Anti-Plasmodium activity of imidazole-dioxolane compounds

A series of imidazole-dioxolane compounds, which we hypothesize should bind to heme and thus interfere with heme catabolism in the parasite, were assayed for inhibitory activity in Plasmodium falciparum cultures and the results were compared to those obtained with Chinese hamster ovary (CHO) cells. The majority of the compounds displayed a similar ratio of inhibitory activity in the two culture systems; however, a number of the compounds tested showed promising anti-Plasmodium activity. The mechanism of action of these compounds remains unclear, however their inability to act synergistically with chloroquine suggests that, if they are inhibiting heme detoxification, they do so in a manner that does not complement the action of chloroquine.     

Antifungal activity of lactobacilli isolated from salami

Sixty-five strains of lactobacilli isolated from salami were tested for their antifungal activity in early and late phases of growth. Ten strains showed inhibitory activity in the early phase of growth towards moulds such as Aspergillus and Penicillium. The active compounds identified were phenyl-lactate and hydroxy-phenyl-lactate. All strains tested had activity in the late phase, after autolysis. The compounds released were peptidic and showed antifungal activity.     

Synthesis and antimycobacterial activity of novel camphane-based agents

A series of six new amidoalcohols was designed and synthesized on the base of the camphor scaffold. Natural amino acids were transformed into their α-hydroxy analogues with retention of configuration, and attached to isobornylamine. The compounds were evaluated for their in vitro activity against Mycobacterium tuberculosis H37Rv. Some of the new compounds show 25 times higher activity than the classical anti-TB drug ethambutol. The activity shifts from micromolar to nanomolar inhibitory concentrations depending on the α-hydroxy acid moiety. Two of the most potent compounds exert low level of cytotoxic activity. These camphane-based amido-alcohols present promising potential lead compounds for further elaboration of antimycobacterial agents.     

Investigating the anti-proliferative activity of styrylazanaphthalenes and azanaphthalenediones

A group of styrylazanaphthalenes and azanaphthalenediones were synthesized and tested for their anti-proliferative activity. Most of the compounds were obtained with the use of microwave-assisted synthesis. The lipophilicity of the compounds was measured by RP-HPLC and their anti-proliferative activity was assayed against the human SK-N-MC neuroepithelioma and HCT116 human colon carcinoma cell lines. Active compounds were also tested in clonogenity and comet assays. Several quinazolinone and styrylquinazoline analogues were found to have markedly greater anti-proliferative activity than desferoxamine and cis-platin.     

Screening of natural compounds with hypolipidemic activity]

In the screening programme for natural hypolipidemic compounds 702 strains of soil microorganisms were tested and 25 of them were selected because of their ability to produce compounds inhibiting sterol synthesis in Hep G2 hepatoma cells. The compounds were estimated in the microbiological model with Tolypocladium inflatum 106 as the test microbe. The 2nd stage of the screening resulted in isolation of 13 strains producing compounds with high hypolipidemic activity, analogous to or higher than the activity of lovastatin in the experimental models.     

The anti-malarial activity of bivalent imidazolium salts

A series of compounds containing bivalent imidazolium rings and one triazolium analog were synthesized and evaluated for their ability to inhibit the replication of Plasmodium falciparum cultures. The activity and selectivity of the compounds for P. falciparum cultures were found to depend on the presence of electron-deficient rings that were spaced an appropriate distance apart. The activity of the compounds was not critically dependent on the nature of the linker between the electron-deficient rings, an observation that suggests that the rings were responsible for the primary interaction with the molecular target of the compounds in the parasite. The bivalent imidazolium and triazolium compounds disrupted the process whereby merozoites gain entry into erythrocytes, however, they did not appear to prevent merozoites from forming. The compounds were also found to be active in a murine Plasmodium berghei infection, a result consistent with the compounds specifically interacting with a parasite component that is required for replication and is conserved between two Plasmodium species.     

Antihyperglycemic activity of compounds isolated from Indian medicinal plants

Eleven antidiabetic Indian medicinal plants were investigated in streptozotocin induced diabetic rat model and provided scientific validation to prove their antihyperglycemic activity. Antidiabetic principles from five plants were isolated. All the compounds isolated were evaluated for antihyperglycemic activity in streptozotocin induced diabetic rat model and activities were compared with standard drug metformin. Some compounds were also screened in db/db mice. Two compounds (PP-1 and PP-2) inhibited significantly the activity of PTPase-1B in an in vitro system. This might be the underlying mechanism of antihyperglycemic activity of these compounds.     

Antimicrobial activity of the marine alkaloids haminol and pulo'upone and related compounds

The marine alkaloids haminol A, haminol B and pulo'upone as well as 17 related compounds (twelve 2-substituted pyridine derivatives, four 3-substituted ones and one analogue of the bicyclic terminus of pulo'upone) were tested for antimicrobial activity against a panel of six microbes (Bacillus cereus, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus epidermidis, Candida albicans and Saccharomyces cerevisiae) using the paper disc agar diffusion method. Six compounds were tested also against the mold Aspergillus niger. Some of the compounds displayed noteworthy antimicrobial activity, only one congener being completely devoid of activity. Nearly all compounds had activity against B. cereus and S. epidermidis. The growth of E. coli, C albicans and S. cerevisiae was also distinctly inhibited by many compounds. In contrast, most compounds were inactive or had minimal activity against P. aeruginosa. Interestingly, most of the compounds tested against the opportunistic pathogen A. niger were active, one of them having noteworthy inhibitory potency.     

Antimalarial activity of ferrocenyl chalcones

A series of ferrocenyl chalcones were synthesized and evaluated for in vitro antimalarial activity against a chloroquine-resistant strain of Plasmodium falciparum. The most active compounds were 1-(3-pyridyl)-3-ferrocenyl-2-propen-1-one (6) and 1-ferrocenyl-3-(4-nitrophenyl)-2-propen-1-one (28) with IC(50) of 4.5 and 5.1 microM, respectively. Differences in activity were not readily explained by the size and lipophilicity characteristics of these compounds.     

Synthesis and antimycobacterial activity of some phthalimide derivatives

Structurally modified phthalimide derivatives were prepared through condensation of phthalic and tetrafluorophthalic anhydride with selected sulfonamides with variable yields. All compounds were screened for their antimycobacterium activity against Mycobacterium tuberculosis H37Ra (ATCC 25177) using a micro broth dilution technique. The fluorinated derivatives (compounds 2c, 2d, 2f and 2h) had antimycobacterium activity comparable with classical sulfonamide drugs. The minimum inhibitory concentration (MIC) of compounds 2c, 2d, 2f and 2h was greater than that of isoniazid (MIC<0.02 μg/mL) and in vitro activity was greater than that of pyrazinamide, another first line antimycobacterium drug (MIC 50-100 μg/mL). The new compounds could be considered new lead compounds in the treatment of multi-drug resistant tuberculosis.     

Synthesis and biological activity of flavanone derivatives

A series of new flavanone derivatives of farrerol was synthesized by a convenient method. The in vitro anti-tumor activity of these compounds was evaluated against human Bel-7402, HL-60, BGC-823 and KB cell lines, the protein tyrosine kinase (PTK) inhibitor activity was also tested. Their cytoprotective activity was tested using hydrogen peroxide (H₂O₂)-induced injury in human umbilical vein endothelial cells. Their in vitro anti-atherosclerosis activity was tested on vascular smooth muscle cells by the MTT method using tetrandrine as a positive contrast drug. The structures of all compounds synthesized were confirmed by ¹H, ¹³C NMR and ESI-MS. Most of the compounds exhibited good pharmacological activity and the preliminary structure–activity relationships were described.     

Syntheses and antibacterial activity of phendioxy substituted cyclic enediynes

Syntheses and antibacterial activity of 13-membered 1,3-phendioxy substituted cyclic enediynes are reported. The compounds were screened against gram-positive and gram-negative strains and some of the compounds exhibit potent antibacterial activity.     

Syntheses and biological activity of bisdaunorubicins

To study the length and flexibility of the linkers between two monomers of bisdaunorubicins for their activity against cancer cells, seven bisdaunorubicins were rationally designed and synthesized through click chemistry. Their cytotoxicity was tested in leukemia cells with MTS assay. The results showed that the compounds with short linkers exhibited higher activity than the compounds with long linkers, while the flexibility of the linker also contributed to their activity. These results indicated that the length and flexibility of the linkers between two monomers in bisdaunorubicins are very critical to maintain their activity against cancer cells.     

Contribution to investigation of antimicrobial activity of styrylquinolines

Series of new ring-substituted styrylquinolines and two oxorhenium complexes were prepared and characterized. The compounds were analyzed using RP-HPLC to determine lipophilicity. Primary in vitro screening of the synthesized compounds was performed against fungal and bacterial strains. Some compounds were active against bacteria at micromolar level and against fungi at submicromolar level. Compounds 5,7-dichloro-2-[2-(2-ethoxyphenyl)vinyl]quinolin-8-ol expressed excellent antifungal activity comparable with or higher than the standard fluconazole as well as antibacterial activity against Staphylococcus strains comparable with or higher than the standards bacitracin, penicillin and ciprofloxacin. The structure–activity relationships are discussed.     

Synthesis and immunological activity of water-soluble thalidomide prodrugs

A series of new water-soluble thalidomide prodrugs was prepared. All compounds were derivatized on the nitrogen of the glutarimide ring. Esters of natural amino acids and succinic acid derivatives have been introduced by reaction with the hydroxymethyl thalidomide 2. Nicotinic acid derivatives were prepared from halomethyl derivatives. Additionally, a methoxymethyl derivative and a carboxymethyl derivative were prepared directly from thalidomide. Most compounds showed a very large increase in water solubility compared to thalidomide itself (0.012mg/mL). The amorphous hydrochlorides of the N-methylalanine ester 8, valine ester 9, and glycylglycine ester 10, respectively, were the most soluble compounds showing solubility greater than 300mg/mL, which equals an increase greater than 15,000-fold. The lipophilicity of the prodrugs has been determined by their HPLC capacity factors k'. The stability of selected compounds was determined. The hydrolysis rates follow pseudo-first order kinetics. In order to assess the immunological activity, the prodrugs were tested using tumor necrosis factor-alpha and interleukin-2 inhibition assays. Selected compounds were additionally investigated on their abililty to inhibit the local Shwartzman reaction, an assay to determine the vascular permeability. The prodrugs retained high effectiveness in the inhibition of TNF-alpha release. Our results indicated that the more stable prodrugs exhibited higher activity in the immunological assays. Some compounds showed higher activity than thalidomide itself, suggesting a high affine binding to the pharmacophore. In conclusion, the prodrugs exhibited high water solubility and high activity and might therefore be used in therapeutic applications.     

Acetophenones with selective antimycobacterial activity

AIMS: Mycobacteria are a serious cause of infections in humans, with limited treatment options, as no new antibiotics have been developed against mycobacteria since the 1960s. In this study, the antimycobacterial activity of a small library of acetophenone (AP) compounds was analysed. METHODS AND RESULTS: Twenty-three AP derivatives were examined for activity against mycobacteria using a microbroth assay. The compounds were bacteriostatic, with the most effective (cyclohexylacetophenone and piperidinoacetophenone) having minimal inhibitory concentrations of 246 microM. Active compounds tended to be more hydrophobic, and may work by alkylation of as yet undetermined intracellular target protein(s). Cytotoxicity against eukaryotic cells was also determined and appears to be unrelated to the bacteriostatic activity. SIGNIFICANCE AND IMPACT OF THE STUDY: AP may serve as a novel group of useful therapeutics against the mycobacteria.     

Antimicrobial activity of some 2-aminopyrimidines

The minimum inhibitory concentration values for a group of pyrimidine derivatives were determined for Gram-positive and Gram-negative bacteria and yeast. The active compounds were further screened. The effect of these compounds on growth and morphology was tested, and their structural antimicrobial activity is discussed.     

Chlorine atom substitution influences radical scavenging activity of 6-chromanol

Synthetic 6-chromanol derivatives were prepared with several chlorine substitutions, which conferred both electron-withdrawing inductive effects and electron-donating resonance effects. A trichlorinated compound (2), a dichlorinated compound (3), and three monochlorinated compounds (4, 5, and 6) were synthesized; compounds 2, 3, and 6 were novel. The antioxidant activities of the compounds, evaluated in terms of their capacities to scavenge galvinoxyl radical, were associated with the number and positioning of chlorine atoms in the aromatic ring of 6-chromanol. The activity of compound 1 (2,2-dimethyl-6-chromanol) was slightly higher than the activities of compounds 2 (2,2-dimethyl-5,7-dichloro-6-chromanol) or 3 (2,2-dimethyl-5,7,8-trichloro-6-chromanol), in which the chlorine atoms were ortho to the phenolic hydroxyl group of 6-chromanol. The scavenging activity of compound 3 was slightly higher than that of 2, which contained an additional chlorine substituted in the 8 position. The activities of polychlorinated compounds 2 and 3 were higher than the activities of any of the monochlorinated compounds (4-6). Compound 6, in which a chlorine was substituted in the 8 position, exhibited the lowest activity. Substitution of a chlorine atom meta to the hydroxyl group of 6-chromanol (compounds 2 and 6) decreased galvinoxyl radical scavenging activity, owing to the electron-withdrawing inductive effect of chlorine. Positioning the chloro group ortho to the hydroxyl group (compounds 4 and 5) retained antioxidant activity because the intermediate radical was stabilized by the electron-donating resonance effect of chlorine in spite of the electron-withdrawing inductive effect of chlorine. Antioxidant activities of the synthesized compounds were evaluated for correlations with the O-H bond dissociation energies (BDEs) and the ionization potentials. The BDEs correlated with the second-order rate constants (k) in the reaction between galvinoxyl radical and the chlorinated 6-chromanol derivatives in acetonitrile. This indicated that the antioxidant mechanism of the synthesized compounds consisted of a one-step hydrogen atom transfer from the phenolic OH group rather than an electron transfer followed by a proton transfer. The synthesized compounds also exhibited hydroxyl radical scavenging capacities in aqueous solution.     

苯并异噻唑啉酮类化合物的生物活性研究

对合成的5种苯并异噻唑啉酮类化合物进行了生物活性研究。抑菌试验结果表明,化合物a与化合物b对大肠杆菌最小抑菌浓度为12.5mg/L。对金黄色葡萄球菌都表现出良好的抑菌活性。对亚心形扁藻,蛋白核小球藻,球等鞭金藻,化合物都有抑制其生长的活性,亚心形扁藻耐受性最高,球等鞭金藻的耐受性最低,蛋白核小球藻的耐受性居中。     

生姜中6个姜辣素类成分的抗菌活性研究

为了探究生姜化学成分的抗菌活性及初步构效关系,采用色谱法从生姜中分离得到6个姜辣素类化合物,采用波谱法对这6个成分进行鉴定,分别为5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)-4-decen-3-one(1)、5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)-4-dodecen-3-one(2)、5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)-4-tetradecane-3-one(3)、[6]-姜酚(4)、[8]-姜酚(5)和[10]-姜酚(6)。采用抗菌纸片扩散法测定6个化合物对15株病原菌株的抗菌活性。结果表明化合物1和4抗菌活性最好,而6对所有菌株均无活性。初步构效关系分析表明:烯醇型化合物对革兰氏阳性菌的抗菌活性优于姜酚型化合物;而姜酚型化合物对革兰氏阴性菌的抗菌活性优于烯醇型化合物。此外,姜辣素类成分脂肪链的长度增加,可能导致抗菌活性降低。