Eco-friendly synthesis and antimicrobial activities of some 1-phenyl-3(5-bromothiophen-2-yl)-5-(substituted phenyl)-2-pyrazolines

Background

Green catalyst fly ash: H₂SO₄ was prepared by mixing fly ash and sulphuric acid. Microwave irradiations are applied for solid phase cyclization of 5-bromo-2-thienyl chalcones and phenyl hydrazine hydrate in the presence of fly ash: H₂SO₄ yields, 1-phenyl-3(5-bromothiophen-2-yl)-5-(substituted phenyl)-2-pyrazolines. These pyrazolines were characterized by their physical constants and spectral data. The antimicrobial activities of all synthesized pyrazolines have been studied.

Results

Scanning electron microscopy (SEM) analysis shows the morphology changes between fly ash and the catalyst fly ash: H₂SO₄. The SEM photographs with the scale of 1 and 50 μm show the fly-ash particle is corroded by H₂SO₄ (indicated by arrow mark), and this may be due to dissolution of fly ash by H₂SO₄. The yields of 1-phenyl-3(5-bromothiophen-2-yl)-5-(substituted phenyl)-2-pyrazolines is more than 75% using this catalyst under microwave heating. All pyrazolines showed moderate activities against antimicrobial strains.

Conclusion

We have developed an efficient catalytic method for synthesis of 1-phenyl-3(5-bromothiophen-2-yl)-5-(substituted phenyl)-2-pyrazolines by solid phase cyclization using a solvent-free environmentally greener catalyst fly ash: H₂SO₄ under microwave irradiation between aryl chalcones and hydrazine hydrate. This reaction protocol offers a simple, economical, environment friendly, non-hazardous, easier work-up procedure, and good yields. All synthesized pyrazoline derivatives showed moderate antimicrobial activities against bacterial and fungal strains.     

Synthesis, characterization, and SAR studies of new (1H-indol-3-yl)alkyl-3-(1H-indol-3-yl)propanamide derivatives as possible antimicrobial and antitubercular agents

In this article, we report herein the SAR studies of a series of (1H-indol-3-yl)alkyl-3-(1H-indol-3-yl)propanamide 10(a–j), 11(a–j). The synthesized compounds were evaluated for their preliminary in vitro antibacterial, antifungal activity and were screened for antitubercular activity against Mycobacterium tuberculosis H37Rv strain. The synthesized compounds displayed interesting antimicrobial activity.     

Synthesis and antimicrobial activities of some new 5-((3-(aryl)-1-phenyl-1H-pyrazol-4-yl)methylene)-3-phenylthiazolidine-2,4-diones

A series of nine new compounds of 5-((3-(aryl)-1-phenyl-1H-pyrazol-4-yl)methylene)-3-phenylthiazolidine-2,4-diones was synthesized by Knoevenagel condensation of various 3-(aryl)-1-phenyl-1H-pyrazole-4-carbaldehydes with 3-phenylthiazolidine-2,4-dione in ethanol in the presence of piperidine as a catalyst. The reaction afforded the desired products in good yields. All the nine compounds were screened for their in vitro antibacterial (Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa and Escherichia coli) and antifungal (Aspergillus niger and A. flavus) activity. Biological activities of these compounds were compared with those of commercially available antibiotics, ciprofloxacin and antifungal agent fluconazole. Two compounds 3e and 3i were found to be most effective against S. aureus and B. subtilis. Out of the nine compounds tested for antifungal activity, five, 3c–f and 3h showed more than 50% inhibition against the A. flavus, whereas the three compounds 3a, 3d and 3f showed more than 50% inhibition against A. niger.     

Synthesis and in vitro cytotoxicity study of 3-(1H-indol-3-yl)-1,3-diphenylpropan-1-ones

A series of 3-(1H-indol-3-yl)-1,3-diphenylpropan-1-ones 3a–l were synthesized in good to excellent yield by Michael addition of indole 1 with α,β-unsaturated ketones 2a–l in presence of indium(III) sulphate (20 mol%). The structure of the title compounds were established by ¹H NMR, ¹³C NMR, mass and elemental analysis. All the synthesized compounds were evaluated for in vitro cytotoxicity against five different cancer cell lines such as ACHN (human kidney adenocarcinoma), Panc1 (pancreatic), Calu1 (lung), H460 (non small cell lung), HCT116 (human colon cancer cell) and MCF10A (normal breast epithelium) using propidium iodide staining assay protocol. The result showed that the compounds 3e and 3l have excellent cytotoxic activity with the IC₅₀ value ranging from 1.4–2.7 to 2.4–3.4 μM, respectively, in comparison with the other compounds, Flavopiridol and Gemcitabine were employed as a positive control. The findings conferred 3-(1H-indol-3-yl)-1,3-diphenylpropan-1-ones seem to be promising candidates for the development of new anticancer drugs.     

Convenient synthesis and antimicrobial activity of new 3-substituted 5-(benzofuran-2-yl)-pyrazole derivatives

The reaction of ethyl 4-(benzofuran-2-yl)-2,4-dioxobutanoate 2 with two moles of hydrazine hydrate afforded 5-(benzofuran-2-yl)-1H-pyrazole-3-carbohydrazide 4a, while its reaction with equimolar amount of phenylhydrazine gave ester 3b which then converted to 5-(benzofuran-2-yl)-1-phenyl-1H-pyrazole-3-carbohydrazide 4b. Various new compounds such as imides 5 and 6, acyl hydrazones 7 and 8, bi-pyrazoles 9-12, and 1,3-thiazole derivatives 14 and 15 were prepared from carbohydrazide derivatives 4a, b. The new compounds are tested for their antimicrobial activity. Compounds 2, 5, 7, and 8 showed antifungal activities against C. albicans. Also, compounds 2, 6, 8, and 15 showed antibacterial activities.     

Improved method of synthesizing 2,2-dimethyl-4,6-dioxo-1,3-dioxane (Meldrum's Acid)

Translated from Khimiko-farmatsevticheskii Zhurnal, Vol. 48, No. 8, pp. 41–43, August, 1994.     

Synthesis and evaluation of the biological activities of some 3-{[5-(6-methyl-4-aryl-2-oxo-1,2,3,4-tetrahydropyrimidin-5-yl)-1,3,4-oxadiazol-2-yl]-imino}-1,3-dihydro-2H-indol-2-one derivatives

Reaction of ethyl-6-methyl-2-oxo-4-aryl-1,2,3,4-tetrahydropyrimidin-5-carboxylates (1a-i) with hydrazine hydrate yielded 6-methyl-2-oxo-4-aryl-1,2,3,4-tetrahydropyrimidin-5-carbohydrazides (2a-i). These products, on reaction with cyanogen bromide, gave 5-(5-amino-1,3,4-oxadiazol-2-yl)-6-methyl-4-aryl-3,4-dihydropyrimidin-2 (1H)-ones (3a-i). The resultant aminooxadiazolylpyrimidinones were condensed with isatin to obtain various 3-{[5-(6-methyl-4-aryl-2-oxo-1,2,3,4-tetrahydropyrimidin-5-yl)-1,3,4-oxadiazol-2-yl]-imino}-1,3-dihydro-2H-indol-2-ones (4a-i). These products were characterized by IR, 1H NMR, mass spectra and elemental analysis. Products (4a-i) revealed promising antibacterial, antifungal and antioxidant activity.     

Syntheses and complement inhibitory activities of 4-(2-phenyl-1H-indol-3-yl)cyclohexane-1-carboxylic acids

The syntheses of 4-(2-phenyl-1H-indol-3-yl)cyclohexane-1-carboxylic acids are described. These compounds express potent in vitro inhibition of the human classical complement pathway, and qualitative SAR have been determined. Several of the in vitro active compounds also suppressed the complement dependent reverse passive Arthus reaction (RPAR) in guinea pigs.     

Synthesis and anticonvulsant activities of functionalized 5-(isoindole-1,3-dione)-pyrimidinones

The present work involves the synthesis of previously unknown 5-(isoindole-1,3-dione) pyrimidinones by [4 + 2] cycloaddition reactions of functionalized 1,3-diazabuta-1,3-dienes with phthalimidoketene, generated in situ from phthaloylglycine, tosyl chloride, and triethylamine. The 5-(isoindole-1,3-dione)-pyrimidinones have been screened in vivo for their anticonvulsant activities using MES and PTZ methods. A comparative study for in vivo anticonvulsant activities of these functionalized pyrimidinones with a variety of substitutions at different positions was also conducted. 2-(4-Dimethylamino-6-oxo-1,2-diphenyl-1,6-dihydro-pyrimidin-5-yl)-isoindole-1,3-dione has shown the maximum anticonvulsant activities at 100 mg/kg test dose using MES and PTZ tests.     

Cycloaddition reactions of 5-(2-thienyl)methylene derivatives of thiazolidinone-4-thiones and their antimicrobial activities

The cycloaddition of the newely synthesized 5-(2-thienyl)methylene derivatives of thiazolidinone-4-thiones,2a?c to acrylonitrile (3a), ethyl acrylate (3b), N-phenylmaleimide (6) and dimethyl fumarate (8) has been evaluated. Under thermal reaction conditions [4+2] cycloaddition proceeds with complete site and regioselectivity to yield the cycloadduct,4, 5, 7 and9, respectively. The antimicrobial activities of some of the new products were tested.     

Interferon inducing activities of derivatives of 1,3-dimethyl-4-(3-dimethylaminopropylamino)-1H-pyrazolo(3,4-b)quinoline and related compounds.

Syntheses and interferon inducing acitivites are reported for 137 relatives of 1,3-dimethyl-4-(3-dimethylamino-propylamino)-1H-pyrazolo[3,4-b]quinoline (1). Three different generalized synthetic schemes for the preparation of pyrazolo[3,4-b]quinolines are presented and limitations contrasted. Other heterocyclic nuclei containing the 3-dimethylaminopropylamino side chain include pyridine, quinoline, acridine, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-B][1,8]naphthyridine, pyrazolo[4',3':5,6]pyrido[2,3-d]pyrimidine, dipyrazolo[3,4-b:4',3'-e]pyridine, pyrrolo-[2,3-b]quinoline, isothiazolo[5,4-b]quinoline, and pyrido[2,3-h]pyrazolo[3,4-b]quinoline. Structural requirements for interferon induction in this series are discussed and two of the more active compounds (172 and 196) are compared directly with tilorone.     

Synthesis and antimicrobial activity of 5-((3-aryl-1-phenyl-1H-pyrazol-4-yl)methylene)thiazolidine-2,4-diones

A series of 5-((3-aryl-1-phenyl-1H-pyrazol-4-yl)methylene)thiazolidine-2,4-diones was synthesized by Knoevenagel condensation of various 3-aryl-1-phenyl-1H-pyrazole-4-carbaldehydes (1a–h) with thiazolidine-2,4-dione (2) in ethanol in the presence of piperidine. All compounds were screened for their in vitro antibacterial (Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa and Escherichia coli) activity and compared with the commercially available antibiotic, ciprofloxacin. All compounds showed good activity against gram-positive bacteria, however, none of the compounds were found to be effective against gram-negative bacteria. Compound 3g was found to be most potent member among all the compounds showing MIC of 16?μg/ml against S. aureus and 32?μg/ml against B. subtilis. All the synthesized compounds were also tested for their in vitro antifungal (Aspergillus niger and A. flavus) activity and compared with commercially available fluconazole. They showed excellent antifungal activity. Compounds 3b, 3e, 3f and 3g were active against both fungi showing more than 60% inhibition. Compound 3e was found to be superior to the reference drug.     

Synthesis and analgesic activity of (2,3-diphenyl-1H-indol-5-YL)piperazin-1-yl methanone derivatives

Series of 1,4-disubstituted piperazine and of N,N-disubstituted ethylenediamine having the 2,3-diphenyl- 1H-indole-5-carbonyl group as one of the two substituents were prepared. Compounds 3, 4, 11, 15 – 17, and 20 – 22 were tested for analgesic activity. After ip administration all compounds induced significant visceral antinociceptive activities where acetic acid-induced writhing was significantly reduced by all compounds.     

The synthesis and screening of the antimicrobial activity of some novel 3-(furan-2-yl)-1-(aryl)-3-(phenylthio) propan-1-one derivatives

A series of thiophenol adducts (3a–m) were prepared by addition of thiophenol to chalcones (1a–m) in the presence of a catalytic amount of KOt-Bu in solvent free conditions. In addition, the antibacterial and antifungal in vitro properties were tested against some human pathogenic microorganisms by employing the disk diffusion technique. A majority of compounds were remarkably active against several of the microorganisms. Compound 3i was determined to be the most active compound.     

Synthesis and evaluation of antibacterial and antifungal activities of new (Z)-3-bromo-4-(1,3-diaryl-1H-pyrazol-4-yl)but-3-en-2-ones and 4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)-1,3-diaryl-1H-pyrazoles

Bromination of 4-(1, 3-diaryl-1H-pyrazol-4-yl) but-3-en-2-ones, triggered by a combination of potassium bromide and cerium(IV) ammonium nitrate in a biphasic system consisting of water and dichloromethane furnishes the corresponding monobromo compounds 2 directly, instead of the expected dibromo compounds. The α-bromo compounds 2 were utilized as efficient precursors for the synthesis of several bipyrazolyl derivatives, 4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)-1, 3-diaryl-1H-pyrazoles (3). All the α-bromoenones 2 and bipyrazoles 3 are new compounds and their identity was established by m.p., spectral and analytical data. The new products 2 and 3 were tested for their in vitro antibacterial activity against Staphylococcus aureus, Bacillus subtilis (Gram positive), Escherichia coli, and Pseudomonas aeruginosa (Gram negative) and antifungal activity against Aspergilus flavus and Aspergillus niger. The antimicrobial activity of the tested compounds is compared with the commercially available antibiotic, ciprofloxacin and antifungal agent, fluconazole.     

5-(Ethoxymethylene)thiazolidine-2,4-dione derivatives: reactions and biological activities

The 5-(ethoxymethylene)-4-thioxothiazolidin-2-ones 2a-c were synthesized and reacted with acrylonitrile, ethyl acrylate. β-nitrostyrene, N-phenylmaleimide and malononitrile under different conditions, to yield the cycloaddition products 3–14. The antibacterial and antifungal activities of the new products were tested.     

Anticonvulsant properties of N-(4-methylpiperazin-1-yl)- and N-[3-(4-methyl-piperazin-1-yl)propyl] derivatives of 3-aryl- and 3-spirocycloalkyl-pyrrolidine-2,5-dione

Two series of N-(4-methylpiperazin-1-yl)- and N-[3-(4-methylpiperazin-1-yl)-propyl]-3-aryl- and 3-spirocycloalkyl-pyrrolidine-2,5-dione derivatives were synthesized and tested for anticonvulsant activity in the maximum electroshock (MES) seizure and pentetrazole (sc PTZ) seizure threshold tests. Compounds with an aromatic ring at position-3 of pyrrolidine-2,5-dione exhibited anticonvulsant activity in the MES test. For that series of compounds, ED50 values were determined. The most potent in the series were derivatives and with a chlorine atom at position-3 or 4 of the aromatic ring. Those compounds exhibited strong anticonvulsant activity, and their ED50 values ranged from 29 to 48 mg/kg. Introduction of the spirocycloalkyl ring into the position-3 of pyrrolidine-2,5-dione made those compounds inactive.     

Novel (E)-alpha-[(1H-indol-3-yl)methylene]benzeneacetic acids as endothelin receptor ligands

Endothelin-1 (ET-1), a peptide of 21 amino acid residues, is the most potent vasoconstrictor substance known and now it is understood to be one of a family of three mammalian vasoactive peptides that also includes ET-2 and ET-3. The endothelins (ETs) affect multiple organ systems and seem to be involved in the pathogenesis of many diseases such as hypertension, pulmonary hypertension, atherosclerosis, apoptosis inhibition and angiogenesis. The ETs exert their effects via activation of two distinct G-protein coupled receptor subtypes termed ET(A) and ET(B). To date a number of ET receptor ligands with good affinity and selectivity is known, nevertheless these compounds belong only to few chemical classes. The aim of this work was the identification of a "hit compound" with novel chemical structure, endowed with reasonable ET affinity and selectivity. Accordingly, a new class of (E)-alpha-[(1H-indol-3-yl)methylene]benzeneacetic acid derivatives (1-23) was synthesized for evaluation of their binding profiles.     

Design, synthesis, and SAR of new pyrrole-oxindole progesterone receptor modulators leading to 5-(7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile (WAY-255348)

We have continued to explore the 3,3-dialkyl-5-aryloxindole series of progesterone receptor (PR) modulators looking for new agents to be used in female healthcare: contraception, fibroids, endometriosis, and certain breast cancers. Previously we reported that subtle structural changes with this and related templates produced functional switches between agonist and antagonist properties ( Fensome et al. Biorg. Med. Chem. Lett. 2002, 12, 3487; 2003, 13, 1317 ). We herein report a new functional switch within the 5-(2-oxoindolin-5-yl)-1 H-pyrrole-2-carbonitrile class of compounds. We found that the size of the 3,3-dialkyl substituent is important for controlling the functional response; thus small groups (dimethyl) afford potent PR antagonists, whereas larger groups (spirocyclohexyl) are PR agonists. The product from our optimization activities in cell-based systems and also for kinetic properties in rodents and nonhuman primates was 5-(7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1 H-indol-5-yl)-1-methyl-1 H-pyrrole-2-carbonitrile 27 (WAY-255348), which demonstrated potent and robust activity on PR antagonist and contraceptive end points in the rat and also in cynomolgus and rhesus monkeys including ovulation inhibition, menses induction, and reproductive tract morphology.