Synthesis, characterization and antibacterial activity of 2-[1-(5-chloro-2-methoxy-phenyl)-5-methyl-1H-pyrazol-4-yl]-5-(substituted-phenyl)-[1,3,4]oxadiazoles

In the present investigation a series of novel 2-[1-(5-chloro-2-methoxy-phenyl)-5-methyl-1H-pyrazol-4-yl]-5-(substituted-phenyl)-[1,3,4]oxadiazoles (4a–j) were synthesized by cyclization of substituted-benzoic acid N′-[1-(5-chloro-2-methoxy-phenyl)-5-methyl-1H-pyrazole-4-carbonyl]-hydrazide by using phosphorousoxychloride at 120 °C. The chemical structure of the newly synthesized compounds was characterized by analytical and spectral (IR, ¹H NMR, ¹³C NMR and LC–MS) methods. The title compounds were screened for qualitative (zone of inhibition) and quantitative antibacterial activity (MIC) by agar cup plate and microtitration methods, respectively. Among the synthesized compounds in this series compound 2-[1-(5-chloro-2-methoxyphenyl)-5-methyl-1H-pyrazol-4-yl]-5-(4-fluorophenyl)-1,3,4-oxadiazole (4b) was found to exhibit significant antibacterial activity with MICs of 22.4, 29.8, 29.6 and 30.0 μg/mL against Bacillus subtilis, Staphylococcus aureus, Escherichia coli and Klebsiella pneumoniae, respectively. The other compounds exhibited moderate activity when compared to standard substance Ampicillin.     

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.     

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.     

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 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.     

Synthesis and anticancer evaluation of novel 2-cyclopropylimidazo[2,1-b][1,3,4]-thiadiazole derivatives

A series of 2,5,6-trisubstituted imidazo[2,1-b][1,3,4]-thiadiazole derivatives 4(a-k) have been prepared by reaction of 2-amino-5-cyclopropyl-1,3,4-thiadiazole and an appropriate phenacyl bromide. Further 5-bromo 5(a-k) and 5-thiocyanato 6(a-k) derivatives were synthesized in order to study the effect of these substituents on antitumor activity. Structures of these compounds were established by IR, ¹H NMR, ¹³C NMR and Mass spectroscopy. Seven compounds were granted NSC code at National Cancer Institute (NCI), USA for anticancer activity at a single high dose (10⁻⁵ M) in full NCI 60 cell panel. Among the compounds tested, 5-bromo-6-(4-chlorophenyl)-2-cyclopropylimidazo[2,1-b][1,3,4]thiadiazole 5b (NSC D-96022/1) was found to be the most active candidate of the series at five dose level screening with degree of selectivity toward Leukemic cancer cell line.     

Synthesis, characterization and evaluation of antibacterial activity of some thiazolo[3,2-b][1,2,4]triazole incorporating diphenylsulfone moieties

A series of thiazolo[3,2-b][1,2,4]triazole incorporating diphenylsulfone moieties were synthesized starting from 5-[4-(4-X-phenylsulfonyl)phenyl]-4H-1,2,4-triazole-3-thioles 3a–c, X = H, Cl, Br. Thus, alkylation of 1,2,4-triazoles 3 with phenacyl bromide or 4-bromophenacyl bromide afforded S-substituted 1,2,4-triazoles 4, 5. These new intermediates 4 and 5, in the presence of H₂SO₄ (c), were cyclized to 2-[4-(4-X-phenylsulfonyl)phenyl]-6-(4-Y-phenyl)[1,3]thiazolo[3,2-b]-[1,2,4]-triazoles 6, 7 (I) and not to isomeric thiazolo[2,3-c][1,2,4]-triazoles 6, 7 (II). The newly synthesized compounds were characterized by IR, ¹H, ¹³C NMR and elemental analysis. MS spectra confirmed the formation of thiazolo[3,2-b][1,2,4]triazole 6, 7 (forms I) in detriment of [2,3-c] isomeric compounds (forms II). The potential antibacterial effects of the synthesized compounds were investigated using standard bacterial strains: Acinetobacter baumannii ATCC 19606, Citrobacter freundii ATCC 8090, Escherichia coli ATCC 11775, Pseudomonas aeruginosa ATCC 9027, Enterococcus faecalis ATCC 19433, Staphylococcus aureus ATCC 12600, Staphylococcus epidermidis ATCC 14990, Bacillus cereus ATCC 14579.     

Design, synthesis and biological activity of pyrazolo[1,5-a]pyrimidin-7(4H)-ones as novel Kv7/KCNQ potassium channel activators

Voltage-gated Kv7/KCNQ/M-potassium channels play a pivotal role in controlling neuronal excitability. Genetic reduction of KCNQ channel activity as a result of mutations causes various human diseases such as epilepsy and arrhythmia. Therefore, discovery of small molecules that activate KCNQ channels is an important strategy for clinical intervention of membrane excitability related disorders. In this study, a series of pyrazolo[1,5-a]pyrimidin-7(4H)-ones (PPOs) have been found to be novel activators (openers) of KCNQ2/3 potassium channels through high-throughput screening by using atomic absorption rubidium efflux assay. Based on structure-activity relationship (SAR), the substituted PPOs have been optimized. The 5-(2,6-dichloro-5-fluoropyridin-3-yl)-3-phenyl-2-(trifluoromethyl) pyrazolo[1,5-a]pyrimidin-7(4H)-one (17) was identified as a novel, potent, and selective KCNQ2/3 potassium channel opener by patch-clamp recording assay.     

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.     

Design, synthesis and in vitro antimicrobial evaluation of novel Imidazo[1,2-a]pyridine and imidazo[2,1-b][1,3]benzothiazole motifs

New antimicrobial agents, imidazo[1,2-a]pyridine and imidazo[2,1-b][1,3]benzothiazole, have been synthesized. Their antimicrobial activities were conducted against various Gram-positive, Gram-negative bacteria and fungi. Compounds 6c, 7a, 10b, 11a, 12b, 14a, 14b, 15a and 15b, exerted strong inhibition of the investigated bacterial and fungal strains compared to control antibiotics amoxicillin and cefixime and the antifungal agent fluconazole. Results from this study showed that the nature of the substituents on the armed aryl groups determines the extent of the activity of the fused imidazopyridine and/or imidazobenzothiazole derivatives. Preliminary structure-activity observations revealed that bromo-fluoro substituents enhanced the antimicrobial activity significantly compared to other substituents.     

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.     

Synthesis and CNS activity of tricyclic theophylline derivatives. 8-substituted imidazo[2,1-f]theophyllines

Based on previously described results of pharmacological in vitro and in vivo tests of some series of pyrimido- and diazepino-[2,1-f]theophylline derivatives, N8-unsubstituted, N8-benzyl and N8-arylpiperazino-alkyl derivatives of imidazo[2,1-f]theophyllines were synthesized and tested for their CNS activity. It has been shown that tricyclic [2,1-f]theophyllines possess sedative and analgesic activity. N8-Phenylpiperazinopropyl-1,3,6,7-tetrahydro-(8H)-imidazo[2,1-f]theophylline 6 showed significant anti-serotonin and long-lasting hypothermic effects. N8-Benzyl-1,3,6,8-tetrahydroimidazo-7-on[2,1-f]theophylline 8 possess anticonvulsant properties.     

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.     

Synthesis and biological activity of 7H-benzo[4,5]indolo[2,3-b]-quinoxaline derivatives

New 7-(2-aminoethyl)-7H-benzo[4,5]indolo[2,3-b]quinoxalines (13-20) were synthesized with high yields starting from 3H-benzo[e]indole-1,2-dione. These compounds were screened for the cytotoxicity, anti-viral activity, interferon inducing ability and DNA affinity compared with the corresponding 6-(2-aminoethyl)-6H-indolo[2,3-b]quinoxaline derivatives (1-12). It was shown, that compounds 13-20 bind to DNA stronger (lg К_a = 6.23-6.87) than compounds 1-12 (lg К_a = 5.57-5.89). Anti-viral activity is significantly reduced with annulations of benzene ring in Indoloquinoxaline moiety 13-20.     

Synthesis and biological activity of novel N-cycloalkyl-(cycloalkylaryl)-2-[(3-R-2-oxo-2H-[1,2,4]triazino[2,3-c]quinazoline-6-yl)thio]acetamides

In this paper the novel N-cycloalkyl-(cycloalkylaryl)-2-[(3-R-2-oxo-2H-[1,2,4]triazino[2,3-c]quinazoline-6-yl)thio]acetamides synthesis by aminolysis of activated by thionyl chloride or carbonyldiimidazole [(3-R-2-oxo-2H-[1,2,4]triazino[2,3-c]quinazolin-6-yl)-thio]acetic acids and alkylation of the 3-R-6-thio-6,7-dihydro-2H-[1,2,4]triazino[2,3-c]quinazoline-2-ones potassium salts with N-cycloalkyl-(cycloalkylaryl)-2-chloroacetamides are proposed. The structures of compounds are determined by ¹H, ¹³C NMR, LC-MS and EI-MS analysis. The in vitro anticancer, antibacterial activity and Photobacterium leiognathi Sh1 bioluminescence inhibition of synthesized compounds were revealed. SAR results were discussed. Compound 4.10 was found to be the most anticancer active one, selectively influenced on the non-small cell lung and CNS cancer cell lines, especially on the HOP-92 (log GI₅₀ = −6.01) and U251 (log GI₅₀ = −6.00).     

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.     

New imidazole anti-fungal agents derived from benzo[b]thiophene. Part II

1-[(Aryl)(benzo[b]thienyl)methyl]-1H-imidazoles 22, 1-[(benzo[b]thien-3-yl)(thienyl)methyl]-1H-imidazoles 25 and 1-[(diaryl)(benzo[b]thien-3-yl)methyl]-1H-imidazoles 28 have been synthesized and tested for anti-fungal activity. All compounds showed good activity against a broad spectrum of fungi (yeasts, dermatophytes).     

A regioselective synthesis of some new pyrazol-1'-ylpyrazolo[1,5-a]pyrimidines in aqueous medium and their evaluation as antimicrobial agents

An efficient and environmental benign regioselective synthesis of some new pyrazol-1′-ylpyrazolo[1,5-a]pyrimidines (7b-h) has been accomplished via treatment of 3(5)-amino-5(3)-hydrazinopyrazole dihydrochloride (5) with several unsymmetrical 1,3-diketones (6b-h) using water as a solvent without any catalysts or additives. The structure of 7b-h was established on the basis of rigorous analysis of ¹H, ¹³C NMR, IR spectral data and MS. Eight compounds (7a-h) were screened for their antibacterial activity against two gram-positive and two gram-negative bacteria and compounds (7a, b, d and e) for antifungal activity against four phytopathogenic fungi. Compounds 7c and 7e manifest rather broad antibacterial activity than standard antibiotics. One lead compound, 7a (10 mg/ml and 200 mg/ml) exhibited equipotent or more potent antifungal activity against all tested microorganisms than standard drug.     

Synthesis and calcium channel antagonist activity of dialkyl hexahydro-1,2′,6′-trimethyl[bipyridine]-3′,5′-dicarboxylates

Reaction of dialkyl 1′,4′-dihydro-2′,6′-dimethyl[bipyridine]-3′,5′-dicarboxylates 2 with methyl iodide yielded the corresponding 4′-(1-methylpyridinium) iodide salts 3 in quantitative yield. The sodium borohydride reduction of 3 in aqueous ethanol gave the corresponding dialkyl hexahydro-1,2′,6′-trimethyl[bipyridine]-3′,5′-dicarboxylate analogs 4–5. The calcium channel antagonist activities for 4–5 were determined using the muscarinic receptor-mediated Ca²⁺-dependent contraction of guinea pig ileal longitudinal smooth muscle. The relative activities for the 3′,5′-diethyl series 5 was 3-tetrahydropyridinyl 5b > 4-tetrahydropyridinyl 5c > 2-tetrahydropyridinyl 5a. Increasing the size of the 3′,5′-alkyl substituents enhanced activity. An approximate 1:1 correlation between the IC₅₀ value for the inhibition of [³H]nitrendipine binding and inhibition of the tonic component of the muscarinic-induced contractile response was observed for 4a and 5b. NMR studies suggest that the 4′-[2-(1-methyl-1,2,3,6-tetrahydropyridinyl)] ring systems of 4a and 5a are anti-periplanar to the 1,4-dihydropyridine ring system.     

3-Aryl-2-[1H-benzotriazol-1-yl]acrylonitriles: a novel class of potent tubulin inhibitors

During a screening for compounds that could act against Mycobacterium tuberculosis, a series of new cellular antiproliferative agents was identified. The most cytotoxic molecules were evaluated against a panel of human cell lines derived from hematological and solid human tumors. In particular, (E)-2-(1H-benzo[d] [1,2,3]triazol-1-yl)-3-(4-methoxyphenyl)acrylonitrile (1) was found to be of a potency comparable to etoposide and greater than 6-mercaptopurine in all cell lines tested. Accordingly, a synthesis of a new series of (E)-2-(5,6-dichloro-1H-benzo[d] [1,2,3]triazol-1-yl)-3-(4-R-phenyl)acrylonitriles was conducted in order to extend the studies of structure-activity relationship (SAR) for this class of molecules. With the aim to evaluate if 3-aryl-2-[1H-benzotriazol-1-yl]acrylonitriles were able to act like tubulin binding agents, the effects on cell cycle distribution of the most active compounds (1, 2a, 3 and 4) were analyzed in K562 cells. A detailed molecular modeling study of the putative binding mode of this series of compounds on tubulin is also reported.