The synthesis of 6-(N-Arylamino)-7-chloro-5,8-quinolinedione derivatives for evaluation of antifungal activities

A series of 6-(N-arylamino)-7-chloro-5,8-quinolinedione derivatives was newly synthesized for the evaluation of antifungal activities. 5-Amino-8-hydroxy-quinoline (II) was treated with KClO₃ in HCl to give 6,7-dichloro-5,8-quinolinediones (III). 6-(N-arylamino)-7-chloro-5,8-quinolinediones1–12 were prepared by regioselective nucleophilic substitution of III with arylamines. In the presence of CeCl₃, the N-arylamino groups were introduced at the 6-position of 5,8-quinolinedione ring by the regioselective substitution. These derivatives1–12 were tested for antifungal and also antibacterial activities,in vitro, againstCandida albicans, Aspergillus niger, Tricophyton mentagrophytes, Bacillus subtilis, Pseudomonas aeruginosa, Staphylococcus aureus andEscherichia coli. The MIC values were determined by the two-fold agar/streak dilution method. Newly obtained 6-(N-arylamino)-7-chloro-5,8-quinolinedione derivatives showed potent antifungal and antibacterial activities. Among these derivatives,1, 3, 5, 7, 8 and9 showed more potent antifungal activities than fluconazole and griseofulvin. Also most of derivatives were found to be more active than ampicillin against gram-positive bacteria.1 and7 showed the very potent antifungal activities.1 was the most effective in preventing the growth ofCandida albicans, Aspergillus niger, Tricophyton mentagrophytes, Bacillus subtilis andStaphylococcus aureus at MIC 1.6 μg/ml.     

In vitro andin vivo antifungal activities of 6-[(N-4-bromophenyl) amino]-7-chloro-5,8-quinolinediones

Antifungal activities of 6-[(N-4-bromophenyl)amino]-7-chloro-5,8-quinolinedione (RCK7) were tested. The MIC values of RCK7 were determined for antifungal suceptibility,in vitro againstAspergillus niger, Cryptococcus neoformans andTrichophyton mentagrophyte by standard agar streak method.In vitro, RCK7 showed more potent antifungal activity than fluconazole and ketoconazole. Also, RCK7 was tested forin vivo antifungal activity in the treatment of systemic infection withCandida albicans in normal mice. The therapeutic potential of RCK7 had been assessed by evaluating their survival rate against systemic infections compared with that of ketoconazole. ED₅₀ of intraperitoneally administered RCK7 was 2.05±0.30 mg/kg but that of ketoconazole was 8.00±0.73 mg/kg, respectively. When RCK7 was administered intravenously at the ED₅₀ (2.05 mg/kg), the colony counts ofCandida albicans in the liver after 7 days and 14 days were reduced as likely as ketoconazole at the ED₅₀ (8.00 mg/kg), and the better survival rates than ketoconazole’s were achieved after 14 days. The results suggest that RCK7 may be a potent antifungal agent.     

Synthesis and antibacterial activity of N-[5-chlorobenzylthio-1,3,4-thiadiazol-2-yl] piperazinyl quinolone derivatives

A series ofN-[5-(chlorobenzylthio)-1,3,4-thiadiazol-2-yl] piperazinyl quinolone derivatives (4a-1) have been synthesized by reaction of piperazinyl quinolones with 5-chloro-2-(chloroben-zylthio)-1,3,4-thiadiazoles. Their structures were confirmed by elemental analysis, IR and NMR spectra. The antibacterial activities of4a-1 against a variety of Gram-positive and Gram-negative bacteria were determined. Several compounds showed a good antibacterial activity against Gram-positive bacteria among which, compound 4e with a 2-chlorobenzylthio moiety in ciprofloxacin derivative, exhibited high activities againstStaphylococcus aureus andStaphylococcus epidermidis (MIC=0.06 μg/mL). The structure-activity relationship (SAR) study revealed that the position of chlorine atom on benzyl moiety would dramatically affect the antibacterial activities of the synthesized compounds.     

Synthesis and antifungal activity of 6,7-bis-[S-(aryl)thio]-5,8-quinolinediones

6,7-Bis-[S-(aryl)thio]-5,8-quinolinediones 4 and 5 were synthesized by the substitution of 6,7-dichloro-5,8-quinolinediones with appropriate arylthiols. Their antifungal activity were tested in vitro for their growth inhibitory activities against pathogenic fungi in comparison with flucytosine. The antifungal activities were significantly improved by S-(aryl)thio moieties of the compounds 4 and 5. The all tested compounds 4 and 5 showed generally good activities against C. albicans and A. niger ranging from 0.8 to 25 microg/ml. Among them, compounds 4d-4h and 5a-5c exhibited also good activities against C. krusei and C. tropicalis. The activities of compounds 4j and 4l were comparable to those of flucytosine against all tested fungi.     

The synthesis and antimicrobial activities of some 1,4-naphthoquinones (II)

In order to evaluate the antimicrobial effect of 2,3-disubstituted-1,4-naphthoquinone derivatives we newly synthesized several 2-chloro and 2-bromo-3-(substituted)-1,4-naphthoquninones. Amination reaction of 2,3-dihalo-1,4-naphthoquinones with aryl and aliphatic amines in ethanol gave 2-halo-3-(N-alkyl or N-aryl)-1,4-naphthoquinone derivatives (1a,b–10a,b) in 60%–90% yield. These derivatives subjected to antibacterial and antifungal activities,in vitro, againstBacillus subtilis ATCC 6633, Candida albicans 10231 and local, Pseudomonas aeruginosa NCTC10490, Staphylococcus aureus ATCC 6538p, Escherichia coli NIHJ, Aspergillus niger KCTC 1231. Tricophyton mentagrophytes KCTC 6085. Among these derivatives,1b, 6b and7a showed the potent antibacterial activities.1b, 8b and9b have the antifungal activities.1b is most effective in preventing the growth ofBacillus subtilis and Pseudomonas aeruginosa, Candida albicans, Aspergillus niger. Tricophyton mentagrophytes. The several of these compounds demonstrated a broad spectrum of activitiesin vitro.     

Isolation of 3-O-(4′-Hydroxybenzyl)-β-sitosterol and 4-[4′-(4″-Hydroxybenzyloxy)benzyloxy]benzyl methyl ether from fresh tubers ofGastrodia elata

Two new 4-hydroxybenzyl alcohol derivatives (1 and2) were isolated from the methanol extract obtained from fresh tubers ofGastrodia elata together with 4-hydroxybenzyl methyl ether, 4-hydroxybenzyl alcohol, bis(4-hydroxyphenyl)methane, 4-hydroxybenzaldehyde, β-sitosterol and palmitic acid.1 and2 were identified as 3-O-(4′-hydroxybenzyl)-β-sitosterol and 4-[4′-(4″-hydroxybenzyloxy) benzyloxy)benzyl methyl ether, respectively, according to the spectroscopic data.     

Simple and efficient synthetic routes to bioactive s-triazinyl dithiocarbamate derivatives

Series of 2,4-diarylamino-6-[N-(3′-methylphenyl)dithiocarbamoyl]-s-triazines (4a–l) and 2,4-bis[N-(3′-methylphenyl)dithiocarbamoyl]-6-arylamino-s-triazines (7a–l) were synthesized by two different synthetic routes. In the first route (A), 2,4,6-tricholoro-s-triazine (1) was condensed with N-(3-methylphenyl)ammoniumdithiocarbamate to afford compounds 3 or 6, which on reaction with different aryl amines afforded compounds 4a–l or 7a–l. In the second route (B), condensation of 1 with different aryl amines yielded compounds 2a–l or 5a–l. On further treatment with N-(3-methylphenyl)ammoniumdithiocarbamate these afforded compounds 4a–l or 7a–l. The newly synthesized compounds 4a–l and 7a–l were characterized by elemental analyses, infrared (IR), and ¹H nuclear magnetic resonance (NMR) spectroscopic investigation. All the products were evaluated for their antibacterial and antifungal activity.     

Antiviral triterpenes fromPrunella vulgaris

Two triterpenes 1 and 2 with antiviral activity againstHerpes simplex virus type 1in vitro were isolated fromPrunella vulgaris. Each compound caused a significant reduction in viral cytopathic effect whenvero cells were exposed to them for 72 hours after viral challenge. They were identified asbetulinic acid(1) and 2α, 3α-dihydroxyurs-12-en-28-oic acid(2) on the basis of their spectroscopic properties. The antiviral activity of them was estimated as EC₅₀=30 μg/ml(1) and 8 μg/ml(2), respectively by plaque reduction assay.     

Synthesis and biological evaluation of 5,7-diaryl-4,4-dimethyl-4,5,6,7-tetrahydropyridino[3,4-d]-1,2,3-thiadiazoles

New 5,7-diaryl-4,4-dimethyl-4,5,6,7-tetrahydropyridino[3,4-d]-1,2,3-thiadiazoles 23–27 are synthesized, characterized by melting point, elemental analysis, magnetic spectroscopy (MS), Fourier-transform infrared spectroscopy (FT-IR), nuclear magnetic resonance (NMR) (¹H and ¹³C) spectra and evaluated for their in vitro antibacterial and antifungal activities. Compounds 23–27 are more potent against Gram-positive bacterial strains, namely Staphylococcus aureus and β-Haemolytic streptococcus. However compounds 23–27 possess potent activity against Klebsiella pneumonia, a Gram-negative bacterial strain, compared to the standard drug used, ciprofloxacin. In general, all the synthesized compounds exert a wide range of modest in vitro antifungal activity against Rhizopus and Microsporum gypsuem than the standard drug, fluconazole.     

Synthesis and in vitro anti-Helicobacter pylori activity of 2-[(chlorobenzyl)thio]-5-(5-nitro-2-furyl)-1,3,4-thiadiazoles

A new series of 2-[(chlorobenzyl)thio]-5-(5-nitro-2-furyl)-1,3,4-thiadiazoles (6a–h) were synthesized and evaluated by the disc diffusion method against Helicobacter pylori. Four compounds which exhibited strong anti-H. pylori activity at concentration of 8–32 μg/disc (average of inhibition zone >20 mm) were further tested against 20 clinical isolates of H. pylori at lower concentrations. The averages of inhibition zone diameters indicated that all selected compounds exhibit better anti-H. pylori activity profile against clinical isolates of H. pylori with respect to standard drug metronidazole. Compound 6c, containing the 3-chlorobenzylthio moiety, was the most potent compound tested.     

Cystocin,a novel antibiotic,produced byStreptomyces sp. GCA0001: Biological activities

Cystocin belongs to the class of nucleoside antibiotics fromStreptomyces sp. GCA0001. Cystocin showed good activity against Gram-positive bacteria, but showed less activity against the Gram-negative bacteria. Cystocin exhibited about two to four folds higher activity than puromycin. Especially, cystocin shows relatively strong activity againstStreptococcus strains. Cystocin shows quite potent antitumor activity against all of the cells tested showing IC₅₀ values of 0.10 to 0.14 μg/mL Thisin vitro result indicates that the cytotoxocity of cystocin is two ten folds more active than puromycin’s.     

In vitro andin vivo evaluations of LB10517, a novel parenteral broad-spectrum cephalosporin

Thein vitro activity of LB10517, a new catechol-substituted cephalosporin, was compared with those of E-1077, cefpirome and ceftazidime against 1034 clinical isolates collected in Japan. LB10517 showed a broad-spectrum antibacterial activity against a wide range of gram-positive and gram-negative bacteria including non-glucose fermenting rods,Pseudomonas aeruginosa. Against the methicillin-susceptible strains ofStaphylococcus aureus (MSSA) andStreptococcus pyogenes, the MIC₉₀ values of LB10517 which required to inhibit 90% of the strains were 3.13 μg/ml and 0.1 μ/ml, respectively. It was as active as E-1077 but more active than cefpirome and ceftazidime. Methicillin-resistant strains ofS. aureus (MRSA) andEnterococcus spp. were highly resistant to all the test compounds. LB10517 was highly active against most members of the familyEnterobacteriaceae, 90% of which were inhibited at a concentration of less than 0.78 μg/ml, except forEnterobacter cloacae (1.56 μg/ml) andSerratia marcescens (3.13 μg/ml). Its activity was comparable to those of E-1077 and cefpirome but it was greater than that of ceftazidime. AgainstPseudomonas aeruginosa, LB10517 showed the most potent antibacterial activity among the compounds tested. Ninety percent ofP. aeruginosa isolates were susceptible at the concentration of 0.39 μg/ml. Its activity was 32- to 128-fold higher than those of E-1077, cefpirome and ceftazidime. Against imipenem- or ofloxacinresistantP. aeruginosa, LB10517 with MIC₉₀s of 6.25 μg/ml and 3.13 μg/ml, respectively, showed 16-fold more potent activity than the other test compounds. LB10517 showed a relatively high plasma level and long plasma elimination half-life in rats (t_1/2(β), 52 min) and dogs (t_1/2(β), 103 min).     

Synthesis and Antimicrobial Activity of Some New 2-(3-(4-Aryl)-1-phenyl-1H-pyrazol-4-yl) Chroman-4-ones

Seven new 2-(3-(4-aryl)-1-phenyl-1H-pyrazol-4-yl) chroman-4-ones (4a-4g) have been synthesized by cyclization of 2-hydroxychalcone analogues of pyrazole 3a-3g using conc. HCl in acetic acid. The structures of the compounds 4a-4g were established by the combined use of (1)HNMR, IR and mass spectra. All the seven compounds were tested in vitro for their antibacterial activity against two Gram positive bacteria namely Staphylococcus aureus and Bacillus subtilis and two Gram negative bacteria Escherichia coli and Pseudomonas aeruginosa. The compounds 4b, 4c, 4e, 4f, 4g have displayed good antibacterial activity when compared with commercially available antibiotic, ciprofloxacin. These compounds also were screened for their antifungal activity against two ear pathogenic fungi, namely Aspergillus Niger and A. flavus. The compounds 4a, 4c, 4d, 4g exhibited good antifungal activity when compared with commercially available antifungal, fluconazole.     

Synthesis of hexaprofen [2-(4-cyclohexylphenyl) propionic acid]

A novel preparative method for hexaprofen, which is a potent antiinflammatory agent, is described. Friedel-Crafts reaction of cyclohexylbenzene with ethyl α-chloro-α-(methylthio) acetate1 and α-chloro-α-(methylthio) acetonitrile2 afforded ethyl 2-(methylthio)-2-(4-cyclohexylphenyl) acetate7 and 2-methylthio-2-(4-cyclohexylphenyl) acetonitrile8, respectively. Compounds7 and8 were converted into the corresponding ethyl 2-methylthio-2-(4-cyclohexylphenyl) propionate9 and 2-methylthio-2-(4-cyclohexylphenyl) propionitrile10 by methylation with sodium hydride and methyl iodide. Hexaprofen13 was prepared by hydrolysis of ethyl 2-(4-cyclohexylphenyl) propionate11 and of 2-(4-cyclohexylphenyl) propionitrile12 followed by desulfurization of compounds9 and10.     

Reactions with activated nitriles: A new route for the synthesis of new pyridine and pyrazolopyridine derivatives

It has been found that α, β-unsaturated nitrile derivatives1–3 reacted with S-methylisothiourea to give the propene derivatives4–6 respectively. Cyclisation of4–6 using ethanolic hydrochloric acid afforded the pyridine derivatives7–9 in good yields. On the other hand, the reactions of hydrazine hydrate and of phenylhydrazine with each of7–9 gave the corresponding pyrazolopyridine derivatives10–15. The structures of the newly synthesised derivatives were assigned on the basis of elemental analyses, IR and¹H-NMR spectral data studies.     

Anti-oxidative and inhibitory activities on nitric oxide (NO) and prostaglandin E<Subscript>2</Subscript> (COX-2) production of flavonoids from seeds of <Emphasis Type="Italic">Prunus tomentosa</Emphasis> Thunberg

Chemical investigation of the 80% Me₂CO extract from the seeds of Prunus tomentosa led to the isolation and identification of six flavonoids: kaempferol (1), kaempferol 3-O-α-L-rhamnopyranoside (2; afzelin), kaempferol 3-O-β-D-(6-acetyl)-glucopyranosyl(1→4)-α-L-rhamnopyranoside (3; multiflorin A), kaempferol 3-O-β-D-glucopyranosyl(1→4)-α-L-rhamnopyranoside (4; multiflorin B), quercetin 3-O-α-L-rhamnopyranoside (5; quercitrin), and quercetin 3-O-β-D-glucopyranosyl (1→4)-α-L-rhamnopyranoside (6; multinoside A). Anti-oxidative and inhibitory activities on nitric oxide (NO) and prostaglandin E₂ production in interferon-γ (INF-γ) and lipopolysaccharide (LPS)-activated RAW 264.7 cells in vitro (COX-2) of the isolated compounds were evaluated. Compounds 1, 5, and 6 exhibited potent anti-oxidative activity in the DPPH radical scavenging assay with IC₅₀ values of 57.2, 59.4, and 54.3 μg/mL respectively. The positive control, ascorbic acid, had an IC₅₀ of 55.5 μg/mL. Compounds 1, 5, and 6 also reduced COX-2 levels in a dose dependent manner with IC₅₀ values of 10.2, 8.7, and 9.6 μg/mL respectively, with the positive control, indomethacin, having an IC₅₀ of 5.1 μg/mL. All six compounds inhibited NO production in a dose dependent manner with IC₅₀ values of 35.1, 42.8, 40.0, 44.8, 43.7, and 43.9 μg/mL respectively, while the positive control, L-NMMA, had an IC₅₀ of 42.1 μg/mL.     

Synthesis of 2-(2-fluorenyl)propanoic acid

Friedel-Crafts reaction of fluorene with methyl α-chloro-α-(methylthio)acetate1 gave methyl α-methylthio-2-fluoreneacetate2. Cicloprofen8, a potent antiinflammatory agent, was prepared by methylation of2 followed by reductive desulfurization of methyl 2-(2-fluorenyl)-2-(methylthio)propionate6 and hydrolysis of methyl 2-(2-fluorenyl)propionate7.     

A new pyrrole alkaloid isolated from<Emphasis Type="Italic">Arum palaestinum</Emphasis> Boiss. and its biological activities

The phytochemical analysis of the ethyl acetate fraction ofArum palaestinum Boiss. (Araceae) led to the isolation and identification of a new polyhydroxy alkaloid compound; (S)-3,4,5-trihydroxy-1H-pyrrol-2(5H)-one (1), and other five known compounds; caffeic acid (2), isoorientin (3), luteolin (4) and vicenin II (5), as well as the rare compound 3,6,8-trimethoxy, 5,7,3′,4′-tetrahydroxy flavone (6). The structural elucidations of all the compounds were based on spectroscopic data (¹H- and¹³C-NMR, DEPT, HSQC, HMBC and NOE difference techniques) and comparison with literature data. Investigation of the antioxidant activity of the ethyl acetate fraction indicated its strong scavenging capacity for 1, 1-diphenyl-2-picrylhydrazyl (DPPH) radicals (SC₅₀ 3.1 ±0.82 μg/mL). Moreover, the treatment of different human cancer cell lines with the ethyl acetate fraction led to dose-dependant suppression in the proliferation of both breast carcinoma cells (MCF-7; IC₅₀ 59.09±4.1 μg/mL) and lymphoblastic leukemia cells (1301; IC₅₀ 53.1±2.9 μg/mL); however, it was found to have no effect on the growth of hepatocellular carcinoma cells (Hep G2).     

Design, synthesis and in vitro antibacterial and antifungal activities of some novel spiro[azetidine-2,3��-indole]-2,4(1��H)-dione

The present study deals with the synthesis of novel spiro[azetidine-2,3′-indole]-2′,4(1′H)-dione derivative from the reactions of 3-(phenylimino)-1,3-dihydro-2H-indol-2-one derivatives with chloracetyl chloride in the presence of triethylamine (TEA). All the compounds were characterized using IR, ¹H-NMR, MS, and elemental analysis. They were screened for their antibacterial and antifungal activities. The bacterial strains used were Gram-positive Staphylococcus aureus (MTCC-96) and Gram-negative Escherichia coli (MTCC-521) and Pseudomonas aeruginosa (MTCC-647). The antifungal screening was done on Candida albicans (MTCC-183) and Asperigillus niger (MTCC-343) fungal strains. Results revealed that, compounds (7a), (7b), (7c), (7d), and (7e) showed very good activity with MIC value of 6.25–12.5 μg/ml against three evaluated bacterial strains and the remaining compounds showed good to moderate activity comparable to standard drugs as antibacterial agents. Compounds (7c) and (7h) displayed equipotent antifungal activity in comparison to standard drugs. Amoxicillin, gentamycin, and streptomycin were used as standard drugs for antibacterial activity while fluconazole and itraconazole were used as standard drugs for antifungal activity. Structure–activity relationship study of the compounds showed that the presence of electron withdrawing group substitution at 5′ and 7′ positions of indoline ring and on ortho or para position of phenyl ring increases both antibacterial and antifungal activity of the compound. Henceforth, our findings will have a good impact on chemists and biochemists for further investigations in search of spiro-fused antimicrobial agents.     

Fluconazole Review and situation among antifungal drugs in the treatment of opportunistic mycoses of human immuno-deficiency virus infections

Fluconazole is a novel triazole antifungal drug chiefly used in the treatment of opportunistic mycoses in immuno-compromised patients, particularly those with the acquired immuno-deficiency syndrome (AIDS). In comparison with other antifungal drugs, fluconazole has outstanding physical and pharmacokinetic properties, such as an excellent aqueous solubility allowing a parenteral formulation, high bioavailability by the oral route, even distribution throughout the tissues, including the central nervous system and the cerebro-spinal fluid, a long half-life (permitting once daily administration), and low binding to plasma proteins. It is excreted mainly as unchanged drug in the urine. Fluconazole is a broad-spectrum antifungal agent, especially effective againstCandida spp.,Cryptococcus neoformans and dermatophytes. Its antifungal efficacy was mainly proved by testing in animal models, since there is no relationship betweenin vitro andin vivo activities. It possesses a low toxicity and it is well-tolerated. Fluconazole is currently marketed for the treatment of oropharyngeal candidiasis in immuno-compromised patients and of atrophic oral candidiasis. Its place in the treatment of opportunistic mycoses in human immuno-deficiency virus-positive patients, in particular cryptococcal meningitis, is still under investigation but is promising.