Synthesis and antitumor evaluation of novel tetrahydrobenzo[4′,5′]thieno[3′,2′:5,6]pyrimido[1,2-b]isoquinoline derivatives

In the present study, a novel 8,9,10,11-tetrahydro-7H,14H-benzo[4′,5′] thieno[2′,3′:4,5]-1,3-oxazino[3,2-b]isoquinoline-7,14-dione 5 was prepared by condensation of 2-amino-3-carbethoxy-4,5,6,7-tetrahydrobenzothiophene with homophthalic anhydride under microwave irradiation, followed by alkaline hydrolysis and cyclization using acetyl chloride. Compound 5 was further allowed to react with different nitrogen nucleophiles to get new tetrahydrobenzothienopyrimido isoquinolinone derivatives. The structures of the prepared compounds were elucidated by IR, ¹H-NMR, ¹³C-NMR, and mass spectroscopy. The newly prepared compounds were tested in vitro against a panel of two human tumor cell lines, namely, hepatocellular carcinoma (liver) HepG2, and mammary gland breast MCF-7. Almost all the tested compounds showed satisfactory activity.     

A Greener Approach Synthesis and Docking Studies of Perimidine Derivatives as Potential Anticancer Agents

Microwave solvent‐free technique was employed to the synthesis of series of 2‐(1H‐perimidin‐2(3H)‐ylidene) derivatives, 4‐(1H‐perimidin‐2‐yl)‐1H‐pyrazole‐3‐carboxamides, pyrrolo[1,2‐a]perimidin‐10‐ones, and 8H‐[1,2,4]triazolo[4,3‐a]perimidine. Compared with conventional method, the obvious feature of microwave method is higher in chemical yield, faster reaction rate, and cleaner reaction condition. The structures of the synthesized compounds were confirmed based on their elemental analyses and spectroscopic data (FT‐IR, ¹H‐NMR, ¹⁹F‐NMR, ¹³C‐NMR, and LC‐MS/MS). Some of the synthesized compounds exhibit anticancer potential against the growth of both the human breast (MCF‐7) and the liver carcinoma (HepG2) tumor cells. The most active cytotoxic perimidine derivatives were docked against topoisomerase II to investigate their binding and DNA intercalating activity against the protein crystal structure.     

Substituted Pyrazolo[3,4‐d]pyrimidines: Microwave‐Assisted,Solvent‐Free Synthesis and Biological Evaluation

A simple and efficient method has been developed for the synthesis of various pyrazolo[3,4‐d]pyrimidines by using microwave irradiation under solvent‐free conditions. The advantages of applying microwave irradiation compared with the classical method were demonstrated. The structures of all the compounds were confirmed by the usual techniques and, in two cases, by X‐ray analysis. The compounds did not display appreciable ability to inhibit xanthine oxidase activity. Screening for antifungal activity showed that some derivatives were active against four fungi, with more significant results for Botrytis.     

Preparation,characterization and use of new lignocellulose-based bio nanocomposite as a heterogeneous catalyst for sustainable synthesis of pyrimido benzazoles

A sustainable combinatorial synthesis of densely substituted pyrimido [1,2-b] benzazole derivatives in water under microwave irradiation was performed using a new lignocellulose-based bio nanocomposite (BNC) as heterogeneous catalyst. The lignocellulosic waste peanut shells (LCWPS) were turned into a value-added product, a new BNC PS/ZnO, which was prepared via in situ hydrothermal synthesis. The as-prepared BNC was characterized by Fourier transform infrared spectroscopy, scanning electron microscopy, transmission electron microscopy, energy-dispersive X-ray spectroscopy and X-ray diffraction spectrum. PS/ZnO has been successfully used in a sustainable catalytic method for the synthesis of pyrimido [1, 2-b] benzazole derivatives in water under microwave irradiation. The time of this reaction was significantly reduced. This catalytic system has a very high turnover number (TON?～?10³) and turnover frequency (TOF?～?10^5?h^?1). This paper presents the benefit of sustainable management of LCWPS, a bio-sourced polymeric carbohydrate for production of new nanocatalyst.     

Microwave Promoted One‐Pot Synthesis of Some Novel N‐Aryl Isoquinoline Derivatives

Homophthalic anhydride 1 reacts with different aromatic amines to produce N‐substituted homophthalimides 2 under microwave irradiation. A rapid microwave‐assisted chemical synthesis of condensed 4‐substituted furo[2,3‐c]isoquinoline‐1,5(2H,4H)‐diones 3 and 5‐substituted‐2,3‐dihydro‐1H‐pyrano[2,3‐c]isoquinoline‐1,6(5H)‐diones 4 involving the condensation of a variety of alkanoyl chlorides with 2‐arylisoquinoline‐1,3‐diones 2 in the presence of base and aprotic solvent is described for the first time. By contrast, the facile ring opening reaction of furo[2,3‐c]isoquinoline‐1,5(2H,4H)‐dione 3 with Vilsmeier–Haack reagent under microwave irradiation yielded the α‐β unsaturated carboxyaldehyde 5 . This novel and clean one‐pot methodology, which is characterized by very short reaction time and easy workup procedure, can be exploited to generate some novel condensed isoquinoline derivatives.     

A Convenient and Efficient Synthesis of 2‐Thioxoquinazolinone Derivatives via Microwave Irradiation

The synthesis of 2‐thioxoquinazolinone derivatives was achieved by condensation of isatoic anhydride, primary amine, and carbon disulfide under microwave irradiation. This convenient and efficient method affords the desired products with good to excellent yields. Satisfactory infrared spectroscopy, ¹H NMR, and high‐resolution mass spectrometry (electrospray ionization) spectra were obtained for all compounds described.     

Molecular iodine‐catalyzed one‐pot synthesis of tetrahydrobenzo[a]xanthene‐11‐one and diazabenzo[a]anthracene‐9,11‐dione derivatives under microwave irradiation

An efficient one‐pot condensation of β‐naphthol, aldehydes, and cyclic 1,3‐dicarbonyl compounds has been achieved with molecular iodine as a catalyst under microwave irradiation, thus a variety of tetrahydrobenzo[a]xanthene‐11‐one and diazabenzo[a]anthracene‐9,11‐dione derivatives were prepared in good yields. J. Heterocyclic Chem., (2011).     

Synthesis of Certain Fused Thienopyrimidines of Biological Interest

4‐(4‐Acetylphenylamino)cycloocteno[4,5]thieno[2,3‐d]pyrimidine ( 4 ) was prepared and condensed with certain aldehydes, phenylhydrazine, malononitrile to obtain 5a‐d , 6 and 7 , respectively. 4‐Hydrazino & 4‐substituted amino derivatives of 2‐arylcycloocteno[4,5]thienopyrimidines 10a‐c & 11a‐i were synthesized. Cyclization of the hydrazino compounds 10a‐c with orthoalkanoate esters or the arylidene derivatives 12a‐c with bromine in acetic acid afforded the fused triazolo system 13a‐i . Reaction of the hydrazino compound 10c with acetic anhydride gave 15 while the reaction of 10b,c with acid chlorides gave 16a‐d . Furthermore, the tetrazolothienopyrimidines 17a‐c were synthesized. Some of the newly synthesized compounds were tested for their antimicrobial activity.     

A Novel Procedure to Synthesize 3‐Chloro‐1‐(4a,10b‐diazaphenanthrene‐2‐yl)‐4‐phenyl Azetidin‐2‐ones and Exploration of Their Anti‐Inflammatory Activity

Some new derivatives of 3‐chloro‐1‐(4a,10b‐diazaphenanthrene‐2‐yl)‐4‐phenyl azetidin‐2‐one were synthesized through the reaction of N‐{4‐[phenyldiazenyl] phenyl}‐N‐[phenyl methylene] amine with 4‐[phenyldiazenyl] aniline. The resulting 3‐chloro‐4‐phenyl‐1‐{4‐[phenyldiazenyl] phenyl} azetidin‐2‐one intermediate in benzene was irradiated in a Pyrex vessel with 350 nm UV light in a photochemical reactor to give the desired derivatives (4a–j) . Structures of the new compounds were verified on the basis of spectral and elemental methods of analyses. Nine of the prepared compounds were tested for their anti‐inflammatory effects; most of these compounds showed potent and significant results compared with indomethacin.     

An Eco‐friendly Synthesis and Biological Screening of Fused Heterocyclic Compounds Containing a Thiophene Moiety via Gewald Reaction

5‐Amino‐3‐phenyl‐1‐(2,4,6‐trichlorophenyl)‐1H‐thieno[3,2‐c]pyrazole‐6‐carbonitrile ( 2 ) was designed and synthesized by one‐pot multicomponent reaction. Compound 2 was reacted with different reagents to obtain new condensed moieties with our thienopyrazole skeleton. The compounds were prepared by using environmentally benign techniques as microwave irradiation, ultrasonic irradiation, and ball‐milling. The structure of the prepared compounds was elucidated through spectroscopic methods. The new compounds were evaluated for their in vitro antibacterial and antifungal potentialities.     

[BMIM]Cl Catalyzed One‐Pot Synthesis of α‐Aminophosphonate Derivatives Containing a 4‐Phenoxyquinazoline Moiety under Microwave Irradiation

[BMIM]Cl catalyzed three component Mannich‐type reaction of 4‐(quinazolin‐4‐yloxy)benzenamine and aldehyde with dialkyl phosphite under microwave irradiation has been described. The salient features of the reaction leading to new α‐aminophosphonates include shorter reaction time and good yields. The method is environmentally friendly and does not require toxic catalysts or solvents. To the best of our knowledge, this is the first report for [BMIM]Cl induced one‐pot synthesis of α‐aminophosphonate derivatives.     

Synthesis and Reactions of Some Heterocyclic Candidates Based on 2‐Amino‐4,5,6,7‐tetrahydrobenzo[b]thiophene Moiety as Anti‐Arrhythmic Agents

In continuation of our previous work, a series of novel thiophene derivatives 4 , 5 , 6 , 8 , 9 , 9a , 9b , 9c , 9d , 9e , 10 , 10a , 10b , 10c , 10d , 10e , 11 , 12 , 13 , 14 , 15 , 16 were synthesized by the reaction of ethyl 2‐amino‐4,5,6,7‐tetrahydrobenzo[b]thiophene‐3‐carboxylate ( 1 ) or 2‐amino‐4,5,6,7‐tetrahydrobenzo[b]thiophene‐3‐carbonitrile ( 2 ) with different organic reagents. Fusion of 1 with ethylcyanoacetate or maleic anhydride afforded the corresponding thienooxazinone derivative 4 and N‐thienylmalimide derivative 5 , respectively. Acylation of 1 with chloroacetylchloride afforded the amide 6 , which was cyclized with ammonium thiocyanate to give the corresponding N‐theinylthiazole derivative 8 . On the other hand, reaction of 1 with substituted aroylisothiocyanate derivatives gave the corresponding thiourea derivatives 9a , 9b , 9c , 9d , 9e , which were cyclized by the action of sodium ethoxide to afford the corresponding N‐substituted thiopyrimidine derivatives 10a , 10b , 10c , 10d , 10e . Condensation of 2 with acid anhydrides in refluxing acetic acid afforded the corresponding imide carbonitrile derivatives 11 , 12 , 13 . Similarly, condensation of 1 with the previous acid anhydride yielded the corresponding imide ethyl ester derivatives 14 , 15 , 16 , respectively. The structures of newly synthesized compounds were confirmed by IR, ¹H NMR, ¹³C NMR, MS spectral data, and elemental analysis. The detailed synthesis, spectroscopic data, LD₅₀, and pharmacological activities of the synthesized compounds are reported.     

Design and Synthesis of Antimicrobial Active (E)‐(3‐(Substituted‐styryl)‐7H‐furo[2,3‐f]chromen‐2‐yl)(phenyl)methanone Derivatives and Their In Silico Molecular Docking Studies

Nine new (E)‐(3‐(substituted‐styryl)‐7H‐furo[2,3‐f]chromen‐2‐yl)(phenyl)methanone derivatives, 7 ( a – i ), with an efficient microwave‐assisted synthetic method was achieved by reacting with (E)‐3‐(aryl)‐1‐(5‐hydroxy‐2H‐chromen‐6‐yl)prop‐2‐en‐1‐ones and 2‐bromo‐1‐(4‐bromophenyl)ethanone. The microwave irradiation method was found to be best with high yields and with shorter reaction times compared with the conventional method. All the new products structural assignments were confirmed by spectral data like FTIR, ¹H NMR, ¹³C NMR, ESI MS, and analytical data. Moreover, these newly synthesized compounds were tested in vitro for their antimicrobial activity against various bacterial and fungal strains. Some of these new chromen derivatives like 7b , 7c , and 7d exhibits good antibacterial and antifungal activities. Furthermore, these biological evolution results were a good correlation with molecular docking studies performed based on their computational DFT minimized structures exhibited high binding energies.     

A Convenient Synthetic Method and Spectral Characterization of New Tetrahydro[1,3]oxazinothieno[2,3‐c]isoquinoline and Its Pyrimidine Derivatives

Acetylation of 1‐amino‐5‐morpholin‐4‐yl‐6,7,8,9‐tetrahydrothieno[2,3‐c ]isoquinoline‐2‐phenyl carboxamide 3 afforded the corresponding tetrahydro[1,3]oxazinothieno[2,3‐c ]isoquinolinone compound 4 . The oxazinone compound 4 underwent nucleophilic substitution reactions with various primary aliphatic and aromatic amines including some sulfa drugs such as sulfanilamide, sulfaguanidine, and sulfathiazole to afford the substituted pyrimidinone compounds 6–10 . Chlorination of the pyrimidinone 10 with phosphorus oxychloride yielded the chloropyrimidine derivative 11 . The latter compound was used as a versatile precursor for the synthesis of other heterocyclic rings containing the tetrahydropyrimidothienoisoquinoline moiety 12–23 through reaction with a variety of organic reagents. The newly synthesized compounds were fully characterized by elemental and spectral analyses, including melting point, TLC, and FT IR and ¹H NMR spectroscopy, as well as ¹³C NMR and mass spectroscopy for most of them. These molecules should allow to us in the future to investigate their pharmacological activities.     

Conventional and Microwave‐Assisted Synthesis and Biological Activity Study of Novel Heterocycles Containing Pyran Moiety

Under both conventional and microwave methods, 2‐amino‐4H‐pyran‐3‐carbonitrile derivative 1 was synthesized and reacted with different reagents. Thus, 2‐amino‐4H‐pyran‐3‐carbonitrile derivative was treated with chloroacetyl chloride, phenyl isocyanate, cyanoacetic acid, benzoyl chloride, triethyl orthoformate, acetic anhydride/H₂SO₄, arylidene malononitrile, urea, and/or p‐aminosulphaguanidine producing chloroacetamide, 3‐phenylurea, cyanoacetamide, N‐benzoylpyran, ethylformimidate, pyranopyrimidin‐4‐one, pyranopyridine, pyranopyrimidin‐2‐one, and pyranopyrimidin‐2‐imine derivatives, respectively. Meanwhile, compound 1 was reacted with ethyl bromoacetate, phenacyl bromide, phthalic anhydride, different aromatic amines, and/or acetic acid/H₂SO₄ to produce 5‐aminopyrano[2,3‐b]pyrrole‐6‐carboxylate, dihydropyrano[2,3‐b]pyrrole‐6‐yl‐(phenyl)methanone, 1,3‐dioxoisoindolinyl pyran, 1,4‐dihydropyridine, and 2‐hydroxy‐1,4‐dihydropyridine derivatives, respectively. On the other hand, when compound 1 was allowed to react with maleic anhydride and/or hydrazine hydrate, pyran‐4‐oxobut‐2‐enoic acid and 3‐aminopyranopyrazole derivatives were obtained, respectively. Reaction of pyran‐4‐oxobut‐2‐enoic acid with malononitrile under different conditions gave 2‐(furan‐2‐yl)‐4H‐pyran and 2‐(4H‐pyran‐2‐yl)‐1H‐pyrrole derivatives, while condensation of 3‐aminopyranopyrazole with benzaldehyde gave 1,4‐dihydropyrano[2,3‐c]pyrazol‐3‐yl‐1‐phenylmethanimine derivative. The newly synthesized compounds were characterized by the spectroscopic tools IR, ¹H‐NMR, ¹³C‐NMR, MS, and elemental analysis. Some of these compounds have been screened in vitro for antimicrobial activity against different strains of bacteria and fungi and also were tested against two cancer cell lines: mammary gland breast cancer (MCF‐7) and colon cancer (HCT‐118).     

Characterization and Comparative Studies on Conventional and Microwave Synthesis of Some Disulfides

Abstract

Some disulfide derivatives have been prepared by microwave assisted synthesis methodology from thiophthalimides(sulfenimides) and thiols in a modified microwave oven under reflux at 600 Watt in ethanol. Elucidation of the structures of the synthesized compounds has been performed by IR, ¹H NMR, and ¹³C NMR spectroscopic methods.

[Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements for the following free supplemental files: Additional figures]     

BTADCI Promoted One‐pot Synthesis of 14‐aryl‐14H‐dibenzo [a,j] Xanthenes

A convenient eco‐friendly one‐pot synthesis of 14‐aryl‐14H‐dibenzo [a, j] xanthenes were developed by the condensation of aromatic aldehydes and β‐naphthol with BTADCI (Benzyltrimethylammonium dichloroiodate) as catalyst under solvent free conditions and microwave irradiation with much more rate accelerations and afford very good yields. Developed protocols involve mild reaction conditions, simple isolation of derivatives with inexpensive reagents.     

Synthesis and Antifungal Activity of Novel 1,2,4‐Triazole Derivatives Containing 1,2,3‐Thiadiazole Moiety

Starting from carbonic acid diethyl ester, a series of 1,2,4‐triazole derivatives containing 1,2,3‐thiadiazole were synthesized. Reactions were performed by microwave irradiation or ultrasonic irradiation as well as by conventional heating. The structure of title compounds was characterized by ¹H‐NMR, MS, and elemental analyses. The fungicidal activities of these compounds were tested in vivo. Most of title compounds exhibited good antifungal activity against Pseudoperonospora cubensis. Some of title compounds displayed moderate antifungal activities against Fusarium oxysporum, Pseudoperonospora cubensis, Sphaerotheca fuligenea, Corynespora cassiicola, and Xanthomonas axonopodis.     

Synthesis,Reactions, and Pharmacological Evaluations of Some Novel Pyridazolopyridiazine Candidates

Herein, we report the synthesis, characterization, and preliminary pharmacological activity of a new series of substituted pyrazolopyridazine derivatives. Compound 1 was reacted with ethoxymethylene malononitrile 2 in refluxing ethanol to give the corresponding compound 3 , which was treated with hydrazine hydrate or formamide to give pyrazolo[3,4‐c]pyrazole 4 and pyrazolo pyrimidine 5 derivatives, respectively. Also, compound 3 was reacted with NH₄SCN or carbon disulphide or ethyl acetoacetate to yield the corresponding pyrazolo derivatives 6 , 7 , 8 , respectively. Additionally, compound 3 was reacted with triethyl orthoformat in acetic anhydride to give 9 , which was treated with hydrazine hydrate to give hydrazino derivative 10 . The latter compound transformed into the pyrazolo[4,3‐e][1,2,4]triazolo[1,5‐c]‐pyrimidine 11 via refluxing with acetic anhydride. Finally, compound 9 was reacted with benzoic acid hydrazide or mercapto acetic acid to give compounds 12 and 13 , respectively. The latter compound was treated with refluxing ethanolic sodium ethoxide solution to afford the pyrazolothiazolopyrimidine 14 . Some of the compounds exhibited better activities as anti‐inflammatory and antimicrobial agents than the reference controls. The detailed synthesis, spectroscopic data, anti‐inflammatory, and antimicrobial activities of the synthesized compounds was reported.     

Synthesis of Some New Benzo[b][1,4]diazepine Based Heterocycles

Preparation of 4‐chloro‐3H‐benzo[b][1,4]diazepine‐2‐carbaldehyde 5 , which is used as a key intermediate in the synthesis of chalcones derivatives, via its condensation with some aromatic acetophenone derivatives under ethanol piperidine condition was described. Also illustrated was the reaction of such chalcones with available nucleophilics and reagents of active methylene group to afford new series of fused and isolated pyrazoles, isoxazolines pyrimidines, pyridines, triazolo[1,5‐a]pyrimidines, benzo[1,4]oxa(thia)zepines, and pyrido[1,2‐a]benzimidazoles incorporating 4‐chloro‐3H‐benzo[b][1,4]diazepine moiety, which have a potential pharmaceutical interest. Furthermore, condensation reaction of 4‐chloro‐3H‐benzo[b][1,4]diazepine‐2‐carbaldehyde with aromatic amine derivatives to afford the Schiff's bases was described. The C═N double bond of the latter compounds has been reacted with chloroketene to give β‐lactams and with sulfanylacetic acid to give the 2‐(4‐oxo‐1,3‐thiazolidinyl)‐substituted derivative. The structures of the newly prepared compounds were established by elemental analysis, IR, MS, and ¹H NMR spectral analysis.