Synthesis,structural studies and antituberculosis evaluation of new hydrazone derivatives of quinoline and their Zn(II) complexes

The quinoline hydrazone ligands were synthesized through multi-step reactions. The 2-hydroxy-3-formylquinoline derivatives (1a–1c) were prepared from acetanilide derivatives as starting materials using Vilsmeier–Haack reaction. Then the condensation of 2-hydroxy-3-formylquinoline derivatives with hydrazide derivatives (2a–2c) yielded quinoline hydrazone ligands (3a–3i). The synthesis of a new series of Zn(II) complexes carried out by refluxing with these quinoline hydrazone ligands (3a–3i) is reported. The molecular structures of the ligands (3a–3i) and the Zn complexes were characterized by elemental analysis and spectral studies like FT-IR, ¹H and ¹³C NMR, MS, UV–Visible and fluorescence. The preliminary results of antituberculosis study showed that most of the Zn(II) complexes 4a–4i demonstrated very good antituberculosis activity while the ligands 3a–3i showed moderate activity. Among the tested compounds 4e and 4g were found to be most active with minimum inhibitory concentration (MIC) of 8.00 μM and 7.42 μM respectively against Mycobacterium tuberculosis (H37 RV strain) ATCC No-27294 which is comparable to “first and second line” drugs used to treat tuberculosis.     

Flash vacuum pyrolysis of azolylacroleins and azolylbutadienes

2-Aryl-5-acroleinyl-1,2,3,4-tetrazoles (1a–d) and 2-aryl-5-butadienyl-1,2,3,4-tetrazoles (1e–g) were subjected to flash vacuum pyrolysis. Acroleinyl derivatives resulted in nitrogen extrusion to give nitrilimines followed by ring closure to give the corresponding indazoles 3a–d in good yields. On the other hand, butadiene derivatives underwent ring fragmentation to give p-substituted anilines without formation of the expected indazoles. Differences between thermal behaviour of 2-(4-chlorophenyl)-5-acroleinyl-1,2,3,4-tetrazole (1c) and 1-(4-chlorophenyl)-4-acroleinyl-1,2,3-triazole (2) were studied in details. DFT calculations have been used to examine the nitrilimine and carbene nature of the intermediates involved in the thermal reactions of azolyl derivatives.     

Stereoselective synthesis of 2-(α-hydroxyalkyl)benzimidazoles

Lithiated oxazolo[3,4-a]benzimidazole 4 reacted with various alkyl halides to give oxazolo[3,4-a]benzimidazoles 5a–d in good yields as single diastereoisomers. (R)-Benzimidazol-2-yl carbinols 6a–d were obtained upon hydrolysis under acidic conditions of 1H,3H-oxazolo[3,4-a]benzimidazole derivatives.     

Functionalized enamines—XXII : Annelation of enamines of polycyclic α,β-unsaturated ketones; a facile partial synthesis of furano- indolo- and benzsteroids. Total synthesis of 3-oxa-A-norsteroid

Reaction of dienamine 4a with substituted phenacyl bromides gave steroidal[3,4-b] furans 5a–g. The same principle reaction was utilized for the total synthesis of (±) 2 - (p - chlorophenyl) - 3 - oxa - A - nor - estra - 1,5(10), 9(11) - triene - 17 - acetate 12a. Treatment of 4a, b with benzenediazonium salts, in DMF, followed by a Fischer-indole cyclization yielded steroidal[6, 7-b] indoles 8a–k. Dienamine 4b could be annelated to benz[4, 5, 6] steroids 9a and 9b by reaction with methyl vinyl ketone and crotonaldehyde, respectively.     

Characterization and pharmacological evaluation of new pyridine analogs

Reaction of 5-ethyl pyridine-2-ethanol 1 and methane sulphonyl chloride gives corresponding sulphonate 2; which on condensation with p-hydroxy benzaldehyde will give 4-[2-(5-ethylpyridin-2-yl)ethoxy]benzaldehyde 3. A series of chalcones 4a–o were prepared from 3 and substituted aromatic acetophenone. Chalcones 4a–o further react with guanidine nitrate to give a series of pyrimidines 5a–o which condense with 3,4-dichlorobenzylchloride to give amide derivatives 6a–o. Newly synthesized compounds have been examined on the basis of spectral analysis. All the compounds were screened against different gram-positive and gram-negative bacteria. Most of these compounds showed better inhibitory activity in comparison with the standard drugs.     

1,2,5-Thiadiazole 2-oxides: selective synthesis,structural characterization,and electrochemical properties

A new general procedure for the selective synthesis of 1,2,5-thiadiazole 2-oxides (including fused derivatives) 8a,b,c,g,h from the reaction of vic-glyoximes with S₂Cl₂ and pyridine in acetonitrile was elaborated together with general procedure for the synthesis of 1,2,5-thiadiazoles 7a–i, 10, 12, and 14 from the same starting materials and reagents. Molecular structures of 3,4-dimethyl-1,2,5-thiadiazole 2-oxide 8a and [1,2,5]thiadiazolo[3,4-b]quinoxaline 10 were confirmed by single-crystal X-ray diffraction. Electrochemical properties of 1,2,5-thiadiazole 2-oxides 8 were studied by cyclic voltammetry and different behavior was observed for monocyclic and benzo-fused derivatives. With compounds 8g and 17, previously unknown deoxygenation of 2,1,3-benzothiadiazole 1-oxides was discovered by electrochemical reduction, and resulted 2,1,3-benzothiadiazoles 7g and 19 were detected in the forms of their radical anions by EPR spectroscopy combined with DFT calculations.     

Microwave assisted synthesis of 3-benzazepin-2-ones as building blocks for 2,3-disubstituted tetrahydro-3-benzazepines

Microwave assisted condensation of primary amines with keto acids 1a–c provided directly 3,4-disubstituted 1,3-dihydro-3-benzazepin-2-ones 2. Whereas small amine size, such as NH₃ afforded high yields of secondary lactams 2a, 2d, and 2g, primary amines with larger substituents in α-position led to lower yields of 2 or even to regioisomeric indanone derivatives 4. However, subsequent alkylation of 2a, 2d, and 2g with various alkyl halides provided the corresponding N-substituted 3-benzazepin-2-ones 2 in good yields. Hydrogenation of 2 followed by BH₃ reduction led to 3-benzazepines 9. 3-Benzyl-2-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (9c) reveals high σ₁ affinity and selectivity over σ₂ and NMDA receptors.     

Synthesis of 1,3-diaryl-1H-benzo[g]indazoles

A facile three-step synthetic route toward 1,3-diaryl-1H-benzo[g]indazoles 1a–1n starting with 3,4-dimethoxy-2-allylbenzaldehyde (6) in modest total yield is described. The facile route was carried by aldol condensation of aldehyde 6 with aryl methyl ketones 5a–5d in alkaline MeOH at reflux, Knorr pyrazole synthesis of the resulting chalcones 4a–4d with aryl hydrazines 3a–3e in EtOH at reflux followed by DDQ-mediated aromatization in toluene at reflux, and oxidative cleavage annulation of olefins 2a–2n with the one-pot combination of OsO₄/NaIO₄/HOAc in the aqueous THF at reflux.     

Anti-isohumulone and its derivatives

Three new humulone derivatives have been isolated and identified as: 3,4-dihydroxy-2-(3-methyl-2-butenyl)-4-(4-methyl-3-pentenoyl)-2-cyclopentenone (6);4-ethanoyl-3,4-dihydroxy-2-(3-methyl-2-butenyl)-2-cyclopentenone (7) and 3,4-dihydroxy-2-(3-methyl-2-butenyl)-2-cyclopentenone (8), respectively. They arise by deacylation of anti-isohumulone (3_a), which is formed from humulone (1a) following an isomerization with ring contraction in opposite direction than the usual one producing isohumulones (2a).     

Synthesis of furan-fused 1,4-dihydrocarbazoles via an unusual Garratt-Braverman Cyclization of indolyl propargyl ethers and their antifungal activity

The reactivity of indole based bis-propargyl ethers 4a-4g under Garratt-Braverman condition (KOBu^t in refluxing toluene) has been studied. Interestingly, these propargyl systems with one arm attached with substituted 3-indolyl derivatives leaving the other arm unsubstituted produced the 3,4-furan fused dihydrocarbazole derivatives 6a-6g (and not the expected carbazole derivatives) as the predominant product (70–82%) making this methodology to access such derivatives an attractive route. The results are supported by computational studies and some of the carbazole derivatives showed good antifungal activities.     

Synthesis of a new series of pyridine and fused pyridine derivatives

The reaction of 4-methyl-2-phenyl-1,2-dihydro-6-oxo-5-pyridine- carbonitrile (1) with arylidene malononitrile afforded isoquinoline derivatives 2a,b. 6-Chloro-4-methyl-2-phenyl-5-pyridinecarbonitile (3) obtained by chlorination of compound 1 with phosphoryl chloride was converted into 6-amino-4-methyl-2-phenyl-5-pyridinecarbonitrile (4) and 6-hydrazido-4-methyl-2-phenyl-5-pyridinecarbonitrile (5) in good yield, through reactions with ammonium acetate and hydrazine hydrate, respectively. Treatment of 4 with ethyl acetoacetate, acetic anhydride, formic acid, urea and thiourea gave the corresponding pyrido [2,3-d] pyrimidine derivatives 7-10a,b. A new series of 6-substituted-4-methyl-2-phenyl-5-pyridine carbonitriles 11-13 has been synthesized via reaction of 4 with phenyl isothiocyanate, benzenesulphonyl chloride and acetic anhydride. Treatment of 4 with malononitrile gave 1,8-naphthyridine derivative 14. The reactivity of hydrazide 5 towards acetic acid, phenylisothiocyanate and methylacrylate to give pyrazolo-[3,4-b]-pyridine derivatives 15-17 was studied. Treatment of 5 with acetic anhydride, phthalic anhydride and carbon disulphide gave pyridine derivatives 18,19 and 1,2,4-triazolo-[3,4-a]-pyridine derivative 20.     

The reaction of cysteine with α,β-unsaturated aldehydes

Cysteine adds in a two step reaction to acroleine, crotonaldehyde and 4-hydroxypentenal. The first addition products are the β-cysteinyl-substituted saturated aldehydes 1a, 1b and 3. Only the monoadduct of 3, which is stabilized through intramolecular hemiacetal formation, could be isolated. The derivatives 1a and 1b reacted rapidly with additional cysteine to give the thiazolidine compounds 2a and 2b. Whereas 2a and 2b were the only products even in reactions carried out with a molar ratio of aldehyde : cysteine ≧ 1, ratio < 1 was required to obtain a thiazolidine derivative in reactions with hydroxypentenal. The structures of compound 2a, 2b, 3 and 4 were ascertained by means of UV, IR and NMR measurements, potentiometric titrations, determination of the rate laws and elemental analysis. All adducts are in solution in equilibrium with cysteine and the parent aldehydes. Rate constants for forward and reverse reactions were estimated. The rate of forward reactions increase approx. 10-fold per pH unit in the pH range 2–10.     

Synthesis,antimicrobial and cytotoxic activity of novel azetidine-2-one derivatives of 1H-benzimidazole

A series of 1-methyl-N-[(substituted-phenylmethylidene)-1H-benzimidazol-2-amines (4a–4g) were prepared via the formation of 1-methyl-1H-benzimidazol-2-amine (3), which was prepared by the cycloaddition of o-phenylenediamine (1) with cyanogen bromide in the presence of aqueous base followed by N-methylation with methyl iodide in the presence of anhydrous potassium carbonate in dry acetonitrile. Moreover, the four-membered β-lactam ring was introduced by the cycloaddition of 4a–4g and chloroacetyl chloride in the presence of triethylamine catalyst to give 3-chloro-1-(1-methyl-1H-benzimidazol-2-yl)-(4′-substituted)-phenylazetidin-2-one 5a–5g. A total of 14 compounds were synthesized and characterized by IR, ¹H NMR, ¹³C NMR and Mass spectral technique, in addition they were evaluated for anti-bacterial and cytotoxic properties. Among the chemicals tested 4a, 4b, 5a, 5b, 5g exhibited good antibacterial activity and 5f, 5g shown good cytotoxic activity in vitro.     

Synthesis and anti-neuroinflammatory activity studies of substituted 3,4-dihydroquinoxalin-2-amine derivatives

We demonstrate the synthesis of multifunctional 3,4-dihydroquinoxalin-2-amine derivatives 4 through a three-component condensation reactions of a substituted o-phenylenediamines 1 (OPDA), diverse ketones 2 and various isocyanides 3 in the presence of a catalytic amount of p-toluenesulfonic acid (PTSA) affording excellent yields (82–96%) and 10 mol % of silica gel supported sulfuric acid with good yields (85–98%) in ethanol at room temperature (2–4 h). We also carried out the anti-neuroinflammatory activity of 3,4-dihydroquinoxalin-2-amine derivatives and some of the compounds exhibited good activity.     

Synthesis,antimicrobial and anticancer activities of some new N-methylsulphonyl and N-benzenesulphonyl-3-indolyl heterocycles: 1st Cancer Update

A series of 1-(N-methyl 2a–c and N-benzenesulphonyl-1H-indol-3-yl)-3-aryl-prop-2-ene-1-ones 3a–c were prepared and allowed to react with urea, thiourea or guanidine and gave the pyrimidine derivatives 4a–c to 9a–c. Base catalyzed reaction of 2a–c or 3a–c with ethyl acetoacetate gave cyclohexanone derivatives 10a–c and 11a–c, respectively. Reaction of the latter compounds with hydrazine hydrate afforded indazole derivatives 12a–c and 13a–c, respectively. On the other hand, condensation of 2c or 3c with some hydrazine derivatives namely, hydrazine hydrate, acetyl hydrazine, phenyl hydrazine and benzyl hydrazine hydrochloride gave pyrazole derivatives 14a,b-17a,b, respectively. Moreover, reaction of 2c or 3c with hydroxyl amine hydrochloride gave isoxazole derivatives 18a,b. The newly synthesized compounds were tested for their antimicrobial activity and showed that, compounds 14a, 14b, 15a and 15b were found to be the most active ones of all the tested compounds toward Salmonella typhimurium (ATCC 14,028) compared to the reference drug chloramphenicol. Eighteen new compounds namely, pyrimidin-2(1H)-ones 4a–c and 5a–c, pyrimidin-2(1H)-thiones 6a–c and 7a–c and pyrimidin-2-amines 8a–c and 9a–c were tested for their in vitro cytotoxicity against human liver carcinoma (HEPG2), human breast cancer (MCF7) and human colon cancer (HCT-116) cell lines and showed that, compounds 4c, 5c, 6c, 8c and 9c were found to be the highly active compounds compared to the reference drug doxorubicin.     

A facile synthesis of pyrrolo[1,2-a]benzimidazoles and pyrazolo[3,4:4′,3′]pyrrolo[1,2-a]benzimidazole derivatives

Reaction of 2-cyanomethylbenzimidazole 1 with hydrazonoyl halides 2 led to formation of pyrrolo[1,2-a]benzimidazole derivatives 7. Similar reaction of 1 with halides 3 afforded 5-amino-4-(benzimidazol-2-yl)pyrazole derivatives 11 or 1-amino-2-arylpyrazolo[3,4:4′,3′]pyrrolo[1,2-a]benzimidazol-4-one 14 depending on the reaction conditions. The mechanisms of the studied reactions are discussed.     

Synthesis of new azetidinonyl/thiazolidinonyl quinazolinone derivatives as antiparkinsonian agents

Several 3-amantadinyl-2-[(2-substituted benzylidenehydrazinyl)methyl]-quinazolin-4(3H)-ones (5a–5l) were prepared by the reaction of 3-amantadinyl-2-hydrazinylmethyl substituted quinazolin-4(3H)-ones (4a–4b) with various substituted aromatic aldehydes. Cycloaddition of compounds (5a–5l) with thioglycolic acid in the presence of anhydrous zinc chloride yielded 3-amantadinyl-2-[((substitutedphenyl)-4-oxo-thiazolidin-3-yl)methylamino]-quinazolin-4(3H)-ones (6a–6l). Compounds 5a–5l on further reaction with chloro acetyl chloride in the presence of triethylamine gave 3-amantadinyl-2-[((substitutedphenyl)-3-chloro-2-oxo-azetidin-1-yl)methylamino]-quinazolin-4(3H)-ones (7a–7l). The compounds 5a–5l, 6a–6l and 7a–7l were screened for their antiparkinsonian activity. The most active compound was 6g i.e. 3-amantadinyl-6-bromo-2-[((3,4-dimethoxyphenyl)-4-oxo-thiazolidin-3-yl)methylamino]-quinazolin-4(3H)-ones. Structures of the newly synthesized compounds were established on the basis of elemental and spectral (IR, ¹H NMR and mass) analysis.     

Reactions of β-keto esters with 2-cyano-1,2,5,6- tetrahydropyridines

Reaction of the sodium salts of β-keto esters 13a and 13b with the 2-cyano-tetrahydropyridines 11 and 12 afforded the 4-substituted piperidine derivatives 21–23. The structures were assigned on the basis of their ¹H- and ¹³C-NMR spectra and by comparison with the model compounds 24–26. The stereochemistry and mechanism of the reactions are discussed.     

Synthesis of helical shaped 1,1′-bibenzo[c]phenanthrene-2,2′-diol (HEBPOL) derivatives by reduction of helical quinones

A new class of helical shaped bi-phenol (1,1′-bibenzo[c]phenanthrene-2,2′-diol; HEBPOL) type derivatives 2a–g were synthesized from quinone derivatives using the conventional 5% Pd-C catalytic reduction process. We obtained excellent yields for all of the 2a–g derivatives. The HEBPOLs were characterized by different analytical techniques including FTIR, ¹H NMR, ¹³C NMR, MS and X-ray crystallography.     

Synthesis,characterization and biological evaluation of purine nucleoside analogues

We present a convenient route for the synthesis of C6-amino-C5′-N-cyclopropyl carboxamido-C2-alkynylated purine nucleoside analogues 11a–g via Sonogashira coupling reaction. The nine step synthesis is easy to perform, employing commercially available reagents. Compound 9 is used as key intermediate for the synthesis of analogues 11a–g. Synthetic intermediates and final products are appropriately characterized by IR, ¹H NMR, ¹³C NMR and Mass. The modified nucleoside analogues 11a–g is evaluated for in vitro anticancer activity against MDA-MB-231 and Caco-2 cell lines. Screening data reveals that compounds 11b and 11e displayed potent IC₅₀ value of 7.9, 6.8 µg/mL respectively against MDA-MB-231 and of 7.5, 8.3 µg/mL respectively against Caco-2 than the standard drug doxorubicin, thus establishing the potential anti-cancer properties of these newer derivatives.