Synthesis, analgesic and anti-inflammatory activities evaluation of some bi-, tri- and tetracyclic condensed pyrimidines

Novel series of bicyclic pyrrolo[1,2-c]pyrimidines 3a–g, 5, 6a, b, and 7a, b, tricyclic pyrimido[5,4-e]pyrrolo[1,2-c]pyrimidines 8a–c, 9a–g, 13a–c, 17, 18a, b, 19, 20a,b and 21 and tetracyclic condensed pyrimidines 14, 22 and 23 were synthesized through different chemical reactions. Structures of all synthesized pyrimidine derivatives were supported by spectral and elemental analyses. Analgesic activity evaluation was carried out using acetic acid-induced writhing assay, and all compounds exerted comparable activity to indomethacin. The anti-inflammatory activity evaluation was performed using carrageenan-induced paw edema in rats, the potency of the bicyclic derivatives 3a–f and 7b revealed comparable activity to indomethacin without gastric ulceration. The tricyclic derivatives 13a and 20a exerted good activity, however, they induced gastric ulcers while 13b and 13c showed moderate activity without ulceration. In case of tetracyclic derivatives, compound 14 exhibited the highest potency and safety profile.     

Synthesis of some new 1,2,4-triazoles starting from isonicotinic acid hydrazide and evaluation of their antimicrobial activities

5-Pyridin-4-yl-1,3,4-oxadiazole-2-thiol (2) was obtained from the reaction of isonicotinic acid hydrazide with carbon disulfide in basic media and converted into 4-amino-5-pyridin-4-yl-4H-1,2,4-triazole-3-thiol (5) by the treatment with hydrazine hydrate. The synthesis of 3 and 6 was performed from the reaction of 2 and 5 with ethyl bromide. The treatment of 5 with 4-fluorobenzaldehyde or indol-3-carbaldehyde resulted in the formation of 4-[(arylmethylene)amino]-5-pyridin-4-yl-4H-1,2,4-triazole-3-thiols (7a and 7b). The reactions of 2, 5 and 7a with some primary and secondary amines in the presence of formaldehyde afforded the corresponding Mannich bases, 4a, 4b, 9a–9c and 8.All newly synthesized compounds were screened for their antimicrobial activity. The antimicrobial activity study revealed that all the compounds screened showed good or moderate activity except compounds 2, 7a, 7b, 8 and 9b.     

Heterocyclic quinones VIII. Synthesis and anti-neoplastic evaluation of 7-substituted-1H-pyrrolo[3,2-c]quinoline-6,9-diones and 3-substituted-11H-indolo[3,2-c]quinoline-1,4-diones

7-Methoxy-2,3,4-trimethyl-1H-pyrrolo[3,2-c]quinoline-6,9-dione 13 and 3-methoxy-6-methyl-11H-indolo-[3,2-c]quinoline-1,4-diones 15 and 19 were obtained by oxidation of quinolinamines 9, 11 and 12 with Fremy's salt. The synthesis method of amines 9 and 11 consists of creating the pyrrole or indole nucleus according to Fisher's indolic reaction applied to hydrazones 8 and 10. Aromatization of 11 yielded quinolinamine 12. The nucleophilic substitution of methoxy by aziridine leads to quinones 14, 16 and 20. These quinones are highly cytotoxic for L1210 cells, but no activity could be established for the P388 lymphocytic leukemia in vivo.     

Synthesis and antibacterial activity of some new thiazole and thiophene derivatives

3-(1,4-Dioxo-3,4,4e,5,10,10a-hexahydro-1H-5,10-benzeno-benzo[g]phthalazin-2-yl)-3-oxo-propiononitrile (1) was utilized as key intermediate for the synthesis of some new iminocoumarin 2, chromenone 3, aminothiazole 4, triazepine 5a, b and 6, hydrazono-propiononitrile 7, pyridopyrazotriazine 8, monobromo 9, dibromo 10 quinoxaline 11, ketene N,S-acetal 13, ketene S,S-diacetal 17 and 18a, b and methyl dithioate 20 derivatives, respectively. The newly synthesized compounds were characterized by IR, ¹H NMR, ¹³C NMR and mass spectral studies. Representative compounds of the synthesized product were tested and evaluated as antibacterial agent.     

Synthesis of some novel pyrazolo[3,4-b]pyridine and pyrazolo[3,4-d]pyrimidine derivatives bearing 5,6-diphenyl-1,2,4-triazine moiety as potential antimicrobial agents

The reaction of 5,6-diphenyl-3-hydrazino-1,2,4-triazine (1) with bis(methylthio)methylene]malononitrile (2) afforded 5-amino-1-(5,6-diphenyl-1,2,4-triazin-3-yl)-3-(methylthio)-1H-pyrazole-4-carbonitrile (3). Compound 3 reacted with thiourea to give 3,4-diaminopyrazolo[3,4-d]pyrimidine 5, which was treated with benzoyl chloride to give pyrazolo[5,4,3-kl]pyrimido[4,3-d]pyrimidine 6. Treatment of 3 with acetic anhydride produced 3-methylthio-pyrazolo[3,4-d]pyrimidine derivative 7, which was allowed to react with hydrazine hydrate to give the corresponding hydrazino derivative 8. Heterocyclization of 8 with benzoyl chloride and sodium pyruvate afforded the polyfused heterocycles 9 and 10, respectively. Reaction of 3 with benzoylacetone yielded pyrazolo[3,4-b]pyridine 12, which was allowed to react with malononitrile and acetanilide to get heterocyclic systems 13 and 14, respectively. Interaction of 3 with cyanoacetone gave pyrazolo[3,4-b]pyridine 15, which was refluxed in formic acid to yield pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidine 16. Reaction of 3 with 2 afforded the triazinylpyrazole derivative 17, which was reacted with hydrazine hydrate to give dipyrazolo[1,5-a:3′,4′-d]pyrimidine 19. Furthermore, treatment of the latter compound with methyl anthranilate furnished tetraheterocyclic compound 21. Structures of the products have been determined by elemental analysis and spectral studies. All compounds have been screened for their antibacterial and antifungal activities. Compounds 9, 10, 13, 19 and 21 showed maximum activity comparable to the standard drugs with lower toxicity in the case of 9 and 10.     

Gadolinium, neodymium, praseodymium, thulium and ytterbium complexes as potential contrast enhancing agents for NMR imaging

Complexes of ferric (3) and gadolinium (5) citrate, gadolinium tricarballylate (6) and complexes of gadolinium, neodymium, praseodymium, thulium and ytterbium with complexons EDTA (7), CDTA (8), EGTA (9), DTPA (10) and TTHA (11) were synthesized and evaluated as potential contrast enhancing agents for NMR imaging by measuring their stability constants and their effectiveness in eliciting spin-lattice (T₁) and spin-spin (T₂) relaxations of protons in water and plasma. High stability constants (log₁₀ k = 22 or higher) and excellent relaxation properties were found for Gd-EGTA 19, Yb-EGTA 20, Gd-DTPA 23, Yb-DTPA 24, Gd-TTHA 28, Yb-TTHA 29 and Tm-TTHA 30. These compounds were considered as potential intravenous contrast agents for NMR imaging. Whereas, the stability constant of 28 was higher (log₁₀ k = 28.4) than that (log₁₀ k = 22.4) of the clinically used 23, the LD₅₀ value, using Swiss male mice, for 28 was lower (2.88 mmol/kg) than that for 23 (3.74 mmol/kg). The somewhat higher toxicity of 28 than that of 23 was explained by a higher osmolality of 28 as compared to 23. The gadolinium citrate 5 and gadolinium tricarballylate 6 were proposed as potential oral contrast agents.     

Synthesis of new 4-isopropylthiazole hydrazide analogs and some derived clubbed triazole, oxadiazole ring systems – A novel class of potential antibacterial, antifungal and antitubercular agents

In the present study a series of 4-isopropylthiazole-2-carbohydrazide analogs, derived clubbed oxadiazole–thiazole and triazole–thiazole derivatives have been synthesized and characterized by IR, ¹H NMR, ¹³C NMR, elemental and mass spectral analyses. The synthesized compounds were evaluated for their preliminary in vitro antibacterial, antifungal and antitubercular activity against Mycobacterium tuberculosis H₃₇Rv strain by broth dilution assay method.The synthesized compounds 7a, 7b, 7d and 4 showed an antitubercular efficacy considerably greater than that of the parent 4-isopropyl-1,3-thiazole-2-carbohydrazide 1, suggesting that the substituted 4-isopropylthiazole-2-carbohydrazide moiety plays an important role in enhancing the antitubercular properties of this class of compounds. Compounds 2c, 3, 4, 6d, 7a and 7b exhibited good or moderate antibacterial and antifungal activity. Compounds 4 and 7b showed appreciable cytotoxicity at a concentration of 250 μM.     

New pyridone, thioxopyridine, pyrazolopyridine and pyridine derivatives that modulate inflammatory mediators in stimulated RAW 264.7 murine macrophage

The reaction of 2-acetyl-5,6,7,8-tetrahydronaphthalene 1 with some aldehydes was conducted in the presence of ethyl cyanoacetate and ammonium acetate, yielded the cyanopyridones 2a–c, which react with phosphorous pentasulphide to afford the corresponding thioxopyridine derivatives 3a–c, respectively. Compounds 2a,b were converted to 2-chloropyridine derivatives 4a,b by heating with phosphorous oxychloride and phosphorous pentachloride, which were fused with hydrazine hydrate and benzyl amine to afford the corresponding pyrazolopyridine 5a,b and cyanopyridine derivatives 6a,b respectively. Compounds 2a,b also afforded 3-cyanopyridinyl oxy acetic acid ethyl ester 7a,b by reaction with ethyl bromoacetate in dry acetone in the presence of anhydrous potassium carbonate, which upon condensation with hydrazine hydrate gave the corresponding acid hydrazide 8a,b and with benzyl amine gave the corresponding acetamide 9a,b. We investigated the effect of those new compounds on the macrophage growth, macrophage binding affinity to fluorescein isothiocyanate-conjugated bacterial lipoopolysaccharide (FITC-LPS), phagocytosis of FITC-zymosan, and radical scavenging affinity against OH, ROO, and O₂⁻, in addition to their influence of the inflammatory mediators [nitric oxide (NO), tumor necrosis factor-α (TNF-α), prostaglandin E-2 (PGE-2), cycloxygenase-2 (COX-2), and 5-lipoxygenase (5-LO)] in LPS-stimulated macrophages. The findings revealed that the derivatives 2b, 3b, 5a, 7b, 9a and 9b can be recognized as promising multi-potent anti-inflammatory agents.     

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.     

Synthesis, characterization, antiamoebic activity and toxicity of novel bisdioxazole derivatives

Cyclization of benzene-1,4-dicarbaldehyde dioxime 1 with different aromatic aldehydes in inert atmosphere yielded the corresponding new bisdioxazoles 2–11. The structure of 2–11 was elucidated by spectral data. In vitro antiamoebic activity was performed against HM1:IMSS strain of Entamoeba histolytica. The results showed that the compounds 3 (IC₅₀ = 1.22 μM), 4 (IC₅₀ = 1.41 μM), 7 (IC₅₀ = 1.05 μM) and 10 (IC₅₀ = 1.01 μM) exhibited better antiamoebic activity than the standard drug metronidazole (IC₅₀ = 1.80 μM). The compounds 3, 4, 7 and 10 were tested for toxicity by MTT assay on H9c2 cardiac myoblasts and the results showed that the compounds 3, 4, 7 and 10 offered remarkable viability of 96.2%, 83.5%, 82% and 89%, respectively at a concentration of 12.5 μg/ml.     

Synthesis and evaluation of in vitro anti-microbial and anti-tubercular activity of 2-styryl benzimidazoles

A new series of novel 5-(nitro/bromo)-styryl-2-benzimidazoles (1–12) has been synthesized by simple, mild and efficient synthetic protocol by attempted condensation of 5-(nitro/bromo)-o-phenylenediamine with trans-cinnamic acids in ethylene glycol. Screening for in vitro anti-tubercular activity against Mycobacterium tuberculosis H₃₇ Rv, anti-bacterial activity against Staphylococcus aureus, Escherichia coli, Enterococcus faecalis, Klebsiella pneumoniae bacterial strains and anti-fungal activity against Candida albicans and Asperigillus fumigatus fungal strains were carried out. Compounds 5, 7, 8, 9, 11 showed higher anti-tubercular activity and compounds 7, 8, 10, 11, 12 have proved to be effective with MIC (μg/ml) and emerged as lead molecules showing excellent activities against a panel of microorganisms. All synthesized compounds were characterized using IR, ¹H, ¹³C NMR, GC–MS and elemental analysis.     

The dihydropteridine reductase (human brain) activity of some lipophilic quinonoid dihydropterins

The syntheses of 6-ethyl 2c, 6-n-propyl 2d, 6-n-hexyl 2c, 6-phenethyl 2f, 6-neopentyl 2g and 7-neopentyl 2h 5,6,7,8-tetrahydropterins are described. The oxidation of these gave the corresponding quinonoid species 3c—3h all of which were good substrates for dihydropteridine reductase from human brain when compared with the natural cofactor quinonoid dihydrobiopterin 3i, the quinonoid 6- and 7-methyl dihydropterins 3a and 3b, and quinonoid dihydrofolic acid 3j. In contrast, 5-2′-propylimino and 5-2′-octylimino 2,4-diaminopyrimidin-6 (1H)-ones 7a and 7b were devoid of substrate or inhibitor activities. The potential use of these lipophilic pterins in the therapy of diseases where there is a deficiency of tetrahydrobiopterin is discussed.     

Comprehensive profiling of α-glucosidase inhibitors from the leaves of Rubus suavissimus using an off-line hyphenation of HSCCC,ultrafiltration HPLC-UV-MS and prep-HPLC

The leaves of Rubus suavissimus (also called “Chinese sweet tea”) is used not only as a beverage tea and food additive but also as a folk herbal medicine for the treatment of diabetes mellitus. To systematically investigate its material foundation of efficacy for treating diabetes, herein, a hyphenated strategy by off-line coupling high-speed countercurrent chromatography, ultrafiltration HPLC-UV-MS and prep-HPLC was developed. And thus, α-glucosidase inhibitors from Rubus suavissimus leaves was comprehensively profiled, purified and characterized. As a result, twenty-six compounds were identified as potential α-glucosidase inhibitors and favorably isolated by prep-HPLC. Their structures were identified via UV, MS, and ¹H-NMR. Notably, fourteen compounds, including protocatechuic acid (1), myketin (3), epicatechin (4), vanillic acid (6), apigenin (11), catechin (12), ferulic acid (15), luteolin (16), 3, 3′-di-O-methylellagic acid (17), chlorogenic acid (19), 3, 3′-di-O-methylellagic acid-4′-O-β-D-glucoside (20), cinnamic acid (21), syringate (24) and ethylbrevifolin-carboxylate (25), were reported in leaves of Rubus suavissimus for the first time. In addition, α-glucosidase inhibitory activities of compounds 1–26 were evaluated, and eighteen compounds exhibited stronger α-glucosidase inhibitory activities than acarbose (IC₅₀ value at 214.24 ± 3.48 μg/mL, positive control). The results indicated that the proposed method is a highly efficient strategy for comprehensive profiling and purification of bioactive target compounds, including both major and minor components, from natural products.     

Studies on azabicyclo systems: syntheses and spasmolytic activity of analogues of 9-methyl-3,9-diazabicyclo[4.2.1]nonane and 10-methyl-3,10-diazabicyclo[4.3.1]decane

The spasmolytic activity of the lactams, 9-methyl-3,9-diazabicyclo[4.2.1]nonan-4-one 1 and 10-methyl-3,10-diazabicyclo[4.3.1]decan-4-one 2 and their reduction products, 9-methyl-3,9-diazabicyclo[4.2.1]nonane 3 and 10-methyl-3,10-diazabicyclo[4.3.1]decane 4 are described. Syntheses and spasmolytic effects of new amides and sulfonamides of the amines 3 and 4 are also reported. 3 possessed specific anti-serotonin activity. Amides of 3 with aromatic acids resulted in specific anti-histaminic compounds, whereas amides of 4 with aliphatic acids showed spasmogenic activity. A number of amides and sulfonamides showed non-specific spasmolytic activity.     

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.     

Antiinflammatory activity of novel indole derivatives

3-[(2-Imidazolyl, benzimidazolyl or benzoxazolyl)alkyl]indoles 2a-h were synthesized by cyclizing the carboxylic group of (3-indolyl)alkanoic acids 1 with ethylenediamine, o-phenylenediamine or o-aminophenol, respectively. Reaction of 1 with p-aminoacetophenone or aryl-substituted thiosemicarbazones yielded N-(4-acetylphenyl)-(2 or 4)-(indol-3-yl)alkylcarboxamides 3a-b or 1-arylidene 4-[2-(indol-3-yl)(acetyl or propionyl)]thiosemicarbazides 5a-h; 3a-b were cyclized into N-[4-(2-aminothiazol-4-yl)-phenyl]-(2 or 4)-(indol-3-yl)alkylcarboxamides 4a-b. Cyclization of 5a-h with malonic acid yielded 1-[2-(indol-3-yl)(acetyl or propionyl)]-3-arylideneamino-2-thiobarbituric acids 6a-h, which were finally converted into corresponding Mannich bases 7a-f. Compounds 2a-h, 4a-b, 6a-h and 7a-f were evaluated for their antiinflammatory activity. Compounds 2e, 2g, 4b, 6c and 6d exhibited promising antiinflammatory activity with a lower ulcerogenic liability than indomethacin.     

Synthesis,cytostatic and trichomonacide activities of 3,5-bis-(halomethyl)pyrazoles

Reduction of 1-methyl- and 1-benzyl-diethylpyrazole-3,5-dicarboxylates 2a and 2b with diisobutylaluminium hydride in toluene gave 3,5-bis-(hydroxymethyl)pyrazoles 4a and 4b in very good yields. Alternatively, 4a was obtained by reduction of S,S-diethyl 1-methylpyrazole-3,5-dicarbothioate 3″ with lithium aluminium hydride in lower yield. Treatment of above diols 4a and 4b with thionyl chloride or phosphorous tribromide in dimethoxyethane gave stable 3,5-bis-(chloromethyl)- and 3,5-bis-(bromomethyl)pyrazoles 5a, 6a and 6b. All the compounds synthesized were evaluated as being cytostatic in in vitro cultures of HeLa cells and both 1-methyl- and 1-benzyl-3,5-bis-(bromomethyl)pyrazoles 6a and 6b were found to be powerful cytostatic agents. In biological tests against Trichomonas vaginalis, Entamoeba invadens and Candida albicans, 6a and 6b showed significant trichomonacide activities.     

Unsaturated dideoxy fluoro-ketopyranosyl nucleosides as new cytostatic agents: A convenient synthesis of 2,6-dideoxy-3-fluoro-4-keto-β-d-glucopyranosyl analogues of uracil, 5-fluorouracil, thymine, N-benzoyl cytosine and N-benzoyl adenine

The β-protected nucleosides of uracil (2a), 5-fluorouracil (2b), thymine (2c), N⁴-benzoyl cytosine (2d) and N⁶-benzoyl adenine (2e) were synthesized by condensation of the peracetylated 3-deoxy-3-fluoro-d-glucopyranose (1) with the corresponding silylated bases. The nucleosides were deacetylated and several subsequent protection and deprotection steps afforded the partially acetylated analogues 6a–e. Selective iodination followed by hydrogenation gave the acetylated dideoxy analogues of uracil (8a), 5-fluorouracil (8b), thymine (8c), N⁴-benzoyl cytosine (8d) and N⁶-benzoyl adenine (8e), respectively. Finally, direct oxidation of the free hydroxyl group at the 4′-position of 8a–e, and simultaneous elimination reaction of the β-acetoxyl group, afforded the desired unsaturated 2,6-dideoxy-3-fluoro-4-keto-β-d-glucopyranosyl derivatives 9a–e. The new analogues were evaluated for antiviral and cytostatic activity. Compounds 9a–e were not active against a broad panel of DNA and RNA viruses at subtoxic concentrations. However, they were markedly cytostatic against a variety of tumor cell lines. The compounds should be regarded as potential new lead compounds to be further investigated for anticancer therapy.     

Synthesis of substituted-phenyl-1,2,4-triazol-3-thione analogues with modified d-glucopyranosyl residues and their antiproliferative activities

A series of d-glucopyranosyl-1,2,4-triazole-3-thione derivatives 1a–1d were synthesized by the reaction of 1,2,4-triazole-3-thione Schiff bases 5a–5d with 2,3,4,6-tetra-O-acetyl-σ-d-glucopyranosyl bromide. We demonstrate the conversion of 2 to 5, without the necessity of purification of both oxadiazole and triazole intermediates to afford the compounds 5. Their structures were confirmed by standard studies of ¹H NMR, IR, MS and elemental analysis. Analogues 5 and 1 have shown cytotoxic activity against human MCF-7 and Bel-7402 malignant cell lines.     

Acetylenic and allenic derivatives of 2-(5-methoxy-1-methylindolyl) alkylamines: Synthesis and evaluation as selective inhibitors of the monoamine oxidases A and B

We report the synthesis and in vitro studies as MAO-A and MAO-B inhibitors of a new series of 2-(5-methoxy-1-methylindolyl)alkylamines, including 2-(5-methoxy-1-methylindolyl)amine 9 and its N-methyl derivative 10, 1-[2-(5-methoxy-1-methylindolyl)]ethylamine 1 and its N-methyl derivative 2 and 3-[2-(5-methoxy-1-methylindolyl)propylamine 11 and its N-methyl derivative 12, so as some of the N-(2-propynyl), N-(2,3-butadienyl) and N-(2-butynyl) derivatives of 1, 2, 11 and 12 (compounds 3–8 and 13–18). All compounds were found to inhibit both MAO-A and MAO-B. Comparison with a previous series of 2-(5-methoxy-1-methylindolyl)methylamine derivatives (A1–A9) shows that in the new series, the inhibitory potency towards MAO-A generally decreases, whereas the inhibitory potency towards MAO-B generally increases, resulting in a loss of the selectivity for MAO-A seen in the reference compounds A1–A9. Structure-activity relationships are discussed.