Synthesis and bioactivity of xyridin A and B,metabolites from xyris indica

A facile synthesis of the title isocoumarins isolated from. Xyris indica was accomplished. Condensation of butanoyl chloride and 2‐oxo‐butanoyl chloride with 3,4‐methylenedioxyhomophthalic acid afforded xyridin A and xyridin B respectively. Xyridin A was saponified to the corresponding keto acid which on reduction furnished the (±)‐3,4‐dihydro‐6,7‐methylenedioxy‐3‐propylisocoumarin. All of the synthesized compounds were examined in vitro for antibacterial and antifungal activities.     

Synthesis of 2,4‐diaminopyrido[2,3‐d]pyrimidines and 2,4‐diamino‐quinazolines with bulky dibenz[b,f]azepine and dibenzo[a,d]‐cycloheptene substituents at the 6‐position as inhibitors of dihydrofolate reductases from pneumocystis carinii,toxoplasma gondii,and mycobacterium avium

The synthesis of four previously undescribed 2,4‐diaminopyrido[2,3‐d]pyrimidines ( 3,4 ) and 2,4‐diaminoquinazolines ( 5,6 ) with a bulky tricyclic aromatic group at the 6‐position is described. Condensation of dibenz[b,f]azepine with 2,4‐diamino‐6‐bromomethylpyrido[2,3‐d]pyrimidine ( 8 ) and 2,4‐diamino‐6‐bromomethylquinazoline ( 17 ) in the presence of sodium hydride afforded N‐[(2,4‐diaminopyrido[2,3‐d]‐pyrimidin‐6‐yl)methyl]dibenz[b,f]azepine ( 3 ) and N‐[(2,4‐diaminoquinazolin‐6‐yl)methyl]dibenz[b,f]‐azepine ( 4 ), respectively. Condensation of 5‐chlorodibenzo[a,d]cycloheptene ( 19 ) and 5‐chloro‐10,11‐dihydrodibenzo[a,d]cycloheptene ( 20 ) with 2,4,6‐triaminoquinazoline ( 13 ) afforded 5‐[(2,4‐diamino‐quinazolin‐6‐yl)amino]‐5H‐dibenzo[a,d]cycloheptene ( 5 ) and the corresponding 10,11‐dihydro derivative ( 6 ), respectively. The bromides 8 and 17 , as hydrobromic acid salts, were obtained from the corresponding nitriles according to a standard three‐step sequence consisting of treatment with Raney nickel in formic acid followed by reduction with sodium borohydride and bromination with dry hydrogen bromide in glacial acetic acid. Compounds 3–6 were evaluated in vitro for the ability to inhibit dihydrofolate reductase from Pneumocystis carinii, Toxoplasma gondii, Mycobacterium avium, and rat liver. Compounds 3 and 4 were potent inhibitors of all four enzymes, with IC₅₀ values in the 0.03–0.1 μM range, whereas 5 was less potent. However the selectivity of all four compounds for the parasite enzymes relative to the rat enzyme was<10‐fold, whereas the recently reported lead compound in this series, N‐[(2,4‐diaminopteridin‐6‐yl)methyl]dibenz[b,f]azepine ( 1 ) has > 100‐fold selectivity for the T. gondii and M. avium enzyme and 21‐fold selectivity for the P carinii enzyme.     

Synthesis and Antimicrobial Evaluation of Some Novel 5‐Phenyl‐5H‐thiazolo[4,3‐b][1,3,4]thiadiazole Systems

Condensation of 2‐amino‐5‐phenyl‐5H‐thiazolo[4,3‐b] [1,3,4] thiadiazoles ( 1 ) with some carboxylic acid derivatives furnished corresponding compounds 2–4 , respectively. Alkylation of 1 with benzoylchloride and 4‐chlorobenzyl chloride afforded thiazolo[4,3‐b][1,3,4]thiadiazole derivatives 5 and 6 , respectively. Similarly, transformation of 1 with chloroacetyl chloride yielded chloroacetamide derivative 7 . The later compound was subjected to react with potassium thiocyanate or piperazine whereby, the binary thiazolidinone derivative 8 and N ¹ ,N⁴‐disubstituted piperazine 9 were produced, respectively. Also, the reactivity of 1 toward various active methylene reagents was investigated. Accordingly, our attempts to synthesize the tricyclic heterocyclic system 10 , 11′ , 12 ^′ by reaction of 1 with chloroacetonitrile, 4‐oxo‐4‐phenylbutanoic acid and/or diethylmalonate in presence of acetyl chloride was furnished 10 , 11 , and 12 . The newly synthesized compounds were screened as antimicrobial agent.     

New Routes to Fused Isoquinolines

Treatment of 6,7‐diethoxy‐3,4‐dihydroisoquinoline ( 8 ) and its 1‐methyl derivative 12 with hydrazonoyl halides 10 in the presence of Et₃N in THF under reflux afforded the corresponding 5,6‐dihydro‐1,2,4‐triazolo[3,4‐a]isoquinolines 11 and 13 , respectively, in high yield (Schemes 2 and 3). The products are formed via regioselective 1,3‐dipolar cycloaddition of the intermediate nitrilimines 9 with the isoquinoline C=N bond. Reaction of 6,7‐diethoxy‐3,4‐dihydroisoquinoline‐1‐acetonitrile ( 4a ) with ethyl α‐cyanocinnamates 15 in the presence of piperidine in refluxing MeCN yielded benzo[a]quinolizin‐4‐ones 16 (Scheme 4). Under the same conditions, 12 and arylidene malononitriles 19 reacted to give benzo[a]quinolizin‐4‐imines 20 (Scheme 5). Instead of 15 and 19 , mixtures of an aromatic aldehyde, and ethyl cyanoacetate or malononitrile, respectively, can be used in a one‐pot reaction.     

Synthesis and Characterization of New Heterocyclic Compounds Containing Thienylbenzo[h]Quinoline Moiety

In this paper the reaction of 2‐(2′‐thienylmethylene)‐3,4‐dihydronaphthalen‐2(1H)‐one ( 1 ) with cyanothioacetamide gave a mixture of 3‐cyano‐5,6‐dihydro‐4‐(2′‐thienyl)‐benzo[h]quinolin‐2(1H)‐thione ( 2 ) and the related disulfide 3 . Compound 2 was reacted with some halo compounds namely; ethyl chloroacetate, chloroacetamide, chloro(N‐(p‐chlorophenyl))acetamide, N¹‐chloroacetylsulfanilamide, and 2‐chloromethyl‐1H‐benzimidazole to produce a series of 2‐(substituted)methylthio‐3‐cyano‐5,6‐dihydro‐4‐(2′‐thienyl)benzo[h]quinolines 4a , 4b , 4c , 4d , 4e and 11 . Upon heating the latter compounds with sodium ethoxide, they underwent intramolecular Thorpe–Zeigler cyclization to furnish the corresponding 2‐(substituted)‐3‐amino‐5,6‐dihydro‐4‐(2′‐thienyl)‐benzo[h]thieno[2,3‐b]quinolines 5a , 5b , 5c , 5d , 5e and 12 . (3‐Cyano‐5,6‐dihydro‐4‐(2′‐thienyl)‐benzo[h]quinolin‐2‐ylthio)acethydrazide ( 8 ) and the related isomer, 3‐amino‐5,6‐dihydro‐4‐(2′‐thienyl)thieno[2,3‐b]benzo[h]quinoline‐2‐carbohydrazide ( 9 ), were also synthesized. Most of the aforementioned compounds were used as key intermediates for synthesizing other benzo[h]quinolines, benzo[h]thieno[2,3‐b]quinolines as well as benzo[h]pyrimido[4′,5′:4,5] thieno[2,3‐b]quinolines. The structure of all synthesized compounds was confirmed by spectroscopic measurements and analytical analyses.     

The synthesis of 5,6-dihydro-6-methylthiazolo-[2,3-b] [1,3] benzodiazepines, 2,3,10,11-tetrahydro-10-methyl-1H-cyclopenta[4,5] thiazolo[2,3-b] [1,3] benzodiazepine,and 7,8,9,10,12,13-hexahydro-13-methylbenzothiazolo[2,3-b] [1,3]-benzodiazepine via 1,3,4,5-tetrahydro-5-methyl-2H-1,3-benzodiazepine-2-thione

Catalytic reductive scission of 4-methylcinnoline (V) with Raney nickel afforded o-amino-β-methylphenethylamine (IV) in 57% yield. Treatment of IV with carbon disulfide followed by thermal cyclization of the product furnished 1,3,4,5-tetrahydro-5-methyl-2H-1,3-benzodiazepine-2-thione (III). Reaction of III with ethyl chloroacetate, ethyl 2-bromohexanoate, ethyl 2-chloroacetoacetate, 2-bromo-2′-methoxyacetophenone, and 2-bromoacetophenone provided a series of substituted 5,6-dihydro-6-methylthiazolo[2,3-b][1,3]benzodiazepines. Condensation of III with 2-chlorocyclopentanone and 2-chlorocyclohexanone gave 2,3,10,11-tetrahydro-10-methyl-1H-cyclopenta[4,5]thiazolo[2,3-b][1,3]benzodiazepine and 7,8,9,10,12,13-hexahydro-13-methylbenzothiazolo[2,3-b][1,3]benzodiazepine, respectively. Structure assignments are discussed. None of the compounds possessed appreciable biological activity.     

7-Benz[c] acridinemethanols as tetracyclic analogs of the 2-phenyl-4-quinolinemethanol antimalarials

A series of new 7-benz[c]acridinemethanols and 5,6-dihydro-7-benz[c]acridinemethanols was prepared as rigid, tetracyclic analogs of the antimalarial 2-phenyl-4-quinolinemethanols. Condensation of 5,7-dichloroisatin with 6-chloro-, 7-chloro-, and 6,7-dichloro-1-tetralone furnished halogenated 5,6-dihydro-7-benz[c]acridinecarboxylic acids, which were transformed into the corresponding acid chlorides, acyl malonates, α-bromomethyl ketones, and epoxides. Fully aromatic members of the series obtained via dehydrogenation of the 5,6-dihydro acids were likewise converted into epoxides via the acylmalonate route. Although all the epoxides studied proved to be exceptionally resistant to ring-opening by di-n-butylamine, probably on account of steric effects, they could be cleaved readily with piperidine or morpholine. Nmr spectra of the resulting amino alcohols suggest that these compounds exist in a single preferred conformation stabilized by internal O-H····N hydrogen bonding, and that free rotation about the side chain C-C bond does not occur at room temperature.     

Synthesis and Antioxidant Activity of Some Novel Nicotinonitrile Derivatives Bearing a Furan Moiety

As a part of ongoing studies in developing new potent antioxidant agents, 2‐amino‐4‐(furan‐2‐yl)‐5,6‐dimethylnicotinonitrile 4 was utilized as a key intermediate for the synthesis of some new pyrimidines 5 and 11 , form (acet)amide 6 , 7 , urea and thiourea 9 , 10 , 1,8‐naphthyridines 12 , 13 , and 14 . Moreover, condensation of 4 with 5,5‐dimethyl‐1,3‐cyclohexanedione and cyclohexanone in ethanol furnished the pyridine derivatives 16 and 17 , respectively. Furthermore, refluxing of 4 with ethylenediamine in carbon disulfide afforded the 4,5‐dihydro‐1H‐imidazol‐2‐yl pyridine derivative 19 . In addition, refluxing of 4 with carbon disulfide and concentrated sulfuric acid furnished the pyridine derivatives 20 and 21 , respectively. The reaction of 4 with phenacyl chloride and ethyl chloroacetate in dimethylformamide in the presence of catalytic amount of triethylamine afforded the pyridine derivatives 22 and 23 , respectively. Finally, heating of 4 with 1‐phenyl‐3‐(piperidin‐1‐yl)propan‐1‐one hydrochloride in glacial acetic acid afforded phenylpropylamino pyridine derivative 24 . The structures of the newly synthesized compounds were confirmed by elemental analysis, IR, ¹H‐NMR, and mass spectral data. Representative compounds of the synthesized products were evaluated as antioxidant agents. Compounds 8 , 19 , and 22 are promising compounds.     

1-Phenyl-6,7-disubstituted-aminopropyl)-1,2,3,4-tetrahydroisoquinolines as possible antituberculer agents

The Condensation of 3,4-disubstituted phenylethylamine and benzaldehyde furnished l-phenyl-6,7-disubstituted-1,2,3,4-tetrahydroisoquinolines l. which on reaction with 1,3-dibromopropane gave l-phenyl-6,7-disubstituted-2-(3-bromoprophyl)-1,2,3,4-tetrahydroisoquinolines 2. The reaction of 2 with different secondary amines resulted in the synthesis of 3. The compounds 3 were screened for their in vitro antituberculer activity against Mycobacterium smegmatis, and some of them have been found to be total inhibitors of M. Smegmatis     

Synthesis of 1‐Amino‐5,6‐diaryl‐3‐cyano‐1H‐pyridin‐2‐ones and 6,7‐Diaryl‐4‐cyano‐3‐hydroxy‐1H‐[1,2]diazepines from Isoflavones

The one‐step cyclocondensation of substituted isoflavones (=3‐phenyl‐4H‐1‐benzopyran‐4‐ones) with cyanoacetohydrazide in the presence of KOH afforded a mixture of 1‐amino‐5,6‐diaryl‐3‐cyano‐1H‐2‐pyridin‐2‐ones and 6,7‐diaryl‐4‐cyano‐3‐hydroxy‐1H‐[1,2]diazepines.     

Syntheses of Three New Pyridyl Thienopyridine Ligands via the Hurtley Reaction

The tridentate pyridyl thienopyridines 5‐phenyl‐7‐(pyridin‐2‐yl)thieno[2,3‐c]pyridine ( L1 ), 7‐(pyridin‐2‐yl)‐5‐(thiophen‐2‐yl)‐thieno[2,3‐c]pyridine ( L2 ) and 5,7‐di(pyridin‐2‐yl)thieno[2,3‐c]pyridine ( L3 ) have been synthesized via the Hurtley reaction. L1 and L2 were synthesized by condensing 3‐bromothiophene‐2‐carboxylic acid with phenyl‐1,3‐butanedione and 1‐thienyl‐1,3‐butanedione respectively. L3 was synthesized by condensing 3‐bromothiophene‐2‐carboxylic acid with benzoylacetonitrile. Ring closure and a subsequent Negishi or Stille cross‐coupling afforded L1 , L2 , and L3 in an overall yield of 20, 3, and 6%, respectively.     

Gas-phase pyrolytic reactions. Part 6. [1] Behavior of ethyl (hetero)arylcarboxylate esters in thermal elimination reactions

Rates, Arrhenius parameters, and Hammett substituent constants are obtained for the gas-phase thermal elimination of ethyl benzoate (1) and ethyl 2—thienyl— (2), 3—thienyl— (3), 2—furyl— (4), 3—furyl— (5), 4—pyridyl— (6), 3—pyridyl— (7), and 2—pyridylcarboxylate (8) esters. The log A/s⁻¹ and the E_a/kJ mol⁻¹ values of these esters averaged 13.60 and 216.3, respectively. The present results are compared with data previously reported for the corresponding isopropyl and t-butyl analogues, and the findings are rationalized in terms of a plausible transition state for the elimination pathway. © 1997 John Wiley & Sons, Inc. Int J Chem Kinet 29: 289–293, 1997.     

Synthesis,characterization, and biological activity of some aza‐uracil derivatives

Thiation of 1 by LR gave the corresponding 3,5‐dithioxo derivative 2 and the trimer 3 . Methylation of 1 afforded the S‐methyl derivative 4 . Compound 1 was fused with 6‐bromo‐2‐phenyl‐benzo[1,3‐d]oxazin‐4‐one ( 5 ) and gave 6 . Condensation of 1 with some acid derivatives 7a , 7b , 7c , 7d and/or 8a , 8b , 8c yielded thiadiazolo‐triazine derivatives 9a , 9b , 9c , 9d and 10a , 10b , 10c . Compounds 9a , 9c and 10c were hydrolyzed to furnish 11a , 11b , 11c Acetylation of 14 afforded mono‐ and diacetyl‐derivatives 15 and 16 . Benzoylation of 14 afforded mono‐ and dibezoyl‐derivatives 17 and 18 . 14 with some aromatic aldehydes yielded 9a , 9b , 9c . Reacting 14 with phenyl (iso‐ and/or isothio‐) cyanate gave the urea derivatives 20a , 20b . Thiation of 14 with P₄S₁₀ furnished 21 . The newly synthesized compounds were tested as antimicrobial agents. J. Heterocyclic Chem., (2011)     

Synthesis of Some Novel 2‐Anilinothiophene, 2,3′‐Bithienyl and Thienylthiopyridine Derivatives Resistance to Penicillium Digitatum Effect the Fruit

Reaction of benzotriazol‐1‐yl acetone 1 with phenyl isothiocyanate followed with α‐chloroacetone or ethyl‐α‐chloroacetate afforded 2‐anilinothiophenes 3 or 4 , respectively. Treatment of 3 with malononitrile at different reaction conditions afforded 6 or 7 . Reaction of 1 with CS₂ in DMF and phenacylbromide afforded S‐alkylated thiophene 10 . Reactions of the latter compound with different active methylene nitriles afforded thienylthiopyridine derivatives 14 and 15 . Condensation of 10 with hydrazine hydrate afforded hydrazon derivative 16 . Reaction of thiophene 17 with formamide in DMF afforded 19 which converted to N‐thienylpyrimidine 20 when treated with malononitrile. The structure of the newly synthesized compounds has been established on the basis of their analytical and spectral data. The compounds were also investigated for antibacterial and antifungal activities.     

New syntheses and spectral properties of pteridine‐related heterocycles from 2,5‐diamino‐3,6‐dicyanopyrazine

The reaction of 2,5‐diamino‐3,6‐dicyanopyrazine ( 1 ) as a new pyrazine raw material with alkyl isocyanate in the presence of sodium hydride gave novel heptahydroirnidazo[4,5‐g]pteridine‐2,6,8‐trione ( 2 ), but with tertiary butyl isocyanate gave trihydroimidazo[4,5‐b]pyrazine‐2‐ones ( 3 ). Similar reaction of 1 with alkyl thioisocyanate followed by alkyl iodide gave tetrahydropyrimido[4,5‐g]pteridines ( 4 ). The reac tion of 1 with alkylamine gave the amine‐adduct of the cyano groups which was further reacted with arylaldehyde to give the pyrimido[4,5‐g]pteridine ( 10 ). The products prepared are all of interest as potential pesticides and fluorescent chromophores.     

Design,Synthesis, and Antimicrobial Evaluation of some Novel Pyridine,Coumarin, and Thiazole Derivatives

Treatment of 2‐cyano‐N′‐(1‐(pyridin‐2‐yl)ethylidene)acetohydrazide 1 with aromatic/heterocyclic aldehydes 2a–f gave arylidene derivatives 3a–f . Polysubstituted pyridine derivatives 4a,b were prepared either from reaction of arylidene 3a,b with malononitrile or from reaction of acetohydrazide 1 with arylidenemalononitrile 5a,b . Cyclocondensation of acetohydrazide 1 with salicylaldehyde derivatives and acetylacetone furnished pyrido‐coumarins 6,7 and 2‐pyridone‐3‐carbonitrile 8, respectively. In addition, pyrido‐thiazoles 13 and 15 were obtained through reaction of 2‐(1‐(pyridin‐2‐yl)ethylidene)hydrazinecarbothioamide 11 with hydrazonyl chlorides and α‐haloketones, respectively. The structures of synthesized compounds were elucidated with spectral and elemental data. The antimicrobial activity of the synthesized compounds was studied.     

Highly efficient total synthesis of Δ-PGJ2, 15-deoxy-Δ-PGJ2, and their analogues

Palladium-catalyzed reaction of TBS ether of 4-cyclopentene-1,3-diol monoacetate (>95% ee) with an anion derived from methyl malonate and a base such as t-BuOK and LDA proceeded highly efficiently and reproducibly. The product obtained in >90% isolated yield was transformed in five steps into the key cyclopentenone possessing the α-chain at the γ position. Aldol reaction of this enone with the ω-chain aldehyde afforded the aldol adduct, and exposure of the derived mesylate to Al₂O₃ furnished the cross-conjugated dienone of the full structure. Finally, functional group manipulation furnished Δ¹²-PGJ₂ efficiently. Similarly, 15-deoxy-Δ^12,14-PGJ₂, 5,6-acetylene analogues, and a 5,6-dihydro analogue were synthesized.     

Synthesis and chemistry of some pyridazine nucleosides related to certain 5-substituted pyrimidine nucleosides

Condensation of 3,4-dichloro-6-[(trimethylsilyl)oxy] pyridazine ( 3 ) with 1-O-acetyl-2,3,5-tri-O-benzoyl-β- D -ribofuranose ( 4 ), by the stannic chloride catalyzed procedure, has furnished 3,4-dichloro-1-(2,3,5-tri-O-benzoyl-β- D -ribofuranosyl) pyridazin-6-one ( 5 ). Nucleophilic displacement of the chloro groups and removal of the benzoyl blocking groups from 5 has furnished 3-chloro-4-methoxy-, 3,4-dimethoxy-, 4-amino-3-chloro-, 3-chloro-4-methylamino-, 3-chloro-4-hydroxy-, and 4-hydroxy-3-methoxy-1-β- D -ribofuranosylpyridazin-6-one. An unusual reaction of 5 with dimethylamine is reported. Condensation of 4,5-dichloro-3-nitro-6-[(trimethylsilyl)oxy]pyridazine with 4 yielded 4,5-dichloro-3-nitro-1-(2,3,5-tri-O-benzoyl-β- D -ribofuranosyl)pyridazin-6-one ( 24 ). Nucleophilic displacement of the aromatic nitro groups from 24 is discussed. Condensation of 3 with 3,5-di-O-p-toluoyl 2-deoxy- D -erythro-pentofuranosyl chloride ( 28 ) afforded an α, β mixture of 2-deoxy nucleosides. The synthesis of certain 3-substituted pyridazine 2′-deoxy necleosides are reported.     

Synthesis of Some New Heterocycles of Pharmaceutical Interest: Pyridinyl and Isoxazolyl Quinoxaline Derivatives

3‐(p‐Acetyl‐anilinomethyl)quinoxalin‐2(1H)‐one ( 3 ) was prepared by the reaction of 3‐bromomethyl‐quinoxalin‐2(1H)‐one ( 1 ) with p‐aminoacetophenone ( 2 ) in pyridine. Reaction of p‐acetylcompound ( 3 ) with aromatic aldehydes yield the corresponding chalcones ( 4a‐c ). Condensation of latter chalcones with malononitrile afforded cyanopyridines ( 5a‐c ). Also, the reaction of chalcones ( 4a‐c ) with hydroxylamine hydrochloride furnished isoxazoles ( 6a‐c ). The reaction of bromo compound ( 1 ) with p‐aminobenzophenone yield ( 8 ) which was condenced with hydrazine hydrate to get the corresponding hydrazone derivatives ( 9 ). Some of the synthesized compounds have been screened for their antimicrobial activity against various strains of bacteria and fungi.