Heterocycles from Pyrazoloylhydroximoyl Chloride: Synthesis of Certain Quinoxaline,Benzothiadiazine, Benzoxadiazine,Quinazolinone, Imidazo[1,2-a]pyridine,Imidazo[1,2-a]pyrimidine,Isoxazole, Pyrazolo[3,4-d]pyridazine and Pyrrolidino[3,4-d]isoxazolin-4,6-dione Derivatives

3-Ethoxycarbonyl-5-methyl-1-(4-methylphenyl)-4-pyrazoloylhydroximoyl chloride (1) reacted with o-phenylenediamine, o-aminothiophenol, o-aminophenol and methyl anthranilate to afford 3-nitrosoquinoxaline, benzothiadiazine, benzoxadiazine, and 3-hydroxyquinazoline, respectively. Imidazo[1,2-a]pyridine, imidazo[1,2-a]pyrimidine and isoxazole derivatives were obtained via the reaction of 1 with 2-aminopyridine, 2-aminopyrimidine and the appropriate active methylene compounds, respectively. Pyrazolo[3,4-d]pyridazines, and pyrrolidino[3,4-d]isoxazolines derivatives were also synthesized. The structures of the newly synthesized compounds were established on the basis of spectral data and alternate synthesis whenever possible.     

Synthesis and Neurotropic Activity of New Heterocyclic Systems: Pyridofuro[3,2-d]pyrrolo[1,2-a]pyrimidines,Pyridofuro[3,2-d]pyrido[1,2-a]pyrimidines and Pyridofuro[3′,2′:4,5]pyrimido[1,2-a]azepines

Background: Neurotic disturbances, anxiety, neurosis-like disorders, and stress situations are widespread. Benzodiazepine tranquillizers have been found to be among the most effective antianxiety drugs. The pharmacological action of benzodiazepines is due to their interaction with the supra-molecular membrane GABA-a-benzodiazepine receptor complex, linked to the Cl-ionophore. Benzodiazepines enhance GABA-ergic transmission and this has led to a study of the role of GABA in anxiety. The search for anxiolytics and anticonvulsive agents has involved glutamate-ergic, 5HT-ergic substances and neuropeptides. However, each of these well-known anxiolytics, anticonvulsants and cognition enhancers (nootropics) has repeatedly been reported to have many adverse side effects, therefore there is an urgent need to search for new drugs able to restore damaged cognitive functions without causing significant adverse reactions. Objective: Considering the relevance of epilepsy diffusion in the world, we have addressed our attention to the discovery of new drugs in this field Thus our aim is the synthesis and study of new compounds with antiepileptic (anticonvulsant) and not only, activity. Methods: For the synthesis of compounds classical organic methods were used and developed. For the evaluation of biological activity some anticonvulsant and psychotropic methods were used. Results: As a result of multistep reactions 26 new, five-membered heterocyclic systems were obtained. PASS prediction of anticonvulsant activity was performed for the whole set of the designed molecules and probability to be active Pa values were ranging from 0.275 to 0.43. The studied compounds exhibit protection against pentylenetetrazole (PTZ) seizures, anti-thiosemicarbazides effect as well as some psychotropic effect. The biological assays evidenced that some of the studied compounds showed a high anticonvulsant activity by antagonism with pentylenetetrazole. The toxicity of compounds is low and they do not induce muscle relaxation in the studied doses. According to the study of psychotropic activity it was found that the selected compounds have an activating behavior and anxiolytic effects on the models of “open field” and “elevated plus maze” (EPM). The data obtained indicate the anxiolytic (anti-anxiety) activity of the derivatives of pyrimidines, especially pronounced in compounds 6n, 6b, and 7c. The studied compounds increase the latent time of first immobilization on the model of “forced swimming” (FST) and exhibit some antidepressant effect similarly to diazepam. Docking studies revealed that compound 6k bound tightly in the active site of GABA_A receptor with a value of the scoring function that estimates free energy of binding (ΔG) at −7.95 kcal/mol, while compound 6n showed the best docking score and seems to be dual inhibitor of SERT transporter as well as 5-HT_1A receptor. Conclusions: Тhe selected compounds have an anticonvulsant, activating behavior and anxiolytic effects, at the same time exhibit some antidepressant effect.     

Synthesis and in vitro anticancer activity of pyrazolo[1,5-a]pyrimidines and pyrazolo[3,4-d][1,2,3]triazines

A novel series of pyrazolo[1,5-a]pyrimidines 14a–j and pyrazolo[1,5-a]quinazolines 18a, b were synthesized via condensation of 5-amino-1H-pyrazoles 10a, b with 3-(dimethylamino)-1-aryl-prop-2-en-1-ones 11a–e and 2-((dimethylamino)methylene)-5,5-dimethylcyclohexane-1,3-dione (15), respectively, in glacial acetic acid. Finally, treatment of 10a, b with sodium nitrite (NaNO₂) afforded pyrazolo[3,4-d]triazines 20a, b. Structures of compounds were confirmed by their spectral data. These compounds were screened for their in vitro cytotoxic activities against human cancer cell lines (HepG-2 and MCF-7) using 3-[4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. The results reveal that, the compounds 14b and 14h were the most potent in comparison with doxorubicin. The structure–activity relationship was discussed.     

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.     

Regioselective Synthesis of Indolizines,Pyrrolo[2,1-a]isoquinolines,and Quinolines

Convenient and regioselective synthesis of indolizine and pyrrolo[2,1-a]isoquinoline/quinoline derivatives by one-pot multicomponent reaction of N-substituted pyridinium and isoquinolinum/quinolinium salts with alkyl propiolates in the presence triphenylphosphine is described.     

Synthesis of Some New Pyrazolo[3,4-b]Pyridlne and Pyrazolo[3,4-d]Pyrimidine Derivatives1

Several pyrazolo[3,4-b]pyridine (3,4) and pyrazolo-[3,4-d]pyrimidine (5-13) derivatives were prepared using 5-amino-l-(5-ethyl-5H-1,2,4-triazino[5,6-b]-indol-3-yl)-lH-pyrazole-4-carbonitrile (2) . The pyridine derivatives 3 and 4 were obtained by reaction of 2 with malononitrile and ethyl cyanoacetate, respectively, while pyrimidine analogs 5-13 were synthesized cither by a one-step or multi-step sequence.     

Synthesis and Biological Evaluation of Novel 5,7-Diphenylimidazo[1,2-a]pyridine Derivatives

A series of novel 5,7-diphenylimidazo[1,2-a]pyridine derivatives was designed and synthesized. The in vitro cytotoxic activities of all the target compounds against human colorectal cancer（HT-29）, human lung can- cer（H460）, human gastric cancer（MKN45） and human breast cancer（MDA-MB-231） cell lines were evaluated. The pharmacological results indicated that most of the target compounds showed moderate to excellent activities against the tested cell lines. The most promising compound 4h（0.20, 0.006, 0.08, 0.021 μmol/L） was 2.6, 5.1, 3.6 and 21.9 times more active than EPC2407（0.52, 0.031, 0.29, 0.46 μmol/L） against HT-29, H460, MKN45 and MDA-MB-231 cell lines, respectively.     

Efficient One-pot Synthesis of Pyrrolo[2,1-a]isoquinoline and Pyrrolo[1,2-a]quinoline Derivatives

A one-pot sequential reaction for efficient synthesis of pyrrolo[2,1-a]isoquinoline and pyrrolo[1,2-a]-quinoline derivatives has been developed. The reaction included firstly the Cu-catalyzed three-component reaction of isoquinoline(quinoline), acetylenedicarboxylate and alkynylbenzene and then Cs₂CO₃-promoted intramolecular cyclization reaction of initially formed 1-alkenyl-2-alkynyl-1,2-dihydroisoquinoline(1,2-dihydroquinoline).     

One-Pot Synthesis of Novel Spiro Pyrano[2,3-d][1,3]thiazolo[3,2-a]pyrimidine Derivatives

In a one-pot synthesis, 1′-methyl-2,3″-dioxo-5″-aryl-1,2,5a″,7″,8″,9a″-hexahydro-5″H,6″H-dispiro[indole-3,2′-pyrrolidine-3′,2″-pyrano[2,3-d][1,3]thiazolo[3,2-a]pyrimidine]-4′-carboxylic acid methyl ester was prepared via the sequential reaction of 4-aryl-octahydro-pyrano[2,3-d]pyrimidine-2-thione, dimethyl acetylenedicarboxylate (DMAD), and a mixture of isatin and sarcosine. All the novel spiro compounds, in moderate yields, were characterized thoroughly by infrared, NMR, mass spectromentry, and elemental analysis together with x-ray crystallographic analysis.     

TFAA‐Catalyzed Annulation Synthesis of Spiro Pyrrolo[1,2‐a]quinoxaline Derivatives from 1‐(2‐Aminophenyl)pyrroles and Benzoquinones/Ketones

A metal‐free trifluorosulfonate anhydride (TFAA)‐catalyzed strategy for the synthesis of spiro pyrrolo[1,2‐a]quinoxalines from 1‐(2‐aminophenyl)pyrroles and benzoquinones/ketones has been developed. With this general method, spiro pyrrolo[1,2‐a]quinoxalines have been accessed via nucleophilic addition and cyclization. This reaction exhibits good functional group tolerance, and a wide range of products are obtained in moderate to good yields.     

Novel Four-Step Synthesis of Thioxo-quinazolino[3,4-a]quinazolinone Derivatives

A novel synthesis of thioxo-quinazolino[3,4-a]quinazolinone framework was developed through a four-step reaction starting from isatoic anhydride. The resulting 2-aminobenzamides from the reaction of isatoic anhydride and different amines underwent coupling–cyclization reaction with 2-nitrobenzaldehydes, reduction of nitro group, and then cyclization reaction with carbon disulfide (CS₂). All steps were carried out under easy and user-friendly conditions in a short time without using expensive catalysts or reagents.

[Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications® for the following free supplemental resource(s): Full experimental and spectral details.]     

Synthesis and Ring Transformation of Pyrrolo[2,3-d][1,3]oxazine to Pyrrolo[2,3-d]Pyrimidines

A convenient route is reported for the synthesis of fused pyrrolo[2,3-d][1,3]oxazine and pyrrolo[2,3-d]-pyrimidine derivatives from 2-amino-1-benzyl-3-t-butoxycarbonyl]-4,5-dimethylpyrrole.     

Novel Synthesis of 1,8-Alkanopyrido[3,4-d]pyridazine: a New Ring System

Cycloalkylidenemalononitriles couple with various diazonium salts to yield the corresponding cycloalkeno[c]pyridazines, which react with trichloroacetonitrile to give the 1,8-alkanopyrido[3,4-d]pyridazines. The reaction of cycloalkenopyridazines with DMF dimethylacetal gives enamine derivatives, which can be converted to 1,8-alkanopyrido[3,4-d]pyridazines via treating with hydrazine hydrate or aromatic amines. Substituted cycloalkenopyridines react with diazoaminobenzene to afford the corresponding 1,8-alkanopyridopyridazines.     

Novel Synthesis of Some New Pyridazine and Pyridazino[4,5-d]pyridazine Derivatives

Phenacyl-malononitrile derivatives 1a and b react with dimethylformamide dimethylacetal (DMFDMA) in refluxing toluene to afford the enaminones 2a and b respectively. Compounds 2a and 2b react with the hydrazine hydrate 3a and phenyl hydrazine 3b in refluxing ethanol to afford the pyridazine derivatives 5a–d, presumably via the intermediates 4. Compounds 5a–d, react with hydrazine hydrate 3a to afford the pyridazino[4,5-d]pyridazines 6a–d respectively. The pyridazines 5a and b and the pyridazino[4,5-d] pyridazines 6a and b could be oxidized into the full aromatic systems 7a and b and 8a and b respectively. Compounds 7a and b react also with hydrazine hydrate 3a to afford 8a and b respectively.

含1,3,4-噻二唑环吡唑并[3,4-d]嘧啶类化合物的合成及生物活性

通过5-氨基-4-氰基-1-苯基吡唑与甲酸发生环合、再经氯化和芳香族亲核取代反应,合成了12种新的含1,3,4-噻二唑环吡唑并[3,4-d]嘧啶类化合物.目标化合物的结构经红外光谱、核磁共振氢谱、质谱和元素分析方法予以确认.初步的生物活性测定试验表明,在50 mg/L浓度下,大部分目标化合物对小麦纹枯病菌(Rhizoctonia cerealis)表现出较好的杀菌活性,其中化合物5b,5d和5j的抑菌率超过90%.     

Dmap-Catalyzed Synthesis of Novel Pyrrolo[2,3-D]Pyrimidine Derivatives Bearing an Aromatic Sulfonamide Moiety

4-(N,N-Dimethylamino)pyridine (DMAP), with a dual role as a basic nucleophilic catalyst, was shown to be a highly efficient catalyst for the synthesis of some new N-(2-aryl-7-benzyl-5,6-diphenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzenesulfonamides through the reaction of 2-aryl-7-benzyl-5,6-diphenyl-7H-pyrrolo[2,3-d]pyrimidin-4-amines (7-deazaadenines) with benzenesulfonyl chlorides. It was also found that the use of DMAP under solvent-free conditions is much more effective than other catalytic systems such as pyridine as both the catalyst and solvent, t-BuOK in t-BuOH, Et₃N in ethanol (EtOH), and even DMAP in dimethylformamide (DMF). The influences of the reaction parameters, temperature, and the catalyst amount, on the catalytic performance have been studied. All synthetic compounds were characterized on the basis of their full spectral data.     

Efficient Synthesis of Pyrrolo[1,2-f]phenanthridine Derivatives via Dipolar Cycloaddition of Phenanthridine,Activated Acetylenes,and Ethyl Bromopyruvate

The three-component reactions of phenanthridine, activated acetylenes, and ethyl bromopyruvate through both of simultaneous and stepwise process are surveyed. The reactions afforded the corresponding pyrrolo[1,2-f]phenanthridine derivatives in good yields without using any catalyst and activation.

[Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications® for the following free supplemental resource(s): Full experimental and spectral details.]     

含吲哚的吡唑并[3,4-d]嘧啶衍生物的设计合成及其生物活性研究

利用药物设计中的生物活性基团拼接原理,设计合成了13个含吲哚的吡唑并[3,4-d]嘧啶衍生物.目标化合物均经核磁共振氢谱(1H NMR)、核磁共振碳谱(13C NMR)和高分辨质谱仪(HRMS)进行了结构确证.对4株肿瘤细胞(HeLa、MGC-803、MCF-7、BEL-7404)的体外抗增殖活性实验结果表明,目标化合物均表现出一定的抗肿瘤活性,MCF-7、MGC-803肿瘤细胞株敏感度高于HeLa和BEL-7404.其中, 6-[(6-甲氧羰基吲哚-3-基)硫基]-1-苯基-吡唑并[3,4-d]嘧啶-4-酮(5m)表现出较好的体外肿瘤抑制活性,对MCF-7、MGC-80和HeLa细胞的IC50均小于30μmol·L^-1,对MCF-7的IC50值为(4.02±0.92)μmol·L^-1,优于对照药物依托泊苷(10.1±0.62μmol·L^-1)和羟喜树碱(5.93±0.56μmol·L^-1).拓扑异构酶抑制实验结果表明,此类化合物对TopoII有选择性抑制活性,所有化合物对TopoⅡ表现出不同程度抑制活性,对Topo Ⅰ未表现出抑制活性.