Condensed heterocycles containing the pyrimidine nucleus

Continuing earlier studies designed to obtain derivatives of 1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one and of the isomeric 7-one of pharmacological interest, some novel compounds 2 and derivatives of 6,7,8,9-tetrahydro-5H-1,3,4-thiadiazolo[2,3-b]quinazolin-5-one ( 3 ) were prepared. Derivatives of pyrimido[2,1-b]benzothiazol-2-one ( 6 ) and of the isomeric 4-one derivatives 8 were also synthesized. Structural identification was obtained by ¹H-nmr, ir and mass spectra.     

Pyrrolothienopyrazines. IV. Synthese de derives de 1′amino-5 pyrrolo[1,2-a]thieno[2,3-e]pyrazine

5-Aminopyrrolo[1,2-a]thieno[2-3-3]pyrazine derivatives were obtained by intramolecular cyclisation of N³(1-pyrrolyl)-2-thienylurea derivaties. Synthesis of these latter compounds was achieved from 2-(1-pyrrolyl)-3-thenoylazide via a curtius rearrangement. The H nmr spectra are discussed.     

Electron ionization mass spectra of novel 2,3:4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose derivatives and related sugar sulfamates

The electron-impact (EI) mass spectral fragmentation of ten bis-O- (1-methylethylidene)fructopyranose derivatives and three related sugar sulfamates were investigated. In particular, 2,3:4,5-bis-O - (1-methylethylidene)-β-D-fructopyranose sulfamate (topiramate), a potent anticonvulsant, was examined in greater detail. The fragmentation of the 2,3:4,5-bis-O-(1-methylethylidene) fructopyranose derivatives in general was not very dependent on the nature of substitution; the mechanisms of the common and unique fragmentation patterns are presented. These compounds showed characteristic peaks at m/z [M – 15]⁺, [M – 15 – 58]⁺, [M – 15 – 58 – 60]⁺, [M ? CH₂X]⁺ and [M ? CH₂X – 58]⁺ where X = OSO₂NR₂ (R ? H, CH₃, and/or Ph), OC (O)NHR, NH₂, CI and OH. The fragmentation of isomeric bis-O-(1-methylethylidene) derivatives of aldopyranose, ketopyranose and ketofuranose sulfamates was also investigated. The results indicate that isomeric sugar sulfamates can be easily distinguished in the EI mode. Key fragmentation pathways are discussed for these compounds.     

1,2,4-Triazolo[4,3-c]pyrimidines from 4-acylhydrazinopyrimidines

The reaction of N¹-acetylacetamidrazones 1 with N-[bis(methylthio)methylene]cyanamide (2) at room temperature in the presence of potassium carbonate in dimethyl sulfoxide affords good yields of ethyl 4-acylhydrazino-2-amino-6-methylthio-5-pyrimidine carboxylate 3 . By briefly refluxing compounds 3 in dimethyl sulfoxide, 1,2,4-triazolo[4,3-c]pyrimidine derivatives 4 were obtained. When equimolecular amounts of N¹-acylacetamidrazones and compounds 2 were refluxed in dimethyl sulfoxide/toluene, compounds 4 were obtained directly.     

1H NMR spectra of the 2-trifluoroacetyl derivatives of benzo[b]furan and benzo[b]thiophene

The ¹H NMR spectra of the 2-trifluoroacetyl derivatives of benzo[b]furan and benzo[b]thiophene were recorded at 200MHz in two solvents, chloroform and acetone. A long-range coupling constant, 5J(HF), between the fluorine nuclei of the trifluoroacetyl group and H-3, of a value higher than 1 Hz, was measured. From the comparison of the ¹H chemical shifts of, and the solvent effects on, the trifluoroacetyl compounds and those of the corresponding 2-acetyl derivatives, and on the basis of an empirical interpretation of the ⁵J(HF) coupling constant, a predominant Z conformation was tentatively assigned to these derivatives.     

Synthesis,Modification, and Anticonvulsant Activity of 3′‐R1‐Spiro[indoline‐3,6′‐[1,2,4]triazino[2,3‐c]quinazolin]‐2,2′(7′H)‐diones Derivatives

Previously unknown 3′‐R¹‐5‐R²‐spiro[indoline‐3,6′‐[1,2,4]triazino[2,3‐c]quinazoline]‐2,2′‐(7′H)‐diones and their N‐substituted analogues were obtained via reaction of 6‐R¹‐3‐(2‐aminophenyl)‐1,2,4‐triazin‐5‐ones with isatin and its substituted derivatives. It was shown that alkylation of 3′‐R¹‐5‐R²‐spiro[indoline‐3,6′‐[1,2,4]triazino[2,3‐c]quinazolin]‐2,2′‐(7′H)‐diones by N‐R³‐chloroacetamides or chloroacetonitrile in the presence of а base proceeds by N‐1 atom of isatin fragment. The spectral properties (¹H and ¹³C NMR spectra) of synthesized compounds were studied, and features of spectral patterns were discussed. The high‐effective anticonvulsant and radical scavenging agents among 3′‐R¹‐5‐R²‐spiro[indoline‐3,6′‐[1,2,4]triazino[2,3‐c]quinazolin]‐2,2′(7′H)‐diones and their N‐substituted derivatives were detected. It was shown that compounds 2.2 , 2.8 , and 3.1 exceed or compete the activity of the most widely used in modern neurology drug—lamotrigine on the pentylenetetrazole‐induced seizures model. The aforementioned fact may be considered as a reason for further profound study of synthesized compounds using other pathology models.     

Synthesis and pharmacological properties of N‐substituted‐N′‐(4,6‐dimethylpyrimidin‐2‐yl)‐thiourea derivatives and related fused heterocyclic compounds

A series of new N‐Substituted‐N′‐(4,6‐dimethylpyrimidin‐2‐yl)‐thiourea derivatives ( 3a , 3b , 3c , 3d ) and related fused heterocyclic compounds ( 4a , 4b , 4c , 4d ) were synthesized using tetrabutylammonium bromide as phase transfer catalyst (PTC). N‐[(2E)‐5,7‐dimethyl‐2H‐[1,2,4] thiadiazolo [2,3‐a] pyrimidin‐2‐ylidene] derivatives ( 4a , 4b , 4c , 4d ) were prepared by oxidative cyclization of 3a , 3b , 3c , 3d . The structures of these novel compounds were characterized by IR, ¹H NMR, ¹³C NMR, mass spectrometry, and the elemental analysis. The crystal structures were determined from single crystal X‐ray diffraction data. The results indicated that the compounds possessed a broad spectrum of activity against the tested microorganisms and showed higher activity against fungi than bacteria. Compounds 3d and 3a exhibited the greatest antimicrobial activity. J. Heterocyclic Chem., 2011.     

Synthesis,antifungal and antibacterial activity of calix[4]arene-based 1,3,4-oxadiazole derivatives

We describe the synthesis of some novel p-tert-butylcalix[4]arene-based (5-aryl-1,3,4-oxadiazol-2-yl)2-chloroethanethioate derivatives ( 4a–e ). These compounds were synthesized by the reaction of tetra-tert-butyl calix[4]arene ( 1 ) with (5-aryl-1,3,4-oxadiazol-2-yl)2-chloroethanethioate ( 3a–e ) in the presence of potassium carbonate as a weak base and dry acetone as the solvent. All the newly synthesized calix[4]arene derivatives were characterized by elemental analysis and various spectroscopic methods such as FT-IR, ¹H NMR,¹³C NMR, DEPT, and ESI-MS. The synthesized compounds were tested in vitro for their antibacterial and antifungal activities against Escherichia coli and Aspergillus fumigates in comparison with enrofloxacin and amphotericin as reference drugs, which are normally used for treating such infections. The synthesized compounds showed different inhibition zones against the tested bacteria and fungi. Compound 4c was found to be most effective against A. fumigates, whereas compound 4e was found to be equally effective against E. coli and A. fumigates.     

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.     

Synthesis of Deuterium Labeled Tryptamine Derivatives

The synthesis of deuterium labeled tryptamine derivatives, [2‐(1H‐indol‐3‐yl)‐[²H₄]‐ethyl]‐dimethylamine (DMT), [²H₁₀]‐diethyl‐[2‐(1H‐indol‐3‐yl)‐ethyl]‐amine (DET), [2‐(1H‐indol‐3‐yl)‐ethyl]‐[²H₆]‐dipropyl‐amine (DPT) and [²H₂]‐alpha‐methyltryptamine (AMT) is described. The isotopically labeled compounds are used as internal standards in gas chromatography‐mass spectrometry (GC‐MS) assays.     

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.     

Synthesis,ABTS-Radical Scavenging Activity,and Antiproliferative and Molecular Docking Studies of Novel Pyrrolo[1,2-a]quinoline Derivatives

A new 2,2′-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS)-radical scavenging and antiproliferative agents of pyrrolo[1,2-a]quinoline derivatives have been synthesized. An efficient method for the synthesis of 14 novel diversified pyrrolo[1,2-a]quinoline derivatives has been described using 4-(1,3-dioxolan-2-yl)quinoline and different phenacyl bromides in acetone and followed by reacting with different acetylenes in dimethylformamide/K₂CO₃. The structure of the newly synthesized compounds was determined by infrared, ¹H NMR, ¹³C NMR, mass spectrometry, and elemental analysis. The in vitro antioxidant activity revealed that among all the tested compounds 5n exhibited maximum scavenging activity with ABTS. Compound 5b has showed good antiproliferative activity as an inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase.     

Heterocyclic synthesis via enaminones: Novel synthesis of (1H)‐pyridin‐2‐one,pyrazolo[1,5‐a]pyrimidine and isoxazole derivatives incorporating a N‐methylphthalimide and their biological evaluation

Novel synthesis of (1H)‐pyridin‐2‐one, pyrazolo[1,5‐a]pyrimidine and isoxazole derivatives incorporating N‐methylphthalimide moiety are reported. Reaction of enaminone 2 with malononitrile affords 4. Condensation of 2 with cyanothioacetamide or benzoylacetonitrile affords compounds 6 and 7 respectively. Reaction of 2 with hydrazine hydrate afford 2,3‐dihydrophthalazine‐1,4‐dione ( 10 ). Condensation of 2 with hydroxylamine and 3‐aminopyrazole derivatives affords compounds 12 and 15a,b respectively. Antimicrobial and antifungal activity were determined for representative compounds and most of them showed moderate activity as antimicrobial agents, while compounds 2 and 7 show strong activity against Aspergillus niger. The structure of the newly synthesized compounds was elucidated by elemental analyses and ¹H nmr spectra and some cases by ¹³C nmr investigation.     

Novel Substituted Imidazo[2,1‐b][1,3,4]Thiadiazole Derivatives: Synthesis,Characterization, Molecular Docking Study,and Investigation of Their In Vitro Antifungal Activities

In this study, a new series of substituted imidazo[2,1‐b][1,3,4]thiadiazole derivatives were synthesized. To this end, first 2‐amino‐1,3,4‐thiadiazole derivatives (compounds 2a and 2b ), the starting materials, were synthesized with high yields (82% and 79%, respectively). Then imidazo[2,1‐b][1,3,4]thiadiazole derivatives ( 4 – 16 ), the target compounds, were synthesized from reactions of 2‐amino‐1,3,4‐thiadiazole derivatives ( 2a and 2b ) with 2‐bromoacetophenone derivatives ( 3a – 3i ) (in yields of 52% to 71%). All of the synthesized compounds were characterized by ¹H NMR, ¹³C NMR, Fourier transform infrared, elemental analysis, mass spectroscopy, and X‐ray diffraction analysis (compounds 4 – 12 , 14 , and 15 ) techniques. In vitro antifungal activity tests were performed for all of the synthesized compounds. Inhibition zones, percentage of inhibition, minimum fungicidal activity, minimum inhibitory concentration, and lethal dose values of the target compounds were determined against some plant pathogens. According to the results of the biological activity tests, all of the synthesized compounds showed moderate to high levels of antifungal activity. Theoretical calculations were performed to support the experimental results. The geometric parameters of selected compounds ( 5 , 6 , and 8 ) were optimized using the density functional theory B3LYP/6‐31G(d) method in the Gaussian 09W package program, and the frontier molecular orbitals (highest occupied molecular orbital–lowest unoccupied molecular orbital) were calculated theoretically. Finally, molecular docking studies were performed for antifungal activity studies of the selected compounds and to determine whether or not these compounds could be inhibitor agents for the 2RKV protein structure.     

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.     

Synthesis of derivatives of a new heterocyclic system,indolo[2,3-f][1,7]naphthyridine

3-(N"-Aryl-N"-chloroacetyl)amino-2-formylindoles were converted into 3-amino-1-aryl-2-oxo-1,2-dihydropyrido[3,2-b]indoles, which were used to synthesize derivatives of a new heterocyclic system, namely, indolo[2,3-f][1,7]naphthyridine. The structures of the resulting compounds were proved by IR and ¹H NMR spectroscopy and mass spectrometry.     

Novel [1,2,4]triazolo[3,4-b][1,3,4]thiadiazine derivatives embedded with benzimidazole moiety as potent antioxidants

Fourteen novel [1,2,4]triazolo[3,4-b][1,3,4]thiadiazine derivatives bearing benzimidazole moiety ( 7a-n ) have been synthesized using the one-pot nitro reductive cyclization method. All the synthesized compounds were confirmed by ¹H nuclear magnetic resonance (¹H NMR), ¹³C NMR, fourier-transform infrared (FT-IR), mass spectrum, and elemental analyses. All the title compounds were subjected to in vitro antioxidant activity. The free radical scavenging activity of the compounds was examined using DPPH, nitric oxide, and superoxide radical scavenging methods. The results demonstrated that compound 3-(2-(3,4-dimethoxyphenyl)-1-propyl-1H-benzo[d]imidazol-5-yl)-6-4-tolyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine ( 7c ) was potent in scavenging both DPPH and nitric oxide radical with IC₅₀ values of 13.57 and 18.55 μg/ml when compared to the standard with IC₅₀ values of 23.75 and 23.14 μg/ml, respectively, which was due to the presence of electron-donating groups. The activity was found to decline when electron-donating groups were replaced by electron-withdrawing groups. Moderate scavenging activity was observed for the superoxide radical. Structure activity relationship and physiochemical properties were studied for all the derivatives.     

SYNTHESIS OF SOME 2-[(BENZAZOLE-2-YL)THIO]-DIPHENYLMETHYLACETAMIDE DERIVATIVES AND THEIR ANTIMICROBIAL ACTIVITY

Some 2-[(benzazole-2-yl)thio]diphenylmethylacetamide[3pc] derivatives were synthesized by reacting 2-chloroacethylaminodiphenylmethane with benzazole-2-thions. The structure elucidation of the compounds was performed by IR, ¹ H NMR, and MS-FAB spectral data.

Antimicrobial activity of the compounds was examined. Some of the compounds have shown similar antifungal activities against C. albicans when compared with ketoconazole. It was also observed that some of these compounds have moderate antimicrobial activity when compared with chloramphenicole.     

Mass spectrometry of homoadamantane derivatives

Homoadamantane derivatives can be divided into two groups according to their mass spectra. To the first group belong compounds with electron attracting substituents (COOH, CI, COOCH₃, Br); compounds with electron releasing substituents (OCH₃, OH, NH₃, NHCOCH₃) constitute the second group. The most characteristic feature of the first group compounds is the splitting off of the substituent. The hydrocarbon fragment [C₁₁H₁₇]⁺ thus formed then loses olefin molecules with the formation of corresponding ionic species C_11?nH_17?2n. The 3-substituted compounds of this group undergo thermal Wagner-Meerwein type rearrangements into adamantane derivatives, resulting in the [C₁₀H₁₅]⁺ (m/e 135) ion formation; this is the main difference between 1- and 3-substituted homoadamantanes. The series of [C_nH_2n?6X]⁺ ions (where X = OCH₃, OH, NH₂, NHCOCH₃, n = 6 to 10) are characteristic of the mass spectra of the second group compounds, the ion [C₆H₆X]⁺, [M ? C₅H₁₁]⁺ being the most abundant. The intensity ratio of [M ? C₅H₁₁]⁺ to [M ? C₄H₉]⁺ ions is 10:1 for 1-substituted and 3:1 for 3-substituted compounds of this group, allowing the location of the substituent. Some individual features of the spectra are also reported.     

Synthesis of Pyrido[2′,3′: 3,4]pyrazolo[1,5‐a]pyrimidine,Pyrido[2′,3′:3,4]pyrazolo[5,1‐c][1,2,4]triazine,and Pyrazolyl Oxadiazolylthieno[2,3‐b]pyridine Derivatives

6‐(2‐Thienyl)‐4‐(trifluoromethyl)‐1H‐pyrazolo[3,4‐b]pyridine‐3‐amine reacted with different active methylene compounds to afford pyridopyrazolopyrimidine derivatives. On the other hand, it reacted with some halo compounds to give the imidazo[1′,2′:1,5]pyrazolo[3,4‐b]pyridine derivatives. Also, it diazotized to give the corresponding diazonium chloride that is coupled with several active methylene compounds to give the corresponding triazine derivatives. Furthermore, compound 3‐amino‐6‐(2(thienyl)‐4‐(trifluoromethyl)thieno[2,3‐b]pyridine‐2‐carbohydrazide reacted with some β‐dicarbonyl compounds and some sulfur‐containing compounds to afford the corresponding pyrazolyl oxadiazolylthieno[2,3‐b]pyridine derivatives.