Synthesis and anticonvulsant activity of novel imidazol“5(4H)”one and 5-oxo-4,5-dihydroimidazol-1-yl)propanamide derivatives

(Z)-1-amino-4-(2,4-difluorobenzylidene)-2-(4-fluorophenyl)-imidazol“5(4H)”one 2 was synthesized from the corresponding oxazolone 1. Condensation with different phenacyl bromide derivatives yielded our target compounds 4-(2,4-difluorobenzylidene)-2-(4-fluorophenyl)-1-(2-oxophenyl/substitutedphenylethylamino)-1H-imidazol“5(4H)”one 3a–f. On the other hand, oxazolone 1 was allowed to react with dl-alanine to obtain (Z)-2-(4-(2,4-difluorobenzylidene)-2-(4-fluorophenyl)-5-oxo-4,5-dihydroimidazol-1-yl)propanoic acid 4. Chlorination followed by reaction with appropriate aromatic amines gave our compounds 2-(4-(2,4-difluorobenzylidene)-2-(4-fluorophenyl)-5-oxo-4,5-dihydroimidazol-1-yl)-N-phenyl/substitutedphenylpropanamide 6a–c. All the target compounds were evaluated for their anticonvulsant activity using mean electroshock (MES) test at an oral dose of 100?mg/Kg. Most of the compounds showed protection against seizures with a potency ranging from 70 to 96%. However, compounds 3d, 6b, and c showed excellent protection against seizures with a potency of 92.84, 96.42, 96.42%, respectively, with respect to the reference standard phenytoin with a potency of 100%. To assess the locomotor coordination and neurological deficit, animals were tested on the rotarod, the most promising compounds did not affect the stability of mice on rotarod at the same dose level.     

Synthesis of pyrazolo [4,5]pyridazine and isoxazolo [3,4d]pyridazine derivatives

Arylhydrazones of diethylacetondicarboxylate3 was treated with formaldehyde to give 1-aryl-4,5,6-trihydropyridaine derivatives4a-f Cyclization of compound4a-f by hydroxylamine afforded [3,4d] 1,3,4,5-tetrahydropyridazine derivatives5a-f. Also cyclization of compound4c with semicarbazide gave 1-amidopyrazolo-5-one-1-aryl-3-carboxypyridazine6. On the other hand compound3 reacted with ethylorthoformate to give diethyl-1,4-dihydro-1-arylpyridazine-4-one-2,5 dicarboxylate7, which on treatment with hydrazine, semicarbazide and thiosemicarbazide gave pyridazine, amido and thioamido derivatives. The spectral and antimicrobial data of these compounds1–8 were studied.     

Synthesis of pyrazolo [4,3-c] pyridazine and isoxazolo [3,4-d] pyridazine derivatives

Arylhydrazones of diethyl acetonedicarboxylate3 was treated with formaldehyde to give 1-aryl-1,4,5,6-tetrahyeheypyridazine derivatives4a-f Cyclization of compound4a-f by hydroxylamine afforded [3,4-d] 1,4,5,6-tetrahydropyridazine derivatives5a-f. Also cyclization of compound4c with semicarbazide gave pyrazolote [4,3-c] pyridazine6. On the other hand compound 3 reacted with ethylorthoformate to give diethyl-1,4-dihydro-1-arylpyridazine-4-one-3,5 dicarboxylate7, which on treatment with hydrazine, semicarbazide and thiosemicarbzide gave pyridazine, amido and thioamido derivatives. The spectral and antimicrobial data of these compounds1–8 were studied.     

Synthesis of 3-amino-1,4-dihydropyridine derivativevia an intramolecular rearrangement of 1,4-dihydropyridine-3-hydroxamate

2,6-Dimethyl-4-(3′-nitrophenyl)-3-methoxylaminocarbonyl-1,4-dihydropyridine-5-carboxylic acid methylester,3b reacted with 2-cyanoethanol or benzylalcohol to give the corresponding cyanoethylurethane compound6c in 40.6% yield and benzylurethane compound6d in 32% yield. The cyanoethylurethane6c was hydrolized in ethanolic NaOH to give 2,6-dimethyl-4-(3′-nitrophenyl)-1,4-dihydropyridine-3-amino-5-carboxylic acid 5-methyl ester. HCl8 in 64.8% yield. Another acid hydrolysis of benzylurethane6d gave 2,6-dimethyl-4-(3′-nitrophenyl)-1,4-dihydropyridine-3-amino-5-carboxylic acid 5-methylester. HBr11 in 54.7% yield.     

Synthesis and pharmacological activities of some novel 5-chloro-N-(4-(1,5-(disubstituted)-4,5-dihydro-1H-pyrazol-3-yl)phenyl)-2-methoxybenzamide derivatives

A series of substituted pyrazole derivatives were prepared from N1-[4-(cinnamoyl) phenyl]-5-chloro-2-methoxybenzamides 2a–c, which were prepared from N-(4-acetylphenyl)-5-chloro-2-methoxybenzamide as starting material. Treating of compound 2a–c with methylhydrazine or phenylhydrazine afforded the corresponding N-substituted pyrazoline derivatives 3a–c and 4a–c, respectively. The acryloyl derivatives 2a–c were reacted with hydrazine hydrate in dioxane afforded a pyrazoline 5a–c, which was acetylated with acetyl chloride in dioxane to yield the N-acetyl analogue 6a–c. In addition, pyrazoline 5c was reacted with morpholine in the presence of paraformaldehyde to give the corresponding N-substituted pyrazoline derivative 7. The structure assignments of the new compounds are based on chemical and spectroscopic evidence. The pharmacological screening showed that many of these compounds have less toxicity and good anti-inflammatory activities.     

In vitro antiproliferative effect of β-phenylethylamine derivatives and doxorubicin combinations on MCF/ADR cell lines

A series of 3,4-dimethoxyphenylethylamine derivatives was prepared from Baylis–Hillman (BH) adducts. The effect of these compounds on the proliferation of breast cancer cell lines (MCF-7) and the corresponding Doxorubicin (Dox) resistant cell lines (MCF-7/ADR) was studied. Aminoalcohols 1a–d were obtained from the Michael addition reaction of 3,4-dimethoxyphenylethylamine and BH adducts. For the preparation of unsaturated amines 2a–d, BH adducts were converted into allylic bromides by treatment with HBr in acidic solution. N-nucleophile introduction could be controlled by the choice of solvent furnishing the corresponding amines 2a–d. A third class of amines (3a–c) was prepared by hydrogenation reaction of amines 2a–d. In respect of the biological evaluation, some of the synthesized compounds exhibited moderate inhibitory effect on the cell growth. In addition, in MCF-7/ADR cell lines, the antiproliferative effect of Dox shifted from 5 to 88 % when co-administrated with compound 2b.     

Synthesis and evaluation of anti-proliferative activity of 1,4-disubstituted phthalazines

A series of new phthalazine derivatives 3a–i and 4a–c were synthesized via the reaction of 1-chlorophthalazine derivative 2 with either N-substituted-piperazines, primary or their secondary amines. The structure of the synthesized, new compounds were characterized by spectral data. The anti-proliferative activity on human breast cancer cell line MCF-7 of the synthesized compounds was determined. The results showed that six of the test compounds (3a, 3g, 3i, and 4a–c) displayed potent cytotoxic activity ranging from 1.4 to 2.3?μmol.     

Ultrasound-assisted synthesis of 2,4-thiazolidinedione and rhodanine derivatives catalyzed by task-specific ionic liquid: [TMG][Lac]

Background

Synthesized arylidene derivatives of rhodanine and 2,4-thiazolidiendione have potent pharmacological activities, and these are also key substrates for the preparation of clinically used antidiabetics.

Findings

Some 1,1,3,3-tetramethylguanidine-based task-specific ionic liquids (TSILs) 1a-1e were prepared and employed to the catalyzed solvent-free Knoevenagel condensation of 2,4-thiazolidinedione 3a and rhodanine 3b with a variety of aldehydes.

Conclusions

Best results were obtained with 1,1,3,3-tetramethylguanidine lactate ([TMG][Lac]) 1c. The TSIL used can be easily recovered and recycled, yielding products 4–5 in excellent yields under ultrasonic environment without the formation of any side products or toxic waste.     

Synthesis, anticancer, anti-HIV-1, and antimicrobial activity of some tricyclic triazino and triazolo[4,3-e]purine derivatives

In an effort to etablish new candidates with improved antineoplastic, anti-HIV-1 and antimicrobial activities, the synthesis of some new triazino and triazolo[4,3-e]purine derivatives is described: 6,8-dimethyl-1,4-dihydro-1,2,4-triazino[4,3-e]purine-7,9(6H, 8H)-diones 3–6; 5,7,9-trimethyl-1,2,4-triazolo[4,3-e]purine-6,8(5H, 7H, 9H)-diones 11–13, together with the synthesis of the 8-substituted purine derivative: 8-(3,5-diamino-1H-pyrazol-4-yl)diazenyl-1,3-dimethyl-1H-purine-2,6(3H, 7H)-dione 7. The prepared compounds were tested for their in vitro anticancer, anti-HIV and antimicrobial activities. The results of the in vitro anticancer screening revealed that compound 3 exhibited considerable activity against melanoma MALME-3?M, non-small lung cancer HOP-92 and breast cancer T-47D (GI₅₀ values of 25.2, 31.8, and 32.9?μM, respectively). The anti-HIV-1 results indicated that compounds 7 and 13c displayed moderate activity (maximum % cell protection 30.52 and 35.54 at 2?×?10^?4 M, respectively). The in vitro antimicrobial data showed that compound 12 was the most active against P. aeruginosa, it was equipotent to ampicillin (MIC?<?100?μg/ml). While compound 11d was the most active against P.?vulgaris, it was as active as ampicillin (MIC?<?50?μg/ml). In addition, compounds 12 and 13c were the most active against S. aureus (MIC?<50 and <25?μg/ml, respectively). On the other hand, the tested compounds devoid of antifungal activity except 6b and 11c which showed weak activity against A.?niger.     

Synthesis, antitumor activity, and structure–activity relationship of some 4H-pyrano[3,2-h]quinoline and 7H-pyrimido[4′,5′:6,5]pyrano[3,2-h]quinoline derivatives

Several 4H-pyrano[3,2-h]quinoline (3a–d, 4a, 7a,b, 9a–c, 10a,b, 11a,b, and 13a–c) and 7H-pyrimido[4′,5′:6,5]pyrano[3,2-h]quinoline derivatives (8a–c) were obtained by treatment of 8-hydroxyquinoline (1a) and 8-hydroxy-2-methylquinoline (1b) with α-cyano-p-chloro/bromocinnamonitrile (2a,b) or 4H-pyrano[3,2-h]quinoline derivatives (3a,c,d) with different electrophilic reagents followed by nucleophilic reagents. Structures of these compounds were established on the basis of spectral data. The antitumor activity of the synthesized compounds was investigated in comparison with Vinblastine. Among them, compounds 3c,d, 4a, 8b, 9b,c, 11a,b, and 13a,c inhibited the growth of cancer cells compared to Vinblastine. The structure–activity relationships were discussed.     

Antimicrobial and antiquorum-sensing studies. Part 2: synthesis, antimicrobial, antiquorum-sensing and cytotoxic activities of new series of fused [1,3,4]thiadiazole and [1,3]benzothiazole derivatives

New series of [1,3,4]thiadiazolo[3,2-a]pyrimidines, [1,3,4]thiadiazolo[2,3-b]quinazolines, and pyrimido[2,1-b][1,3]benzothiazoles have been synthesized and characterized by analytical and spectrometrical methods (IR, MS, ¹H, and ¹³C NMR). Sixteen of the synthesized compounds; namely, 3a, b, 5a–f, 8a, b, 10, 11a–c, and 13a, b were screened for antibacterial activity against Escherichia coli, Staphylococcus aureus, and Bacillus cereus. They were found to be either moderately active, slightly active or inactive against the selected microorganisms. The antifungal activity of these compounds were also tested against Candida albicans, Aspergillus fumigatus 293, and Aspergillus flavus 3375. Compound 11a showed potent antifungal activity against the three selected fungi; the rest of the tested compounds displayed either weaker activity or were completely inactive. The same compounds were examined for antiquorum-sensing activity against Chromobacterium violaceum ATCC 12472, where compounds 3a, 10, 11a, and 13a, b exhibited promising activity. The in vitro cytotoxic activity of these compounds was also studied by brine shrimp lethality bioassay, and results indicated that compounds 3a, 11a, and 13a have the highest cytotoxic activity.     

Synthesis and biological evaluation of novel benzoquinones as potential antimicrobial agents

New series of 2,5-dihydroxyphenyl-1,3-thiazoles 4a–l was synthesized by reacting 2,5-dihydroxyphenacyl bromide with various 4-aryl thiosemicarbazones 3a–l that on oxidation with ferric chloride yielded the corresponding N ¹-substituted benzylidene-N ²-[3-aryl-4-(1,4-benzoquinon-2-yl)-1,3-thiazol-2-ylidene]hydrazines 5a–l. They were evaluated for antibacterial activity against Staphylococcus aureus and Bacillus subtilis as Gram-positive bacteria, Escherichia coli and Pseudomonas aeruginosa as Gram-negative bacteria. They were also evaluated for their in vitro antifungal potential against Candida albicans. Almost all tested compounds were found to possess variable degrees of antimicrobial activity. The obtained data revealed that compounds 4b–h and 5e, 5f and 5l exhibited promising antimicrobial activity against the tested organisms of which compound 4b proved to be the most active.     

Design and synthesis of some azole derivatives as potential antimicrobial agents

Syntheses of 1,2,4-triazol-3-ones, 4a, 4b, and 5 were performed starting from ester ethoxycarbonylhydrazones (1a, 1b) that were reported earlier. The treatment of triazole derivatives, 4a, 4b, and 5 with several sulfonyl halides produced the corresponding sulfonamides, 6–10. Syntheses of carbo(thio)amides, 15, 17, and 18 were carried out by the treatment of (substituted)phenyliso(thio)cyanates with hydrazides 13, 14 which were obtained starting from 4a and 5 by two steps. Cyclization of compounds 15 and 17 in basic media resulted in the conversion of carbo(thio)amide side chain to 5-oxo- or 5-mercapto-1,2,4-triazole ring. Cyclocondensation of 17 with ethyl chloroacetate and 4-nitrophenacylbromide gave 1,3-thiazolidin, 20 and 1,3-thiazol 21, derivatives, respectively. Newly synthesized compounds were screened for their antimicrobial activities, and some of them displayed activity against the test microorganisms. Then the highest activity was observed for compounds 6 and 7 carrying cyclic sulfonamide function beside 1,2,4-triazole nucleus.     

Heteroaromatic analogues of 1,5-diarylpyrazole class as anti-inflammatory agents

A novel series of heteroaromatic analogues of known anti-inflammatory (AI) drug celecoxib replacing the benzenesulfonamide moiety with 6-sulfonamidobenzothiazol-2-yl moiety was synthesized. Regioselective synthesis of the target compounds 2a–i having 1,5-diaryl relationship was achieved by exploring reaction conditions. All the newly synthesized compounds (2a–i and 8) were screened for their in vivo AI activity using carrageenan-induced rat paw edema assay. Five compounds (2c–f and 2i) were found to possess good AI activity (≥60% inhibition), 3?h after the carrageenan injection when compared to that of standard drug indomethacin (78%), whereas the remaining four compounds (2a–b and 2g–h) with 1,5-diaryl relationship have shown moderate activity with 49–56% inhibition after 3?h. However, pyrazole 8 having 1,3-diaryl relationship failed to show appreciable AI activity.     

Synthesis, antimicrobial, and antioxidant activities of some new indole analogues containing pyrimidine and fused pyrimidine systems

To examine new leads with potential antimicrobial and antioxidant activities, a new series of tetrahydropyrimidines (2a–c, 3a–c and 4a–c), pyrazolo[3,4-d]pyrimidines (5a–c), and ditetrazolo[1,5-a;1′,5′-c]pyrimidines (6a–c) were synthesized in this study using appropriate synthetic routes. The newly synthesized compounds have been tested for their antimicrobial and antioxidant activities against DPPH stable free radical. In the case of antibacterial activity, compounds 2a, 6a, and 6c exhibited the maximum zone of inhibition against Staphylococcus aureus; compound 6c exhibited maximum zone of inhibition against Pseudomonas aeruginosa; and compound 2a showed maximum inhibitory growth against Klebsiella pneumonia. While in the case of antifungal activities, compound 5a showed good zone of inhibition against Aspergillus oryzae, compounds 2b and 6a exhibited maximum zone of inhibition against Aspergillus niger. In case of antioxidant activities, compound 2a showed the highest DPPH radical scavenging activity.     

Synthesis of progesterone derivatives and evaluation of their efficiency as pneumococcal vaccines

Progesterone (1) was used as a template to develop new anticancer compounds. Ring D modification of 1, through its reaction with active methylene derivatives, gave the condensate derivatives 3a, b. The latter compounds underwent heterocyclization reactions through the reaction with either hydrazine hydrate or phenyl hydrazine to give the pyrazole derivatives 6a–d, respectively. The reaction of 1 with bromine gave the α-bromo derivative 7, which in turn reacted with potassium cyanide to yield the cyanoacetyl derivative 8. Compound 8 has been subjected to a series of reactions that produced benzylidene, aryl hydrazine, pyrazole, and pyran derivatives. The newly synthesized products were tested for their efficiency as pneumococcal vaccines and the results were promising.     

New thiazolidine-2,4-diones as antimicrobial and cytotoxic agent

New (Z)-5-substituted-2,4-thiazolidinediones (3a–m) were easily prepared by the condensation of thiazolidine-2,4-dione (1) with suitable aldehydes (2a–m) via microwave irradiation technique. The reaction between (Z)-5-substituted-2,4-thiazolidinediones and 4-(bromomethyl) benzoic acid, using potassium carbonate as base in refluxing acetone, followed by a workup in acidic medium provided 4-(((Z)-5-substituted-2,4-dioxothiazolidin-3-yl)methyl) benzoic acid derivatives (4a–m). The structures of the newly synthesized compounds were confirmed by IR, ¹H NMR, ¹³C NMR spectral studies, and elemental analysis. All compounds were evaluated for their in vitro antimicrobial and cytotoxic activities. Antibacterial and antifungal results revealed that most of the compounds showed significant activity where as compounds 4c and 4g are found to be broad spectrum antibacterial and antifungal properties, the MIC values were observed in the range of 2–4 and 2–8?μg/ml, respectively. In MTT cytotoxicity studies, the compound 4g was found most potent. In HeLa, HT29, A549, and MCF-7 cells, the IC₅₀ values were observed in the range of 30–36?μM.     

Preparation and antimicrobial activity evaluation of some new bi- and triheterocyclic azoles

Synthesis of the carbothioamides (5, 13, 22) was performed starting from 3H-1,2,4-triazol-3-ones (2, 17) by several steps, and then, these carbothioamides was converted to triheterocyclic compounds incorporating 1,2,4-triazole, imidazole and 1,3-thiazol(idinone) moieties. The reaction of compound 2 with 3,4-difluoronitrobenzene afforded the 2-(2-fluoro-4-nitrophenyl) derivative, 10. Compound 10 was converted to the arylideneamino derivatives (12a, b) via the reduction of nitro group. On the other hand, the treatment of the hydrazide (20) that was obtained starting from 17, with several aromatic aldehydes generated the corresponding arylidenhydrazides (21a–c). Mannich reaction between compound 2 and a suitable heterocyclic amine resulted in the N-alkylation of 2. All newly synthesized compounds were screened for their antimicrobial activities. In general, most compounds except 22 were Found (%) to be active against Mycobacterium smegmatis, Candida albicans and/or Saccharomyces cerevisiae. Furthermore, 9a and b, which are Mannich bases incorporating morpholine or piperazine nucleus, exhibited excellent antimicrobial activity on test microorganisms. In addition, the hydrazide, 4, was Found (%) to have activity towards Ec and Yp.     

Zn(OTf)2-catalyzed three component, one-pot cyclocondensation reaction of some new octahydroquinazolinone derivatives and access their bio-potential

An efficient synthesis of some new octahydroquinazolinone derivatives 4a–x by the cyclocondensation reaction of corresponding 2-thi(oxo)-1,2-dihydroquinoline-3-carbaldehyde 1a–e, 1,3-dicarbonyl compounds 2a–b, and substituted urea 3a–c using zinc triflate as a catalyst in refluxing ethanol in high yield is described. The structures of new compounds have been characterized on the basis of elemental analysis, FT- IR, ¹H NMR, ¹³C NMR, and mass spectral data. All the synthesized compounds were evaluated for their antimicrobial activities against various microbes. Minimum inhibitory concentration values of all the 24 synthesized compounds were also determined. Some of the synthesized compounds exhibited excellent antimicrobial activity.     

Synthesis and antimicrobial activities of some isoxazolyl thiazolyl pyrazoles

A series of isoxazolyl thiazolyl pyrazoles 5a–d was synthesized by multi-step process, starting from 3-acetyl-4-hydroxy-6-methyl-2H-pyran-2-one (dehydroacetic acid, DHAA) 1. DHAA 1 was easily converted to thiosemicarbazone 2 which on reaction with α-bromoketones yielded thiazolyl hydrazones 3. Refluxing 3 in ethanol-acetic acid furnished 1-(5-hydroxy-3-methyl-1-substituted pyrazol-4-yl)-1,3-butanediones 4. Finally, the title compounds 5a–d were synthesized from 4 on treatment with hydroxylamine. The in vitro antimicrobial activity of compounds 3a–d, 4a–d and 5a–d were tested. Most of the synthesized compounds exhibited significant antibacterial and antifungal activities.