Synthesis of some novel 3,4,5-trisubstituted triazole derivatives bearing quinoline ring and evaluation of their antimicrobial activity

Abstract

Some new 3,4,5-trisubstituted 1,2,4-triazole derivatives were synthesized and studied for their antimicrobial activity. The lead compounds were obtained starting from 8-hydroxyquinoline and ethyl 2-chloroacetate. The obtained ester compound (1) first reacted with hydrazine hydrate (2) then with phenyl isothiocyanate (3). Ring closure by KOH led to 3-mercapto-1,2,4-triazole derivative (4). Lastly, it reacted with 2-chloro-N-(substituted (benzo)/thiazole)acetamide derivatives to obtain the final compounds (5a–j). The structural elucidation of the compounds was performed by ¹H NMR and ¹³C NMR spectroscopy and high resolution mass spectrometry techniques and elemental analysis. The synthesized compounds were investigated for their antimicrobial activities against seven bacteria and four fungi. As a result of the activity studies, it was observed that compounds N-(6-nitrobenzothiazol-2-yl)-2-[[4-phenyl-5-((quinolin-8-yloxy)methyl)-4H-1,2,4-triazol-3-yl]thio]acetamide (5a) and N-(6-fluorobenzothiazol-2-yl)-2-[[4-phenyl-5-((quinolin-8-yloxy)methyl)-4H-1,2,4-triazol-3-yl]thio]acetamide (5d) were the most active molecules. Also, the antifungal activity of the compounds was found to be higher than their antibacterial activity although lower than the standard drug’s potential. Additionally, the physicochemical properties of the compounds were calculated which were evaluated to be at a suitable range for oral administration.     

Synthesis and antimicrobial activity of novel chalcone derivatives

A series of novel 3-[N, N-bis(2-hydroxyethyl)-amino]-chalcone derivatives 3a–3j were synthesized by the aldol condensation of [N, N-bis(2-hydroethyl)-3-amino]-acetophenone 2 with aromatic aldehydes. Their structures were further confirmed by ESI-HRMS, ¹H NMR, IR and elemental analysis. X-ray analysis reveals crystal 3b is a monoclinic system with P2₁/n space group. The antimicrobial activities of the newly synthesized chalcones in vitro were evaluated and the results indicated that most compounds presented moderate to good antimicrobial activities, especially the antifungal capability. Compounds 3a, 3d, 3f and 3g revealed obvious potency against Candida albicans with MIC values of 32 μg/mL, which were better compared with others.     

Synthesis of some novel thiocyanotopurine derivatives and investigation of their antimicrobial activity and DNA interactions

A series of 6-thiocyanatopurine derivatives introduced with different alkyl groups in position 9 was synthesized. The structures of the synthesized compounds were evaluated via spectroscopic methods and elemental methods of analyses. All the synthesized compounds were screened for their antibacterial activities against Gram-positive and Gram-negative bacteria and for their antifungal activities against yeast strains. All the synthesized compounds showed better antibacterial activities against Gram-positive bacteria compared to Gram-negative bacteria. DNA interactions with pBR322 DNA were determined. Most of the compounds caused conformational changes in DNA.     

Synthesis of novel 1,3,4-trisubstituted pyrazole derivatives and their evaluation as antitumor and antiangiogenic agents

Several 1,3,4-trisubstituted pyrazole derivatives were synthesized and screened for their cytotoxic effect in a primary 3 tumor cell line test at 10(-4) M drug concentration. Compounds 19 and 20 reduced the growth of one or more of these cell lines to less than 32% and escalated up to evaluation in the full panel of 60 human tumor cell lines at a minimum of 5 concentrations at 10 fold dilutions. Compound N'-(1-[1-[4-nitrophenyl]-3-phenyl-1H-pyrazol-4-yl]methylene)-2-chlorobenzohydrazide 19 proved to be the most active of these derivatives with full panel median growth inhibition (GI50), total growth concentration (TGI) and median lethal concentration (LC50) mean graph mid-point (MG-MID) of 3.79, 12.5 and 51.5 microM, respectively. In addition, compounds 19, 39, 40, 41, 43, 45, 47 were tested for their antiangiogenic properties by testing their ability to inhibit human umbilical vein endothelial cells (HUVECs) proliferation, cord formation and migration in response to chemoattractant. 3-Acetyl-2-(1-(4-nitrophenyl)-3-phenylpyrazol-4-yl)-5-(4-pyridyl)-1,3,4-oxadiazoline 39 showed significant antiangiogenic profile at non-cytotoxic doses, with HUVEC proliferation inhibition IC50 of 7.60 microM, chemotaxis IC50 of 0.86 microM and was superior to the reference celecoxib 2 in both tests. Furthermore, in contrary to the references TNP-470 and celecoxib, all the tested compounds interfered with the migratory function of HUVECs in response to vascular endothelium growth factor (VEGF) rather than the endothelial cells proliferation.     

Synthesis of novel thiazol-5-ylpyrimidine derivatives and their antimicrobial evaluation

Novel thiazol-5-ylpyrimidine derivatives were designed and synthesized. The chemical structures of all new synthesized compounds were assigned by studying their elemental analyses and spectral data (FT-IR, ¹HNMR, ¹³C NMR, and MS). The target compounds, 8 and 9a-9d were evaluated for their antimicrobial activity in vitro against gram-positive bacteria, Bacillus subtilis and Staphylococcus aureus, gram-negative bacteria, Salmonella abony and Escherichia coli and fungi, Aspergillus flavus and Fusarium oxysporum. In particular, compounds 9a-9c exhibited moderate to good activity against gram-positive bacteria, S. aureus, gram-negative bacteria, S. abony and fungus, Fusarium oxysporum in comparison with reference drugs.     

Synthesis and in vitro antitumor activity of novel naphthyridinone derivatives

A series of naphthyridinone derivatives based on la(a precursor of Voreloxin) were designed and synthesized.Seven compounds having 70%inhibition against HL60 at 30 μmol/L were further evaluated for their in vitro antitumor activity by SRB assay.Results reveal that thiazol-2-yl and 3-aminomethyl-4-benzyloxyimino-3-methylpyrrolidin-l-yl groups are optimal at the N-1 and C-7positions of naphthyridinone core,respectively.10 j exhibits broad-spectrum activity(IC_(50):0.5-6.25 μmol/L) against all of the tested cell lines including Etoposide- and/or la-resistant ones,and is 1.3-fold to 100-fold more potent than the two references against eight of these cell lines.     

Synthesis and in vitro antimicrobial activity of some pyrazolyl-1-carboxamide derivatives

A series of 3,5-disubstituted pyrazole-1-carboxamides were obtained by treatment of chalcones with semicarbazide hydrochloride in dioxane containing sodium acetate/acetic acid as a buffer solution. N-acetyl derivatives of pyrazole-1-carboxamides were isolated in good yields either by treatment of the carboxamide derivatives with acetic anhydride or refluxing chalcones with semicarbazide in ethanol containing few drops of acetic acid to give the corresponding hydrazones. Subsequent treatment of hydrazones with acetic anhydride gave the desired N-acetyl pyrazole-1-carboxamides derivatives. When chalcones were refluxed with dioxane containing few drops of acetic acid, 4,5-dihydropyrazole-1-carboxamides were isolated, which were subsequently oxidized using 5% sodium hypochlorite in dioxane to afford pyrazole-1-carboxamides. The structures of isolated compounds were confirmed by elemental analyses and spectral methods. The isolated compounds were tested for their antimicrobial activities.     

Synthesis of some Mannich base derivatives and their antimicrobial activity study

A series of 2-(phenyl)-2-(morpholin-4-yl)-N-phenylacetamide I–VII were synthesized by Mannich base method. Synthesized compounds I–VII were confirmed by IR, ¹H NMR, ¹³C NMR, mass and elemental analyses. Synthesized compounds I–VII were screened for antibacterial activity against various bacterial strains and compared with standard Ciprofloxacin at concentration 100 μg/mL and for antifungal activity against various fungal strains and compared with Clotrimazole at concentration 100 μg/mL; particularly 3-(4-chlorophenyl)-3-(morp holin-4-yl)-N-phenylpropanamide lll that has high antibacterial activity against Streptococcus epidermidis was compared with standard Ciprofloxacin.     

Synthesis and fungicidal activity of novel 1,2,4-triazole derivatives containing a pyrimidine moiety

Abstract

A series of novel 1,2,4-triazole derivatives containing a pyrimidine moiety were synthesized and their fungicidal activities were evaluated. The preliminary biological test indicated that some of the target compounds exhibited moderate to good fungicidal activities against the tested plant pathogenic fungi compared with the commercial agent. Among them, compounds 9n and 9o exhibited excellent antifungal activity against Phompsis sp., with the half-maximal effective concentration (EC₅₀) values of 25.4 and 31.6?μg/mL, which were even better than the commercial agent of Pyrimethanil (32.1?μg/mL). Meanwhile, compound 9o showed better fungicidal activities against B. dothidea and B. cinerea with 40.1 and 55.1?μg/mL, respectively, in comparison with that of commercial Pyrimethanil (57.6 and 62.8?μg/mL).     

Synthesis and antimicrobial activities of some newly 2,4,6-tri-substituted pyridine derivatives

A series of novel 2-(2-(substituted benzylidene)hydrazinyl)-N′-(substituted benzylidene)-6-chloropyridine-4-carbohydrazide (5a–e), 2-(2-cycloalkylidenehydrazinyl)-6-chloro-N’-cyclo-alkylidenepyridine-4-carbohydrazide (6a,b), 2-(2-(1-(4-substituted phenyl)ethylidene)hydrazinyl)-6-chloro-N′-(1-(4-substituted phenyl)ethylidene)pyridine-4-carbohydrazide (7a,b) and 2-(2-(1-(pyridinyl)ethylidene)hydrazinyl)-6-chloro-N′-(1-(pyridinyl) ethylidene)pyridine-4-carbo-hydrazide (8a–c) derivatives have been synthesized by treating treating 2-chloro-6-hydrazinoisonicotinic acid hydrazide 4 with selected active reagents. Their structures were confirmed by spectral and analytical data. The synthesized compounds were investigated for antimicrobial activities. The antimicrobial screening showed that many of these obtained compounds have good activities comparable to Streptomycin and Fusidic acid as reference drugs.     

Synthesis and in vitro antimicrobial activity of N-arylquinoline derivatives bearing 2-morpholinoquinoline moiety

A new series of N-arylquinoline derivatives 5a-x bearing 2-morpholinoquinoline moiety has been synthesized by one pot base catalyzed cyclocondensation reaction of 2-morpholinoquinoline-3-carbaldehydes 2a-c,malononitrile 3 andβ-enaminones 4a-h. All the synthesized compounds were screened for their in vitro antimicrobial activity against six bacterial pathogens,namely Streptococcus pneumoniae,Clostridium tetani,Bacillus subtilis,Salmonella typhi,Vibrio cholerae,Escherichia coli and against two fungal pathogens,Aspergillus fumigatus and Candida albicans using broth microdilution MIC method.Of the compounds studied,majority of the compounds were found to active against C.tetani,B.subtilis and C.albicans as compared to first-line standard drugs.     

Synthesis and in vitro antitumor activity of novel diaryl urea derivatives

A series of novel diaryl ureas containing 4-[（2-amino-6-trifluromethyl）pyrimidine-4-yl]piperazine-l-yl group were synthesized and evaluated for their cytotoxic activities in a panel of human cancer cell lines. Compared with the reference drug Sorafenib,some compounds showed more potent and a broader spectrum of anti-cancer activities.Among them,compound 2p demonstrated significant inhibitory activities against MDA-MB-231,HT-29 and MCF-7 cell lines with IC₅₀ values of 0.016,0.63,0.001μmol/L, respectively.     

Efficient access to some new pyrimidine derivatives and their antimicrobial evaluation

1-[4-(3-Hydroxyphenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidin-5-yl]ethanone ( 1 ) was used as a precursor for heterocyclic synthesis. Condensation of compound 1 with monochloroacetic acid and benzaldehyde gave thiazolopyrimidine 2 which in turn underwent cyclization with malononitrile dimmer to afford malononitrile derivative 3 . Also, the reaction of compound 1 with benzaldehyde under a basic condition produced chalcone 4 . Chalcone 4 can be used as a key intermediate for further preparation of heterocyclic compounds. In addition, compound 1 was allowed to react with malononitrile dimmer and/or ethyl chloroacetate to give pyrimidines 8 and 9 , respectively. Alkylation of compound 8 with ethyl chloroacetate afforded S-alkylated product 10 which was treated with hydrazine hydrate to yield the hydrazino derivative 11 . Alternative synthesis of compound 10 was taken place through reaction of compound 9 with malononitrile dimmer. The biological activity of the synthesized compounds was investigated. Compounds 1 , 4 , 5 , and 8 recorded high activities against Gram positive bacteria (S. aureus). Structures of the new synthesized compounds were elucidated by elemental analysis and spectral data.     

Synthesis and antitumor activity of novel pyridino[2,3-d]pyrimidine urea derivatives

A series of novel N-(3-((6-bromopyrido[2,3-d]pyrimidin-4-yl)oxy)phenyl)pyrrolidine-1-carboxamide and 1-(3-((6-bromopyrido[2,3-d]pyrimidin-4-yl)oxy)phenyl)-3-propylurea derivatives were synthesized. Their antitumor activities against human breast carcinoma cells (MCF-7) and human colon cancer cells (HCT-116) in vitro were evaluated, using sorafenib as a positive control drug. Anticancer bioassays indicated that several compounds exhibited appreciable anticancer activity against MCF-7 and HCT-116 cells. Particularly, compounds 9g and 8b demonstrated the most significant inhibitory effect against HCT-116 and MCF-7 cells, with inhibition ratios of 25.56% and 26.46%, respectively. Additionally, the synthesized pyridine[2,3-d]pyrimidine derivatives containing a urea group moieties exhibited antitumor activities against MCF-7 and HCT-116 cells in vitro.     

Synthesis and properties of symm-triazine derivatives. 4. Synthesis of 2,4,6-trisubstituted symm-triazines containing sterically-hindered phenol fragments

2,4,6-Trisubstituted symm-triazines containing sterically-hindered phenol fragments were synthesized by the cyclotrimerization of ethyl iminoesters. 2,4,6-Trimercapto-symm-triazine derivatives containing shielded phenol residues may be formed by the cyclotrimerization of the corresponding thiocyanates in acidic medium.For communication 3, see [1].Translated from Khimiya Geterosiklicheskikh Soedinenii, No. 1, pp. 107–113, January, 1986.     

Synthesis,characterization and in vitro antimicrobial activity of some novel 5-substituted Schiff and Mannich base of isatin derivatives

With the aim of developing potential antimicrobials, a series of novel Ciprofloxacin methylene isatin derivatives incorporating different aromatic aldehydes were synthesized and characterized by FTIR, ¹H NMR, Mass spectroscopy and bases of elemental analysis. In addition, the in vitro antibacterial and antifungal properties were tested against some human pathogenic microorganisms by employing the disc diffusion technique. A majority of compounds were showing activity against several of the microorganisms. The relationship between the functional group variation and the biological activity of the evaluated compounds is discussed. From comparisons of the compounds, 3c was determined to be the most active compound.     

Synthesis of new 1,3,5-thiadiazine and 1,3,5-triazine derivatives and their antimicrobial activity

Interaction of ethyl chloroformate with γ-N-substituted trithioallophanic acids has been found to yield the corresponding 6-oxo-5-aryl-2,4-dithio-hexahydro-l,3,5-thiadiazines. These on reaction with amines yield 1,3,5-triazines. γ-N-substituted β-oxo-dithio-allophanic acid with ethyl chloroformate similarly yields 4,6-dioxo-5-aryl-2-thio-1,3,5-thiadiazine. Antimicrobial activity of thiadiazines has been reported.     

Synthesis of 2,4,6-trisubstituted 5-(2-alkylsulfanylethyl)-pyrimidines and some their transformations

New 2,4,6-trisubstituted 5-(2-alkylsulfanylethyl)pyrimidines were synthesized by condensation of ethyl 2-(2-alkylsulfanylethyl)-3-oxobutanoates with various amidines and thiourea. Fusion of substituted 2,6-dimethylpyrimidin-4(3H)-ones with aromatic aldehydes gave the corresponding 6-styrylpyrimidines. Some 5-(2-alkylsulfanylethyl)pyrimidines were oxidized to sulfoxides, and amination of 5-[2-(butylsulfanyl)ethyl]-6-methyl-2-propylsulfanylpyrimidin-4(3H)-one with 4-aminobenzoic acid afforded 4-{5-[2-(butylsulfanyl)ethyl]-4-methyl-6-oxo-1,6-dihydropyrimidin-2-ylamino}benzoic acid.