Synthesis and anticancer effects of some novel pyrazolo[3,4-d]pyrimidine derivatives by generating reactive oxygen species in human breast adenocarcinoma cells

A series of novel substituted pyrazolo[3,4-d]pyrimidines (compounds 2-12) were synthesized starting with pyrimidinone derivative 1. Their in vitro cytotoxicity against human breast adenocarcinoma (MCF-7) cell lines has been investigated and most of the tested compounds exploited potent cytotoxic activity against MCF-7 cell lines comparable to the activity of the commonly used anticancer drug cisplatin. Treatment of MCF-7 cells with increased doses (2, 5, 10, 20 μg/ml) of the tested compounds revealed that the activity of superoxide dismutase and the level of hydrogen peroxide were significantly increased, while the activities of catalase and glutathione peroxidase and the levels of reduced glutathione were significantly lowered compared with control MCF-7 cells. In general, acyclic nucleoside derivative 4 revealed the highest anticancer activity among the other tested compounds.     

Synthesis and in vitro antitumour activity evaluation of 1-aryl-1H,3H-thiazolo[4,3-b]quinazolines

A series of 1H,3H-thiazolo[4,3-b]quinazolines (2a–i) were synthesized and evaluated for their in vitro antitumour activity against ca. 60 human tumour cell lines. They exhibited moderate (2c, 2d, 2f and 2g) to strong (2a, 2b, 2e, 2h and 2i) cell-growth inhibition at a concentration of 10⁻⁴ M, but weak activity at lower concentrations. Only 1-(2,6-dichlorophenyl)-1H,3H-thiazolo[4,3-b]quinazoline (2h) possesses a significant growth inhibitory activity on 22 cell lines at a concentration of 10⁻⁵ M.     

Synthesis of novel bioactive derivatives of 3-(4-chlorophenyl)-2-hydrazino-5,6,7,8-tetrahydrobenzo(b)thieno[2,3-d]pyrimidine-4(3H)-ones

A series of triazolo[4,3-a]tetrahydrobenzo(b)thieno[3,2-e]pyrimidine-5(4H)-ones (12a–n) were synthesized and evaluated for CNS depressant, skeletal muscle relaxant and anticonvulsant activities by photoactometer, Rotarod and pentylenetetrazole induced the convulsions method respectively in Swiss albino mice. Diazepam was used as standard drug. The five derivatives 12b, 12c, 12d, 12i and 12m showed the CNS depressant and skeletal muscle relaxant activities comparable to those of diazepam at a dose of 5 mg/kg. These derivatives also exhibited good activity when tested for anticonvulsant activity in mice at different dose levels. The ED₅₀ values for these derivatives are in the range of 4.40–9.33 mg/kg.     

Synthesis and preliminary pharmacological evaluation of imidazo[2,1-f]purine-2,4-dione derivatives

A series of N-8-arylpiperazinylpropyl derivatives of 1,3-dimethyl-(1H,8H)-imidazo[2,1-f]purine-2,4-dione (2–10) and amide derivatives of 1,3-dimethyl-6,7-dihydroimidazo[2,1-f]purine-2,4-(1H,3H)-dione-7-carboxylic acid (11–13) were synthesized. Compounds (2–10) evaluated in vitro were potent 5-HT_1A receptor ligands. Preclinical studies indicated that 8-[3-(N4-phenyl)-piperazin-N1-yl-propyl]-1,3-dimethyl-(1H,8H)-imidazo[2,1-f]purine-2,4-dione (2) exerts anxiolytic-like activity in the four-plate test in mice; however its effect was weaker, than that produced by Diazepam. This compound and 8-[3-(N4-2′-metoxyphenyl)-piperazin-N1-yl-propyl]-1,3-dimethyl-(1H,8H)-imidazo[2,1-f]purine-2,4-dione (3) behaved like antidepressants in the forced swimming test in mice; and their activity in that model was comparable with the effect of Imipramine. The obtained results suggested that the long-chain arylpiperazines (LCAPs) linked to tricyclic derivatives of the theophylline remain a worthy of future research for obtaining new derivatives with potential anxiolytic/antidepressant activity.     

Single step synthesis of new fused pyrimidine derivatives and their evaluation as potent Aurora-A kinase inhibitors

A simple, facile, efficient and one pot three-component procedure for the synthesis of pyrazolo[1,5-a]pyrimidines, triazolo[1,5-a]pyrimidines and pyrimido[1,2-a]benzimidazoles ring systems incorporating phenylsulfonyl moiety was developed via the reaction of 1-aryl-2-(phenylsulfonyl)ethanone derivatives 1a-d with the appropriate heterocyclic amine and triethyl orthoformate and evaluated as Aurora-A kinase inhibitors. The cytotoxic activity of the newly synthesized compounds against HST116 colon tumor cell line was investigated. 2,7-Diphenyl-6-(phenylsulfonyl)pyrazolo[1,5-a]pyrimidine (4b) and its p-methoxy analogue 4c were found to be equipotent to Doxorubicin as a reference drug. Molecular modeling study was carried out in order to rationalize the in vitro anti-tumor results.     

Pyrroloquinolones and pyrazoloquinolones as potential antibacterial agents. Synthesis and antibacterial activity

Diethyl 1-cyclopropyl-5,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3,6-dicarboxylate 4 as a key-intermediate was synthesized via the Dieckmann reaction. The reaction of 4 with nucleophiles proceeded regioselectively at C-5. Facile cyclization between the C-5 and C-6 side chains of the resulting products gave novel pyrroloquinolones 10 and 12 and pyrazoloquinolones 15. They were converted into a series of cyclic amino-substituted pyrroloquinolones 17–21 and pyrazoloquinolones 22–24, and their in vitro antibacterial activities were tested. 1H-Pyrrolo[2,3-f]quinolone 17a and 2H-pyrrolo[3,4-f]quinolone 21a exhibited a potent in vitro antibacterial activity.     

5H-[1,2,4]Oxadiazolo[5,4-d][1,5]benzothiazepines as anticonvulsant agents in DBA/2 mice

A series of 3a,4-dihydro-5H-[1,2,4]oxadiazolo[5,4-d][1,5]benzothiazepines have been synthesized by 1,3-dipolar cycloaddition reaction of benzonitriloxide to the CN double bond of 1,5-benzothiazepine derivatives, and the stereochemical features of compounds obtained have been determined by NMR spectroscopy. The results of evaluation of their activity in preventing seizures induced by audiogenic stimulation in DBA/2 mice are also reported and discussed. The 5-(4-bromophenyl)-1,3-diphenyl derivative 3b, the most active compound of the series, is over 20 times more active than the parent benzothiazepine 1b and shows an activity comparable to clobazam and better than desmethylclobazam.     

Synthesis and anticonvulsant activity of some new thiazolo[3,2-a][1,3]diazepine, benzo[d]thiazolo[5,2-a][12,6]diazepine and benzo[d]oxazolo[5,2-a][12,6]diazepine analogues

A new series of 6,7-dihydro-thiazolo[3,2-a][1,3]diazepines (9–12), benzo[d]thiazolo[5,2-a][12,6]diazepines (19–21) and benzo[d]oxazolo[5,2-a][12,6]diazepine (24) analogues were synthesized and evaluated for their anticonvulsant activity. Compounds (E)-2-bromo-6,7-dihydro-thiazolo[3,2-a][1,3]diazepine-8(5H)-thione (12), 3-chloro-benzo[d]thiazolo[5,2-a][12,6]diazepin-10-one (20), and 4-chloro-benzo[d]oxazolo[5,2-a][12,6] diazepin-10-one (24) showed 100% protection against PTZ- and bicuculline-induced seizures; 70%, 33%, 70% protection against MES-induced tonic extension; and 70%, 66%, 100% protection against picrotoxin-induced convulsions, respectively. Compounds 12, 20, and 24 proved to act as GABA_A receptor agonists, with ED₅₀ values of 252, 380, 251 mg/kg; TD₅₀ values of 398, 417, 355 mg/kg; PI values of 1.58, 1.09, 1.41; LD₅₀ values of 380, 617, 537 mg/kg and TI values of 1.51, 1.62, 2.14, respectively.     

Novel 4-aryl-pyrido[1,2-c]pyrimidines with dual SSRI and 5-HT1A activity: Part 2

Derivatives of 4-aryl-5,6,7,8-tetrahydro-pyrido[1,2-c]pyrimidine were synthesized. These compounds contain the 3-(4-piperidyl)-1H-indole residue or its 5-methoxy or 2-methyl derivative. In vitro binding tests were performed to determine the affinity of the compounds for the 5-HT_1A receptor and serotonin transporter (SERT) proteins in the rat brain cortex. In vivo studies, particularly the inducible hypothermia test and forced swimming test, were conducted to determine agonistic/antagonistic activity with pre- and postsynaptic 5-HT_1A receptors. Molecular modeling techniques were used to determine the binding modes of the selected compounds at the 5-HT_1A receptor and SERT. The SAR analysis showed that the presence of the 3-(4-piperidyl)-1H-indole group or its 5-methoxy derivative, as well as a para substitution with –OCH₃ or –F in the aryl ring of 4-aryl-5,6,7,8-tetrahydro-pyrido[1,2-c]pyrimidine, results in an increased affinity for both the 5-HT_1A receptors and SERT. In contrast, the presence of the 2-methyl-3-(4-piperidyl)-1H-indole group resulted in a considerable decrease in binding affinity.     

New condensed pyrroles of potential biological interest syntheses and structure-activity relationship studies

The Pyrrole derivatives Ia-d were prepared and utilized for the preparation of pyrrolo[2,3-d]pyrimidine derivatives IIa-c, III, IVa-e, V and VIIIa-c; pyrrolo[3,2-e]tetrazolo[1,5-c]pyrimidine VI and pyrrolo[4,3e][1,2,4]triazolo[1,5-c]pyrimidine derivative derivatives VIIa-c. These some newly synthesized compounds were examined for their in vitro antimicrobial activity and in vivo anti-inflammatory. Result indicated that these compounds showed promising anti-inflammatory activity in comparison to ibuprofen (the standard anti-inflammatory drug). The structure-activity relationships (SAR) and anti-inflammatory activities of these compounds are also discussed in this paper.     

Derivatives of pyrrolo[3,4-d]pyridazinone, a new class of analgesic agents

A series of N2-{2-[4-aryl(benzyl)-1-piperazinyl(piperidinyl)]ethyl}pyrrolo[3,4-d]pyridazinones 4 and related derivatives 5 were synthesized as potential analgesic agents. The structures of the new compounds were elucidated by micro, spectral and X-ray analysis. Analgesic activity of the compounds was investigated in the phenylbenzoquinone induced ‘writhing’ and ‘hot plate’ test in mice and at radioligand binding assay. At ‘writhing’ test all compounds, without exception, were more active than acetylsalicylic acid (ASA) with ED₅₀ values ranging from 0.04 to 11 mg/kg (i.p.) (ED₅₀ for ASA - 39.15 mg/kg). Analgesic effect at the ‘hot plate’ test was observed for three compounds 4c,e,f at the dose 3-5 times higher then that of morphine (ED₅₀-3.39 mg/kg). At radioligand binding assay of 4c,e,f only compound 4f exhibited affinity for the μ-opioid receptors similar to that of Tramadol. The acute toxicity of the pyrrolopyridazinones 4, 5 were also studied and non toxic effect was observed at the 2000 mg/kg (5a 1420 mg/kg) i.p. dose level. On the basis of the available pharmacological data S-A relationship is discussed. The preferred conformational characteristic of 4, taken 4c as an example, was also described.     

Synthesis of thieno[3,2-g]quinoxalines as potential amoebicides

A route for the synthesis of thieno[3,2-g]quinoxalines and their derivatives is described. The anti-amoebic activity of these compounds has been preliminaly assayed against Entamoeba histolytica. Compounds 1a, b, g, l, m, n, o displayed activity against hepatic amoebiasis and compounds 1 a, b, l showed activity against intestinal amoebiasis in animal models.     

Synthesis and anticonvulsant activity of 8-alkoxy-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-1-one derivatives

A series of novel 8-alkoxy-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-1-one derivatives were synthesized and screened for their anticonvulsant activities by the maximal electroshock (MES) test, subcutaneous pentylenetetrazol (scPTZ) test, and their neurotoxicity was evaluated by the rotarod neurotoxicity test (Tox). The results of these tests demonstrated that 8-heptyloxy-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-1-one (3f) and 8-hexyloxy -5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-1-one (3e) were the most promising compounds, with median effective dose (ED₅₀) of 17.6 and 17.9 mg/kg, and protective index (PI) of greater than 63.4 and 62.4 in the MES test, respectively. These PI values were higher than the PI value of the prototype antiepileptic drug carbamazepine. The scPTZ test showed that 8-pentyloxy-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-1-one (3d) was the most potent with ED₅₀ value of 38.0 mg/kg and PI value of greater than 29.4, which is much safer than marketed drug carbamazepine. The possible structure-activity relationship was discussed.     

Design, synthesis and antimycobacterial activity of some novel imidazo[1,2-c]pyrimidines

Tuberculosis, due to its relentless nature, is now a major public health threat. The concomitant resurgence of TB with the MDR- or XDR-TB and HIV/AIDS pandemic has exposed the frailties of the current drug armatorium. Based on isosteric replacement and good 3D structural similarity between PA-824, a novel antimycobacterial agent undergoing clinical trials, and imidazo[1,2-c]pyrimidines, we have designed novel imidazo[1,2-c]pyrimidines. The designed molecules were synthesized by nucleophilic displacement of chloro group of various substituted 4-chloropyrimidines by ethanolamine followed by cyclisation of these 4-(2-hydroxyethyl)aminopyrimidines to imidazo[1,2-c]pyrimidines in good yield. All the compounds were screened for their antimycobacterial activity on Mycobacterium tuberculosis H37Rv strain by 1% proportion method. Some of the synthesized compounds exhibited potent antimycobacterial activity with MIC values in the range of 2–20 μg/mL.     

Synthesis and anticonvulsant activity of 7-phenyl-6,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-ones and their derivatives

Herein, we described the syntheses and anticonvulsant activities of 7-(substituted-phenyl)-6,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-ones (1a-1o) and their derivatives. Most of the synthesized compounds exhibited potent anticonvulsant activities in the maximal electroshock test (MES). The most promising compound 1i showed significant anticonvulsant activity in MES test with ED₅₀ value of 19.7 mg/kg. It displayed a wide margin of safety with protective index much higher than the standard drugs. In addition, the potence of compound 1i against seizures induced by Pentylenetetrazole, Isoniazid, Thiosemicarbazide, 3-Mercaptopropionic acid, and Bicuculline in the chemical-induced seizure tests suggested that compound 1i displayed broad spectrum activity in several models, and it is likely to have several mechanisms of action including inhibiting voltage-gated ion channels and modulating GABAergic activity.     

Novel imidazo[4,5-b]pyridine and triaza-benzo[c]fluorene derivatives: synthesis, antiproliferative activity and DNA binding studies

In the present paper, we have described the synthesis and biological activity of the novel derivatives of imidazo[4,5-b]pyridines and triaza-benzo[c]fluorenes (7-21, 24-26, 28-29). A preponderance of these compounds exerted strong cytostatic effects on the panel of seven human tumour cell lines in a dose-dependent manner. In particular, imidazo[4,5-b]pyridines and triaza-benzo[c]fluorenes including 2-imidazolinyl derivatives showed the most potent antitumour activity. Similarly, triaza-benzo[c]fluorenes 18 and 20 induced strong growth inhibition of tested tumour cell lines, and showed low cytotoxicity in normal human fibroblasts. DNA interaction studies of these compounds demonstrated that N-methylated 16 and 2-imidazolinyl 28 triaza-benzo[c]fluorenes bind to DNA in an intercalative mode.     

Synthesis and antitumor activity of new sulfonamide derivatives of thiadiazolo[3,2-a]pyrimidines

New series of sulfonamide derivatives of [1,3,4]thiadiazolo[3,2-a]pyrimidine were synthesized and investigated as antitumor agents. Some of the newly prepared compounds were tested for their in vitro and in vivo antitumor activities. Preliminary biological studies revealed that compounds 4c, 4f, and 4j exhibited the highest affinity to DNA, while compounds 4h,i, 6a-c, 8 and 12-14 exhibited moderate activity. Also, compounds 4j, 4f and 4c showed the highest percentage increase in lifespan of mice inoculated with Ehrlich ascites cells over 5-flurouracil (positive control). The detailed synthesis, spectroscopic and biological data are reported.     

Synthesis of 4H-chromene, coumarin, 12H-chromeno[2,3-d]pyrimidine derivatives and some of their antimicrobial and cytotoxicity activities

Condensation of 3-N,N-diethylaminophenol (1) with α-cyanocinnamonitriles (2a-c) and ethyl α-cyanocinnamates (2d-f) provided compounds 3a-f and 4a-c. 12H-Chromeno[2,3-d]pyrimidine derivatives 6, 11-13 and 16 were obtained by treatment of 4H-chromene compounds (3) with different electrophiles followed by nucleophilic reagents. Structures of these compounds were established on the basis of IR, UV, ¹H NMR, ¹³C NMR and MS data. Some of the new compounds were evaluated for antimicrobial and cytotoxicity activities.     

Synthesis, benzodiazepine receptor affinity and in vivo testing of 3-aryl-4,7-dihydro-6-(N′-alkylpyrazol-3′ - or 5′-yl)pyrazolo[1,5-a]pyrimidin-7-ones

The synthesis of a series of 3-aryl-4,7-dihydro-6-(N¹′-alkylpyrazol-3′- or 5′-yl)pyrazolo[1,5-a]pyrimidin-7-ones and their in vitro biological evaluation as ligands for benzodiazepine receptor (BzR) are described. The in vitro activities, as determined by an analysis of GABA (γ-aminobutyric acid) shift ratios, and binding affinities of these compounds to BzR are compared in terms of the electronic, lipophilic and steric effect changes of their substituents either at the 3-position or at the N¹′ of 6-(pyrazol-3′(5′)-yl) moiety. The most interesting compounds were tested in vivo.     

Copper(II) chloride mediated synthesis and DNA photocleavage activity of 1-aryl/heteroaryl-4-substituted-1,2,4-triazolo[4,3-a]quinoxalines

A new class of photonucleases, 1-aryl/heteroaryl-4-substituted-1,2,4-triazolo[4,3-a]quinoxalines (4) was synthesized in a facile and efficient manner via copper(II) chloride mediated oxidative intramolecular cyclization of 2-(arylidenehydrazino)-3-substituted-quinoxalines (3). DNA cleavage potency of compounds 4a–d (40 μg each) was quantitatively evaluated on supercoiled plasmid ΦX174 under UV irradiation (312 nm, 15 W) without any additive. Compound 4c was found to be the most efficient DNA photocleaver which had converted supercoiled DNA (form I) into the relaxed DNA (form II) at 30 μg and the DNA photocleavage activity increases with increase in concentration of 4c.