L-Proline catalyzed three component synthesis of pyrano[2,3-c]pyrazole-5-carbonitrile derivatives and in vitro antimalarial evaluation

An efficient one-pot synthesis of 6-amino-4-(2-chloroquinolin-3-yl)-3-methyl-2, 4-dihydro-pyrano[2,3-c]pyrazole-5-carbonitrile derivatives (4a–f)(5a–f) by three component reactions of 2-chloroquinolin-3-carbaldehyde derivatives, malanonitrile, and 3-methyl pyrazolin-5-one derivatives catalyzed by L-proline in ethanol medium under mild conditions is established. The synthesized compounds were evaluated for antimalarial activity and the LC₅₀/LC₉₀ values were described. Compounds 4d, 5d, and 5f exhibits good antimalarial activity when compared to other pyrano[2,3-c]pyrazole scaffolds.     

5-Anthracenylidene and 5-(4-Benzyloxy-3-methoxy)benzylidene-hydantoin and 2-Thiohydantoin Derivatives,Synthesis, and S-Alkylation

Abstract

5-Anthracenylidene- and 5-(4-benzyloxy-3-methoxy)benzylidene-hydantoin and 2-thiohydantoin derivatives 3a-g were prepared by condensation of anthracene-9-carboxaldehyde and 4-benzyloxy-3-methoxybenzylaldehyde with hydantoin and 2-thiohydantoin derivatives. Compounds 3a, b, f undergo Mannich reaction with formaldehyde and morpholine to give the corresponding Mannich products 4a–c. For the synthesis of alkylmercaptohydantoin 5a–o, the potassium salt of compounds 3a, b, e, f were reacted with an alkylhalide, either methyl iodide, phenacyl bromide, ethyl bromo acetate, allyl bromide, or methallyl bromide, under stirring at room temperature to afford the alkylmercaptohydantoins 5a–o. Acid hydrolysis of compounds 5a–c afforded the corresponding arylidene-hydantoin derivatives 3c, d, g. 2-Methylmercapto-hydantoin derivatives 5a, c were reacted with some secondary amines such as morpholine or piperidine to afford 5-(4-benzyloxy-3-methoxy)benzylidene-2-morpholino- or piperidino glycocyamidine derivatives 7a, 5-anthracenylidene-2-morpholin-, or piperidino glycocyamidine derivatives 7b, c.

Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.

GRAPHICAL ABSTRACT     

Organogelation and cytotoxic evolution of phosphonate ester functionalised hydrophobic alkanediamide motifs

Here we report various rigid alkanediamide derivatives, with three different substitution patterns of phosphonate ester for investigation of organogelation properties. The gelation properties of these compounds can be tuned by altering the number and position of the phosphonate esters. It was found that supramolecular self-assembly of the bisphosphonate esters (1a, 1d, 1h and 2a–b) resulted gel formation, whereas that of the tetraphosphonate esters (3a, 3d, 3h) resulted in construction of nanospheres and microspheres. The diverse morphology of the gel formation appears to depend predominantly on the substituted phenyl ring of the phosphonate ester functionality. Subsequent in vitro cytotoxic screening against four human tumour cell lines (A549, MDA-MB-231, MCF-7 and HeLa) using MTT assays revealed that derivatives 1f–h and 3a show cytotoxic potencies at concentrations less than 5 μM (IC₅₀ values). Compounds 1f–h exhibited promising activity against A549 cell line, 1g–h were highly effective against MDA-MB-231, 1f and 3a show potential against MCF-7 and 1f–g were active against the HeLa cell line.     

Synthesis and liquid crystal properties of a new class of calamitic mesogens based on substituted 2,5‐diaryl‐1,3,4‐thiadiazole derivatives with wide mesomorphic temperature ranges

Liquid crystals based on substituted 2,5‐diaryl‐1,3,4‐thiadiazole derivatives (1a–1f, 3a and 3b) and 1,3,4‐oxadiazole analogues (2a–2f, 4a and 4b) were synthesised and characterised by ¹H, ¹³C nuclear magnetic resonance, Fourier transform infrared, mass spectrometry, high‐resolution mass spectrometry techniques and elemental analyses. The X‐ray crystal structure of 1e revealed that it contains tilted lamellar arrangement of molecules in the crystalline solid. The liquid crystal properties have been investigated by polarised‐light optical microscopy, differential scanning calorimetry and in‐situ variable‐temperature X‐ray diffraction. All compounds (except 2e and 2f) exhibited thermotropic liquid crystal behaviours with various mesophases (smectic A and C, nematic N or soft crystal E phases). Notably, the 1,3,4‐thiadiazole derivatives consistently have wider mesomorphic temperature ranges than those of the respective 1,3,4‐oxadiazole analogues. The solutions of all compounds in CH₂Cl₂ individually displayed one or two absorption bands with λ _max values at 297–355 nm and emitted with λ _max values at 363–545 nm and quantum yields of 0.12–0.73. Structure–property relationships of these compounds are discussed in the contexts of their molecular structures and weak intermolecular interactions.     

New 1,2,4‐ and 1,3,4‐oxadiazole materials: synthesis,and mesomorphic and luminescence properties

The synthesis and liquid crystalline properties of new series of 1,2,4‐ and 1,3,4‐oxadiazole derivatives (2a–f and 5a–f respectively) are reported. These compounds contain only one terminal flexible alkoxy chain, the other terminal substituent is a protecting benzyl group. All compounds of series 2 exhibit an enantiotropic nematic phase. The homologue with the longest chain (2f) displays an enantiotropic dimorphism smectic A– nematic. None of the compounds of series 5 shows mesomorphism and only crystal–isotropic transitions were observed. The liquid crystalline properties were investigated by differential scanning calorimetry, polarizing optical microscopy and X‐ray measurements. Luminescence properties, in chloroform solution, of 2f and the series 5 compounds were evaluated. Good photoluminescence quantum yields for compounds of series 5 were observed. Compound 2f, incorporating the 1,2,4‐oxadiazole ring shows a very strong reduction in emissive properties.     

New polycatenar Schiff bases derived from 1,3,4-thiadiazole: synthesis,mesomorphism and luminescence behaviour

Two new series of columnar liquid crystal materials based on tetra- and hexacatenar Schiff bases were synthesised by reaction of 4-aminophenyl-1,3,4-thiadiazole derivatives with terephthalaldehyde (series 2a–f) and with 2,5-thiophenedicarbaldehyde (series 3a–f). The mesomorphic properties of these compounds were studied by differential scanning calorimetry (DSC), polarised optical microscopy (POM) and X-ray diffraction (XRD). The mesomorphic behaviour was found to be dependent on the nature of the central ring (benzene in series 2a–f, thiophene in series 3a–f), on length and on number of alkoxy chains. Both tetra- and hexacatenar compounds in series 2a–f display an enantiotropic hexagonal columnar phase. Whereas, in the case of the series 3, only the tetracatenar Schiff bases (3a, 3c and 3e) display enantiotropic hexagonal columnar mesomorphism, hexacatenar Schiff bases (3b, 3d and 3f) do not show mesomorphic properties. Photophysical studies were realised in solution and in solid state. Also, a thermogravimetric analysis was performed. A fibre obtained from compound 3b was analysed by POM showing that the mesophase is maintained in the fibre.     

1,4-Diazepines Bearing Thieno(2,3-b)Thiophene and Cyclohexene Carboxylate Moieties

Bis[thieno(3,2-b)-1,4-diazepine] (4) and bis[imidazo(1′,2′)thieno(3,2-b)-1,4-diazepine (7) derivatives were prepared starting with thieno(2,3-b)thiophenes (1) and (2), respectively. Also, benzodiazepine derivatives (11a–f) were prepared via a reaction of cyclohexenone carboxylates (8a–f) with cyclohexylamine and chloroacetyl chloride followed by cyclization. Also, dibenzoazepines (13) and (14a,b) were prepared via a reaction of (8a) with o-phenylenediamine and o-aminophenol or o-aminothiophenol.     

Novel Synthesis of N-Arylpyrrole,Pyrrolo[1,2-a]quinazoline,and Pyrrolo[3,4-d]pyridazine Derivatives

Phenacyl-malononitrile derivatives 1a,b react with dimethyl formamide dimethyl acetal (DMFDMA) in refluxing toluene to afford the enaminones 2a,b respectively. Compounds 2a and 2b react with the aromatic amines (aniline, p-toluidine, p-anisidine) in refluxing ethanol to afford the pyrroles 4a–f and with anthranilonitrile and methyl anthranilate to afford the pyrrolo[1,2-a]quinazolines 5a,b and 6a,b respectively. The pyrrole derivatives 4a–f react with hydrazine hydrate and phenyl hydrazine in refluxing ethanol to afford the pyrrolo[3,4-d] pyridazine derivatives 7a–f and 8a–f respectively.     

The synthesis and liquid crystalline behaviour of alkoxy‐substituted derivatives of 1,4‐bis(phenylethynyl)benzene

Despite the prevalence of organised 1,4‐bis(phenylethynyl)benzene derivatives in molecular electronics, the interest in the photophysics of these systems and the common occurrence of phenylethynyl moeties in molecules that exhibit liquid crystalline phases, the phase behaviour of simple alkoxy‐substituted 1,4‐bis(phenylethynyl)benzene derivatives has not yet been described. Two series of 1,4‐bis(phenylethynyl)benzene derivatives, i.e. 1‐[(4′‐alkoxy)phenylethynyl]‐4‐(phenylethynyl)benzenes (5a–5f) and methyl 4‐[(4″‐alkoxy)phenylethynyl‐4′‐(phenylethynyl)] benzoates (18a–18f) [alkoxy = n‐C₄H₉ (a), n‐C₆H₁₃ (b), n‐C₉H₁₉ (c), n‐C₁₂H₂₅ (d), n‐C₁₄H₂₉ (e), n‐C₁₆H₃₃ (f)] have been prepared and characterised. Both series have good chemical stability at temperatures up to 210°C, the derivatives featuring the methyl ester head‐group (18a–18f) offering rather higher melting points and generally stabilising a more diverse range of mesophases at higher temperatures than those found for the simpler compounds (5a–5f). Smectic phases are stabilised by the longer alkoxy substituents, whereas for short and intermediate chain lengths of the simpler system (5a–5c) nematic phases dominate. Diffraction analysis was used to identify the SmB_hex phase in (5d–5f) that is stable within a temperature range of approximately 120–140°C. The relationships between the organisation of molecules within these moderate temperature liquid crystalline phases and other self‐organised states (e.g. Langmuir‐Blodgett films) remain to be explored.     

One‐Pot Synthesis of Oxime Derivatives of 1,3‐Diphenylpyrazole‐4‐carboxaldehydes from Acetophenone Phenylhydrazones Using Vilsmeier–Haack Reagent

A one‐pot synthesis of oxime derivatives 3a–3f of 1‐phenyl‐3‐arylpyrazole‐4‐carboxaldehydes has been accomplished by the Vilsmeier–Haack reaction of acetophenone phenylhydrazones 1a–1f under a new workup procedure.     

Facile Synthesis of Some New Pyrazole-Based 2-Thioxo-4-thiazolidinone

5-Ethoxymethylene-2-thioxo-4-thiazolidinone (1) reacts with hydrazine hydrate at room temperature to afford 5-(hydrazinylmethylene)-2-thioxo-4-thiazolidinone (3). Compound 3 condensed with different aromatic aldehydes 6a–d in ethanol in the presence of a few drops of piperidine to give the corresponding Schiff’s bases 7a–d. On the other hand, compound 3 reacts with o-hydroxybenzaldehyde derivatives 8a and 8b in refluxing ethanol catalyzed by a few drops of piperidine to yield 1H-inadzolyl-2-thioxo-4-thiazolidinones 9a and 9b. Reaction of compound 3 with α-ketoesters 10a and 10b or α-diketones 10c–e in refluxing glacial acetic acid furnished the pyrazolyl-2-thioxo-4-thiazolidinone derivatives 11a–e. Also, compound 3 reacts with some different enaminones 12a–f in refluxing glacial acetic acid to afford the new pyrazolyl-2-thioxo-4-thiazolidinone derivatives 13a–f. Pyrazoles 15a–d was obtained via reaction of compound 3 with chalcones 14a–d in dimethylformamide (DMF). The structures of all the newly synthesized products were confirmed on the basis of their elemental and spectral data, and a plausible mechanism has been postulated to account for their formation.     

Synthesis of Benzo[b]thiophene Carboxamides Connected to 4‐Arylpiperazines through a Benzylic Spacer: Potential Ligands with 5‐HT1A Binding Affinity

New benzothiophene arylpiperazine derivatives 8 (a–f) were synthesized as potential serotoninergic agents with 5‐HT_1A receptor affinity. Preparation of the derivatives was performed by treating N‐[2‐(chloromethyl)phenyl]‐4,7‐dimethoxybenzo[b]thiophene‐2‐carboxamide (7) with a series of substituted 4‐arylpiperazines.     

Facile Access to Mono-Cinchona Alkaloid-Derived Ligands

Two facile accesses to mono-cinchona alkaloid-derived ligands, by conventional heating conditions and solvent-free microwave irradiation, are described. 1,4-Dichlorophthalazine (PHAL) or 3,6-dichloropyridazine (PYDZ) reacted with quinine (QN), cinchonine (CN), or cinchonidine (CND) by using CaH₂ as acid-bonding reagent in DMF at 90–100°C to provide mono-cinchona alkaloid-derived ligands 2a–f (87–95%) in 1.5 h. However, the coupling reactions were performed under solvent-free microwave conditions to yield 2a–f (64–89%) within 15 min.     

N-IODOSUCCINIMIDE MEDIATED REGIOSELECTIVE HETEROCYCLIZATION OF o-CYCLOHEX-2′-ENYL PHENOLS

ABSTRACT

A number of 3,4-benzo-9-iodo-2-oxabicyclo[3.3.1]nonanes (2a–f) are synthesized in excellent yields by regioselective heterocyclization of o-cyclohex-2′-enyl phenols (1a–f) with N-iodosuccinimide in acetonitrile at 0–5°C.     

Synthesis of Some New N‐Substituted Pyrroles,Pyrrolo[1,2‐a]quinazoline,and Diaza‐as‐indacene Derivatives

2‐Phenyl‐1,1,3‐tricyano‐3‐bromopropene 1 reacts with the aromatic amines 2a–f and 6a–c to afford the N‐substituted pyrroles 4a–d, the pyrrolo[1,2‐a]quinazoline derivatives 5a, b, and the diaza‐as‐indacene derivatives 7a–c and 8a–c, presumably via elimination of hydrogen bromide followed by cyclization of the formed acyclic intermediates. All structures are confirmed by analytical and spectral data.     

Studies of Thiazolopyridines,Part 6: Synthesis and Antimicrobial Evaluation of Some Novel Thiazolo[3,2-a] Pyridine and Thiazolo[2′,3′:6,1]-pyrido[2,3-d]pyrimidine Derivatives

Condensation of thiazolinone 1 with aromatic aldehydes yielded the corresponding methylidene derivatives 2a–f. Cyclization of compounds 2a–f with arylidenemalononitrile 3 (1:1 molar ratio) in ethanol in the presence of piperidine furnished the novel thiazolo[3,2-a]pyridines 5a–v, via Michael adduct 4. Compounds 5p, r were cyclized with malononitrile in the presence of piperidine to yield thiazolo[3,2-a][1,8]naphthryidines 7a, b. Thiazolo-[2′,3′:1,6]pyrido[2,3-d]pyrimidine 9a–cwere obtained by cyclization of compounds 5c, p, r with formic acid. The structure of the synthesized compounds was established by analytical and spectral data. Also, some of the synthesized compounds were screened for antimicrobial activity in vitro.     

Synthesis of Some New 3-Oxo-2-[(Z)-1-phenylmethylidene]-5H-[1,3]thiazolo[3,2-a]-and N-Acetylated Pyrimidines

3-Oxo-2-[(Z)-1-phenylmethylidene]-5H-[1,3]thiazolo[3,2-a] pyrimidine derivatives 2a–f were synthesized by the reaction of an appropriate 3,4-dihydro-2(H)-pyrimidone 1 , chloroacetic acid, sodium acetate and benzaldehyde. Reaction of 1 with acetic anhydride under heating afforded only 3-N-acetylated 3,4-dihydro-2(H)-pyrimidines 3a–f . The yields of the products after recrystallization from ethanol were of the order of 60–92 %. IR, ¹ H NMR spectroscopy, and elemental analysis were used for the identification of these compounds.     

Crystal‐smectic E mesophases in a series of 2‐(4‐n‐alkylphenyl)indenes

A series of 2‐(4‐n‐alkylphenyl)indenes (3) with different alkyl substituents (CH₃ to C₁₀H₂₁) were synthesized and systematically characterized using differential scanning calorimetry, polarizing optical microscopy and X‐ray diffraction compared with 2‐phenylindene (3a). Depending on the alkyl chain length, highly ordered crystal‐smectic E mesophases were observed and confirmed by X‐ray diffraction for the derivatives 3h–3k with heptyl to decyl chains (n = 6?9). For 3f with a pentyl side chain (n = 4), an X‐ray crystal structure analysis was carried out.     

SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF SOME NEW PYRIDO[3′,2′:4,5]THIENO[3,2-d]- PYRIMIDINE DERIVATIVES

5-Acetyl-3-amino-4-aryl-6-methylthieno[2,3-b]pyridine-2-carboxamides (1a, b) were reacted with aromatic aldehydes or with some cycloalkanones to give the corresponding tetrahydropyridothienopyrimidinone derivatives 2a–f and 4a–d . The reaction of compound 1b with urea and/or carbon disulfide has been carried out and their products were identified. Some representative compounds were screened in vitro for their antimicrobial activities.     

Synthesis and evaluation of antitumour activity in vitro and in vivo of chrysin salicylate derivatives

A series of chrysin salicylate derivatives as potential antitumour agents were synthesised and evaluated their antitumour activities in vitro and in vivo. Most of the compounds exhibited moderate to good activities against MCF-7 cells, HepG2 cells, MGC-803cells and MFC cells. Among them, compound 3f showed the most potent activity against MGC-803 cells and MFC cells with IC₅₀ values of 23.83 ± 3.68 and 27.34 ± 5.21 μM, respectively. The flow cytometry assay reconfirmed that compound 3f promoted the occurrence of tumour cells’ G1/S block under the inhibiting effect of compound 3f. Compound 3f possessed higher antitumour efficacy in tumour-bearing mice, compared with the positive control 5-Fu and the blank control saline.