Synthesis of variously substituted 1,8-naphthyridine derivatives and evaluation of their antimycobacterial activity

A series of 1,8-naphthyridine derivatives variously substituted in the 2, 3, 4 and 7 positions were synthesized for in vitro evaluation of antimycobacterial activity in accordance with an international program with the tuberculosis antimicrobial acquisition and coordinating facility (TAACF). Several compounds 4, 8, 12, 14, 19, 29 and 30, when tested at a concentration of 6.25 microg/ml against Mycobacterium tuberculosis H37Rv, showed an interesting activity with % inhibition in the range 38-96%. The most effective substituent in position 2, 4 or 7 of the 1,8-naphthyridine nucleus seem to be the piperidinyl group.     

Synthesis and evaluation of antimycobacterial activity of 4-phenyl-1,8-naphthyridine derivatives

Some 4-phenyl-1,8-naphthyridine derivatives with a piperazino group in the 2- and/or 7-position have been synthesized and evaluated for their tuberculostatic activity. The compounds 1, 6, 10, 17b,c and 19i showed a marked activity against Mycobacterium tuberculosis H37Rv. For this series of compounds, submitted to biological screening, no structure-activity relationship can be deduced.     

Synthesis and antiplatelet activity of some 3-phenyl-1,8-naphthyridine derivatives

A series of 2-cycloalkylamino-3-phenyl-1,8-naphthyridine derivatives, variously substituted in the 6- and 7-positions were synthesized and tested for their ability to inhibit human platelet aggregation in vitro induced by arachidonate, collagen and ADP. Compounds 5a,b, 7a,b, 8a and 10c,d showed a remarkable activity similar to that of indomethacin in the test with arachidonate and collagen. In the test with ADP only compound 8a showed a significant activity. The presence of a morpholinyl or piperidinyl group in position 2 and of a chloro or methoxy group in position 7 of the 1,8-naphthyridine nucleus seem to favour a higher activity. However on the basis of the pharmacological results, no structure-activity relationship can be deduced. Compounds 5b and 7b, which possess the best activity in the arachidonate test, were also shown to increase the c-AMP level significantly, without involving the adenylyl cyclase system.     

Synthesis and antiplatelet activity of some 2,7-di(N-cycloamino)-3-phenyl-1,8-naphthyridine derivatives.

Several 2,7-di(N-cycloamino)-3-phenyl-1,8-naphthyridine derivatives were synthesized and tested for their ability to inhibit human platelet aggregation in vitro induced by arachidonic acid, collagen and ADP. Only five compounds showed any appreciable activity, and the results of all the active derivatives were similar to those of papaverine in the test with arachidonic acid and collagen. Moreover, the most active compounds were investigated in the test with ADP and again showed a significant activity. The tested compounds that possessed the best activity were also shown to increase the c-AMP level significantly without involving the adenylyl cyclase system.     

Synthesis and antimycobacterial activity of 1,2,4-triazole 3-benzylsulfanyl derivatives

Series of 3-benzylsulfanyl derivatives of 1,2,4-triazole and 4-methyl-1,2,4-triazole were synthesized by alkylation of starting triazole-3-thiol with appropriately substituted benzyl halide. All members of the set were evaluated for in vitro antimycobacterial activity against Mycobacterium tuberculosis, M. avium, and two strains of M. kansasii. The activities were expressed as the minimum inhibitory concentration. The compounds exhibited only a moderate or slight antimycobacterial activity. Minimum inhibitory concentrations fall into a range of 32->1000 micromol/l. The most active substances bear two nitro groups or a thioamide group on the benzyl moiety. As regards the cytotoxicity effect, the evaluated compounds can be considered as moderately toxic.     

含有取代吲哚满二酮-1-乙基的加替沙星衍生物的合成与抗结核作用研究

目的寻找具有优秀活性的喹诺酮类抗结核药物。方法设计合成脂溶性更大的含有取代吲哚满二酮-1-乙基的加替沙星衍生物,测定其体外抗分枝杆菌活性。结果共合成了14个新化合物,其结构经1H-NMR、MS和HRMS确证。目标物普遍具有良好的抗分枝杆菌活性(MIC为1.56~6.25μg/mL),但均弱于其母药加替沙星。其中,化合物3h对草分枝杆菌CMCC93201和耻垢分枝杆菌CMCC93202的活性分别是利福平的4倍和2倍。结论脂溶性并非决定喹诺酮类化合物抗分枝杆菌活性的唯一因素。     

Design,synthesis, and biological evaluation of 1,8-naphthyridine glucosamine conjugates as antimicrobial agents

In the quest for discovering potent antimicrobial agents with lower toxicity, we envisioned the design and synthesis of nalidixic acid-D-(+)-glucosamine conjugates. The novel compounds were synthesized and evaluated for their in vitro antimicrobial activity against Gram positive bacteria, Gram negative bacteria and fungi. Cytotoxicity using MTT assay over L6 skeletal myoblast cell line, ATCC CRL-1458 was carried out. In vitro antimicrobial assay revealed that 1-ethyl-7-methyl-4-oxo-N-(1,3,4,6-tetra-O-acetyl-2-deoxy-D-glucopyranose-2-yl)-[1,8]-naphthyridine-3-carboxamide (5) and 1-ethyl-7-methyl-4-oxo-N-(2-deoxy-D-glucopyranose-2-yl)-[1,8]-naphthyridine-3-carboxamide (6) possess growth inhibitory activity against resistant Escherichia coli NCTC, 11954 (MIC 0.1589 mM) and Methicillin resistant Staphylococcus aureus ATCC, 33591 (MIC 0.1589 mM). Compound (5) was more active against Listeria monocytogenes ATCC 19115 (MIC 0.1113 mM) in comparison with the reference nalidixic acid (MIC 1.0765 mM). Interestingly, compound (6) had potential antifungal activity against Candida albicans ATCC 10231 (MIC <0.0099 mM). Remarkably, the tested compounds had low cytotoxic effect. This study indicated that glucosamine moiety inclusion into the chemical structure of the marketed nalidixic acid enhances antimicrobial activity and safety.     

小毛茛内酯的合成及抗结核活性的研究(英文)

小毛茛内酯一直被认为是猫爪草抗结核活性的有效成分。本文通过Yamaguchi酯化反应以32.7%的总收率完成了小毛茛内酯的化学合成制备,并采用直观快速药敏实验技术评价了其抗结核活性。文献报道,小毛茛内酯是通过增加外周血淋巴细胞颗粒裂解肽的表达,间接杀死结核杆菌。本文研究结果显示,小毛茛内酯在体外对分支杆菌H37Rv ATCC27294菌株表现出了微弱的抑制活性,其抗结核杆菌作用可能与细胞因子有关。     

Synthesis and pharmacological activities of 1,8-naphthyridine derivatives

In the present study, a series of 2-substituted-4-methyl-7-amino/4,7-dimethyl-1,8-naphthyridines were synthesized and characterized by IR, 1H-NMR and elemental analysis. The compounds were investigated for anticonvulsant (125, 250 mg/kg), cardiac and antimicrobial activities. The compounds were screened for antibacterial activity against gram (+) bacteria (Staphylococcus epidermidis, Bacillus subtilis, Enterococcusfaecalis and Micrococcus luteus) and gram (-) bacteria (Proteus vulgaris, Pseudomonas aeruginosa, Escherichia coli and Salmonella typhi). All the compounds except 2-(3'-phenylaminopropyloxy)-4-methyl-7-amino-1,8-naphthyridine exhibited significant anticonvulsant activity. The anticonvulsant activity of 2-(3-morpholino-2'-hydroxypropyloxy)-4-methyl-7-amino-1,8-naphthyridine, 2-(3'-diphenylamino-2'-hydroxypropyloxy)-4-methyl-7-amino-1,8-naphthyridine and 2-(3'-diethanolamino-propyloxy)-4,7-dimethy-1,8-naphthyridine at the dose of 250 mg/kg were found to be equivalent to diazepam (5 mg/kg). Sympathetic blocking activity was observed with 2-(3'-phenylamino-2'-hydroxypropyloxy)-4-methyl-7-amino-1,8-naphthyridine, 2-(3'-diethanolamino-2'-hydroxypropyloxy)-4-methyl-7-amino-1,8-naphthyridine and 2-(3'-diphenylamino-2'-hydroxypropyloxy)-4-methyl-7-amino-1,8-naphthyridine only. All the compounds were devoid of antibacterial activity against the tested bacteria.     

Synthesis and in-vitro antimycobacterial activity of fluoroquinolone derivatives containing a coumarin moiety

A series of gatifloxacin, ciprofloxacin, and 8-OCH(3) ciprofloxacin coumarin derivatives with remarkable improvement in lipophilicity as compared to the parent fluoroquinolones was designed, synthesized, and characterized by (1) H-NMR, MS, and HRMS. These derivatives were evaluated for their in-vitro activity against Mycobacterium smegmatis CMCC 93202 and MTB H37Rv ATCC 27294. All of the synthesized compounds were less active than the parent compounds against M. smegmatis CMCC 93202, but the activity of compound 6 was found to be 2-8-fold more potent than ciprofloxacin, 8-OCH(3) ciprofloxacin, moxifloxacin, and rifampin, and comparable to gatifloxacin against MTB H37Rv ATCC 27294. These results indicated that the lipophilicity of the tested compounds is not the sole parameter affecting antimycobacterial activity.     

Synthesis and evaluation of a pyrazinoic acid prodrug in Mycobacterium tuberculosis

Tuberculosis (TB) is a disease caused mainly by infection of Mycobacterium tuberculosis affecting more than ten million people around the world. Despite TB can be treated, the rise of MDR-TB and XDR-TB cases put the disease in a worrying status. As pyrazinamide-resistant strains exhibit low or none pyrazinamidase activity, it is proposed that the active form of pyrazinamide (PZA) is pyrazinoic acid (POA), although this acid has poor penetration in mycobacteria. In this work, we present a convenient one-pot synthesis of 2-chloroethyl pyrazinoate, and its activity in M. tuberculosis H₃₇Rv (ATCC27294) in MIC assay using the MABA technique. The obtained MIC of the compound was 3.96 g/mL, and discussion about the activity profile of some previously evaluated pyrazinoates is also performed.     

Synthesis and antimicrobial activity of some pyridinyliminothiazoline derivatives

The synthesis of some pyridinyliminothiazoline derivatives starting from N-pyridine-N'-phenyl thiourea and alpha-halogenoacetophenones is described. The chemical structures of the compounds were elucidated. The prepared compounds were tested for antimicrobial activity.     

1,8-naphthyridine derivatives: synthesis and pharmacological evaluation of beta-receptor blocking activity.

The synthesis of a number of 1-alkyl-7-(2-hydroxy-3-alkylaminopropoxy)-1,8-naphthyridin-2-ones is described. The compounds studied were prepared by reaction of 1-alkyl-7-hydroxy-1,8-naphthyridin-2-ones with epichlorohydrin. The substituted epoxy intermediates obtained were allowed to react with amines and gave the desired products. All the compunds prepared were devoid of beta-blocking activity.     

4-[6-(Dansylamino)hexylamino]-7-methyl-2-phenyl-1,8-naphthyridine as a new potential fluorescent probe for studying A1-adenosine receptor

A new fluorescent ligand for adenosine receptors, obtained by the insertion of a dansylamino-moiety with a linear hexyl spacer in the N4 position of a 1,8-naphthyridine adenosine receptor ligand, proved to possess a high affinity and selectivity for the A1 receptor subtype.     

Synthesis and antimicrobial activity of some bisoctahydroxanthene-1,8-dione derivatives

The bisoctahydroxanthen-1,8-dione derivatives were synthesized effectively via p-dodecylbenzene sulfonic acid the catalysed cyclocondensation of cyclic 1,3-dicarbonyl compounds with 1,3- or 1,4-benzene dicarboxaldehydes in water. The products were obtained with yield ranged from 75 to 95%. The structures of compounds were characterized by FT-IR, ¹H-NMR and elemental analysis. The antimicrobial properties of compounds against pathogens were investigated by the disc-diffusion method. These compounds were evaluated for potential antimicrobial activity against Gram-positive (Staphylococcus aureus, Bacillus cereus, S. epidermidis and Nocardia canis), Gram-negative bacteria (Escherichia coli, Proteus vulgaris and Pseudomonas aeroginosa), yeasts (Candida albicans and Rhodotorula rubra) and mold (Aspergillus niger). The growth of S. aureus, B. cereus, S. epidermidis, E. coli, C. albicans, R. rubra and A. niger were inhibited by 3f and 3g compounds. All compounds were resistant against Gram-negative bacteria (Proteus vulgaris and Pseudomonas aerginosa) and results were upon comparison with reference discs.     

Synthesis and antimicrobial activity of new adamantane derivatives III

Some novel ester imides synthesised from trimellitic acid anhydride and 1-adamantanol or 2-adamantanol, were tested as antimicrobial compounds. Unfortunately, these agents showed a modest antibacterial activity (MIC > 6 microg/ml). However, a comparison of these N-substituted adamantylester imides with the series published previously, indicated that the incorporation of L-alanine and L-phenylalanine into the phthalimide moiety was the best choice regardless of the series and leads to antimicrobial activity against Staphylococcus aureus strains.     

Synthesis antimicrobial and antifungal activity of some new 3 substituted derivatives of 4-(2,4-dichlorophenyl)-5-adamantyl-1H-1,2,4-triazole

The synthesis of a series of substituted hydrazones and thiazolidinones is described, starting from N-[4-(2,4-dichlorophenyl)-5-adamantyl-1H-1,2,4-triazol-3-ylmercaptoacetyl]hydrazine. The new compounds were tested for antimicrobial and antifungal activity and some of them exhibited moderate activity against Candida albicans.     

Synthesis and antimycobacterial activity of (3,4-diaryl-3H-thiazol-2-ylidene)-hydrazide derivatives

[5-(pyridin-2-yl)-1,3,4-thiadiazol-2-ylthio]acetic acid (3,4-diaryl-3H-thiazol-2-ylidene)-hydrazide derivatives were synthesized and tested for their in vitro antimycobacterial activity. Some compounds showed an interesting activity against a strain of Mycobacterium tuberculosis H(37)Rv and three clinical isolates of M. tuberculosis.     

Synthesis and evaluation of 4-amino-5-phenyl-4H-[1,2,4]-triazole-3-thiol derivatives as antimicrobial agents

A series of novel 1,2,4-triazole derivatives have been synthesized by condensing the methyl benzoate and methyl salicylate with various substituents; their structures were established on the basis of elemental analysis, Fourier transform infrared spectroscopy (FTIR), ¹H nuclear magnetic resonance (NMR), and mass spectral data. All title compounds were subjected to in vitro antibacterial and antifungal screening against four different bacterial and fungal strains. Preliminary results indicate that some of them exhibit promising activities and deserve further consideration as potential antimicrobials.