6c, 6d, 6e, 6j, and 6l exhibited moderate to good antibacterial activity against all the tested bacterial strains. Furthermore, from the antioxidant screening results, it has been observed that compounds 6c, 6e, and 6g manifested profound antioxidant potential (IC₅₀ <7.68 μM) in comparison to the standard antioxidant ascorbic acid.     

Synthesis, antitumor activity, and structure–activity relationship of some 4H-pyrano[3,2-h]quinoline and 7H-pyrimido[4′,5′:6,5]pyrano[3,2-h]quinoline derivatives

Several 4H-pyrano[3,2-h]quinoline (3a–d, 4a, 7a,b, 9a–c, 10a,b, 11a,b, and 13a–c) and 7H-pyrimido[4′,5′:6,5]pyrano[3,2-h]quinoline derivatives (8a–c) were obtained by treatment of 8-hydroxyquinoline (1a) and 8-hydroxy-2-methylquinoline (1b) with α-cyano-p-chloro/bromocinnamonitrile (2a,b) or 4H-pyrano[3,2-h]quinoline derivatives (3a,c,d) with different electrophilic reagents followed by nucleophilic reagents. Structures of these compounds were established on the basis of spectral data. The antitumor activity of the synthesized compounds was investigated in comparison with Vinblastine. Among them, compounds 3c,d, 4a, 8b, 9b,c, 11a,b, and 13a,c inhibited the growth of cancer cells compared to Vinblastine. The structure–activity relationships were discussed.     

Synthesis and antimicrobial activity of 5-chloroindoline-2,3-dione derivatives

A series of 3-(5-chloro-2-oxoindolin-3-ylideneamino)-2-arylthiazolidin-4-ones 4a–k and 5-chloro-3-(3-chloro-2-oxo-4-arylazetidin-1-ylimino)indolin-2-ones 5a–k was synthesized. The structures of final compounds were confirmed by analytical (C, H, N) and spectral (FT-IR, ¹H NMR, ¹³C NMR and Mass) data. The synthesized compounds were screened for possible antibacterial and antifungal activity. Compounds 4c, 4f, 4g, 4h, 4i, 4j, 5c, 5f, 5g, 5h, 5i and 5j showed substantially significant activity.