A novel [60]fullerene amino acid for use in solid-phase peptide synthesis

[see structure]. A fullerene derivative containing a free amino group has been condensed with N-Fmoc-L-glutamic acid alpha-tert-butyl ester to give a C60-functionalized amino acid. The carboxylic end of this amino acid has been deprotected in acidic conditions, and the resulting acid has been used for solid-phase peptide synthesis. The final peptide, cleaved from the resin, was very soluble in water solutions and showed antimicrobial activity against two representative bacteria.     

Water Solubilization of Fullerene Derivatives by β‐(1,3‐1,6)‐d‐Glucan and Their Photodynamic Activities toward Macrophages

Anionic and neutral fullerene derivatives were dissolved in water by using β‐(1,3‐1,6)‐d ‐glucan (β‐1,3‐glucan) as a solubilizing agent. In the water‐solubilized complexes, the concentrations of fullerene derivatives were ≈0.30 mm and the average particle sizes were ≈90 nm. The β‐1,3‐glucan‐complexed fullerene derivative with a carboxylic acid was found to have higher photodynamic activity toward macrophages under visible‐light irradiation (λ >610 nm) than other β‐1,3‐glucan‐complexed fullerene derivatives. This result suggests that carboxylic acid moieties in the complex enhance the binding affinity with β‐1,3‐glucan receptors on the surface of macrophages when the β‐1,3‐glucan is recognized. In contrast, all β‐1,3‐glucan‐complexed fullerene derivatives showed no photodynamic activity toward HeLa cells under the same conditions.     

Photodynamic antimicrobial activity of hypocrellin A

Antimicrobial photodynamic therapy is a recently developed therapeutic option that combines a non-toxic photosensitizer with harmless visible light to damage the microbial cell. Hypocrellin A (HA), a natural occurring lipid-soluble perylenequinone pigment, has gained considerable interest since its anticancer and antiviral activities have been reported. Here, we examined the antimicrobial activity of HA against Gram-positive (Staphylococcus aureus, Bacillus subtilis) and Gram-negative bacteria (Escherichia coli, Salmonella typhimurium). The results indicate that HA has a photodynamic antimicrobial activity against both Gram-positive and Gram-negative bacteria when CaCl(2) or MgCl(2) was employed. A loose binding has been established between HA and the organisms. Molecular oxygen is significantly involved in the photodynamic action of HA. Furthermore, HA maintains a photodynamic activity in terms of both types I and II reactions. Our results confirm the potential of HA to be used as a photosensitizer in antimicrobial photodynamic therapy.     

Benzophenothiazine and Benzoporphyrin Derivative Combination Phototherapy Effectively Eradicates Large Murine Sarcomas

Abstract— The tumoricidal effects of photochemotherapy with two photosensitizers, 5-ethylamino-9-diethylaminobenzo[ a ] phenothiazinium chloride (EtNBS) and benzoporphyrin derivative monoacid ring A (BPD-MA), were evaluated separately and in combination against the EMT-6 fibrosarcoma implanted subcutaneously in BALB/c mice. Animals carrying tumors 8-10 mm in diameter were divided into eight different groups (∼20/group) and subjected to various photoirradiation and drug conditions. The tumor response to photodynamic therapy (PDT) was measured as the mean tumor wet weight 2 weeks post-PDT. The combination treatment with 5.25 mg/kg EtNBS and 2.5 mg/kg BPD-MA followed by photoirradiation with 100 J/cm² at 652 nm and then by 100 J/cm² at 690 nm resulted in a 95% reduction in the average tumor weights compared to controls (no light, no drugs) with 76% of the mice being tumor free 2 weeks post-PDT. Because treatment with EtNBS or BPD-MA at twice the light dose and drug concentration resulted in either no significant reduction in tumor weights or increased the lethality of treatment, respectively, the data suggest that the enhanced PDT effect observed with the combination of drugs is synergistic rather than additive. Histology of tumors 24 h post-PDT with the combination of drugs showed nearly complete destruction of the tumor mass with little or no damage to the vasculature and no extravasation of red blood cells. There was no damage to the normal skin adjacent to the tumor. Fluorescence microscopy of EMT-6 cells incubated in vitro with the two photosensitizers revealed that they were localized to different intracellular compartments. The fluorescence pattern from frozen tumor tissue slices following the in vivo administration of the photosensitizers indicated a greater intracellular localization for EtNBS vs BPD-MA.     

Synthesis and antibacterial activity of novel [1,2,4]triazolo [3,4-h][1,8]naphthyridine-7-carboxylic acid derivatives

Novel tricyclic fluoroquinolones,[1,2,4]triazolo[3,4-h][1,8]naphthyridine-8-one-7-carboxylic acid derivatives 4a-4h bearing carrying a functional Mannich-base moiety at the C-8 position,were synthesized and evaluated for their antimicrobial activity.The results showed that some compounds with a piperazine side chain exhibited comparable or better antibacterial activity than comparator cirprofloxacin.Furthermore,the targeted compounds also displayed a broad spectrum of activity against resistant strains including both Gram-negative and Gram-positive bacteria.In particular,compound 4h showed an MIC of 0.25 μg/mL in antibacterial assay against multiple drug-resistant Escherichia coli,which represents an about 30-fold increase of potency compared to ciprofloxacin.Thus,their excellent antibacterial activity against resistant strains suggests that triazole-fused fluoroquinolones warrant further optimization as novel anti-infective chemotherapies.     

中氮茚类羧酸化合物的合成及抑菌活性

合成了8个中氮茚类羧酸化合物, 产物经红外、 核磁、 质谱及元素分析表征, 并研究了其抑菌性能. 结果表明, 化合物3a, 3c, 5a, 5c和5d对大肠杆菌有一定抑制作用, 化合物3a和3c对金黄色葡萄球菌有抑制作用. 其中化合物3c对所选2个菌种均表现出较好的抑菌性能.     

FLUORESCENCE SPECTRAL CHANGES OF HEMATOPORPHYRIN DERIVATIVE UPON BINDING TO LIPID VESICLES, Staphylococcus aureus AND Escherichia coli CELLS

Abstract— The binding of hematoporphyrin derivated (Hpd) to lipid vesicles and bacterial membranes was determined by fluorescence spectroscopy. The fluorescence measurements of Hpd in aqueous solutions showed two bands at 613 and 677 nm. In lipid environments of lecithin vesicles the fluorescence spectrum was shifted to 631 and 692 nm, respectively. Hpd was rapidly bound to the cell membrane of Staphylococcus aureus while much less binding occurred in the presence of Escherichia coli. At the same time, spheroplasts of both bacteria were shown to bind Hpd to a similar extent. These results are well correlated with the photoinactivation of the gram positive bacteria with Hpd while the gram negative cells were shown to be resistant. The pH dependence of both Hpd binding to S. aureus as well as the photodynamic inhibitory effect of the same bacteria are similar. It is concluded that the segregation of Hpd to the cell membrane is a prerequisite for its photodynamic effect.     

Antimicrobial Polyketide Metabolites from Penicillium bissettii and P. glabrum

Screening of several fungi from the New Zealand International Collection of Microorganisms from Plants identified two strains of Penicillium, P. bissettii and P. glabrum, which exhibited antimicrobial activity against Escherichia coli, Klebsiella pneumoniae, and Staphylococcus aureus. Further investigation into the natural products of the fungi, through extraction and fractionation, led to the isolation of five known polyketide metabolites, penicillic acid (1), citromycetin (2), penialdin A (3), penialdin F (4), and myxotrichin B (5). Semi-synthetic derivatization of 1 led to the discovery of a novel dihydro (1a) derivative that provided evidence for the existence of the much-speculated open-chained form of 1. Upon investigation of the antimicrobial activities of the natural products and derivatives, both penicillic acid (1) and penialdin F (4) were found to inhibit the growth of Methicillin-resistant S. aureus. Penialdin F (4) was also found to have some inhibitory activity against Mycobacterium abscessus and M. marinum along with citromycetin (2).     

Synthesis of 2-alkenyl-3-hydroxyquinolin-4(1H)-ones as promising antimicrobial and fluorescent agents

2-Alkenyl-3-hydroxyquinolin-4(1H)-ones were prepared by the rearrangement of anthranilic acid esters synthesized by two alternative methods. The prepared derivatives were screened for their antimicrobial activities against representative Gram-positive and Gram-negative bacteria, displaying notable minimum inhibitory concentration values against specific strains. The emission spectra of the target quinolines exhibited two well-separated emission bands, and the maximum excitation wavelengths of the selected compounds were detected at relatively high values.     

Synthesis and antimicrobial activity of novel substituted 4-[3-(1<Emphasis Type="Italic">H</Emphasis>-benzimidazol-2-yl)-4-hydroxybenzyl]-2-(1<Emphasis Type="Italic">H</Emphasis>-benzimidazol-2-yl)phenol derivatives

A series of novel substituted bis-benzimidazole derivatives were synthesized by reaction of 5,5′-methylenebis(2-hydroxybenzaldehyde) with various substituted o-phenylenediamines in glacial acetic acid. The structure of the newly synthesized compounds was elucidated by ¹H and ¹³C NMR, FT-IR, and MS spectra, and their antimicrobial activity against gram positive and gram negative bacteria and antifungal activity were evaluated. The thienyl-substituted derivative showed significant activity against Bacillus licheniformis. Bacillus subtilis, Staphylococcus aureus, Klebsiella pneumonia (bacteria), and Fusarium solani (fungi). The activities of the fluoro-substituted substituted derivative against some bacterial strains and of the thienyl-substituted derivative against fungi were found to be similar to those of standard drugs.     

Stable gas-phase radical cations of dimeric tryptophan and tyrosine derivatives

Stable radical cations of dimeric amino acid derivatives of tryptophan and tyrosine were generated by collision-induced dissociation of [Cu(II)(diethylenetriamine)(amino acid derivative)2]*2+. The yields of the dimer radical cations were dependent on both the auxiliary ligand and the tryptophan or tyrosine derivatives used. Amino acid derivatives with an unmodified carboxylic acid group did not generate dimer radical cations. For the amino acid derivatives Ac-Trp-OMe and Ac-Trp-NH2 (Ac is N-acetyl; OMe and NH2 are the methyl ester and amide modifications of the C-terminal carboxylic group), no auxiliary ligand was required for generating the dimer radical cations. Collision-induced dissociation of the [Cu(II)(amino acid derivative)4]*2+ precursor generated the dimer radical cation [(amino acid derivative)2]*+. Stabilizing interactions, most likely involving hydrogen bonding, between the two amino acid derivatives are proposed to account for observation of the dimer radical cations. Dissociation of these ions yields protonated or radical cationic amino acid derivatives; these observations are consistent with the expectation of proton competition between monomeric units, whose proton affinities were calculated using density functional theory.     

Synthesis,Antimicrobial Activity and Molecular Modeling of Some Novel 5‐Aminopyrazole,Pyrazolo[1,5‐a]pyrimidine,Bispyrazole and Bispyridone Derivatives Containing Antipyrinyl Moiety

2‐Cyano‐N‐(antipyrin‐4‐yl)‐3‐(ethylthio)‐3‐(naphthalen‐1‐ylamino)acryl‐amide 4 was achieved via a one‐pot, three‐component reactions of cyanoacetamide derivative 2 , 2‐naphthyl isothiocyanate, and diethyl‐sulphate. The cyano acrylamide derivative 4 was hydrazinolysis to furnish 5‐aminopyrazole 5 ; many pyrazolo[1,5‐a ]pyrimidines 10a,b, 14, 15, 16, 18, and 20 have been synthesized via treatment of 5 with some electrophilic reagents. Also, ternary condensation of cyanoacetamide derivative 2 , terephthalaldehyde, and active methylene derivatives afforded bispyridone derivatives 21a,b . The structures of the new compounds were confirmed on the basis of elemental analysis and spectral data. Representative compounds of the synthesized products were tested and evaluated as antimicrobial. In general, the novel‐synthesized compounds showed a good antimicrobial activity against Gram‐positive bacteria, Gram‐negative bacteria, and antifungal activity against Azithromycin and Ketoconazole . The molecular modeling of the 21a and 21b as representative examples of the synthesized compounds has been drawn, and their molecular parameters were calculated.     

Oligolysine‐Conjugated Zinc(II) Phthalocyanines as Efficient Photosensitizers for Antimicrobial Photodynamic Therapy

A series of zinc(II) phthalocyanines conjugated with an oligolysine chain (n=2, 4, and 8) were synthesized and characterized by using various spectroscopic methods. As shown by using UV/Vis and fluorescence spectroscopic methods, these compounds were nonaggregated in N,N‐dimethylformamide, and gave a weak fluorescence emission and high singlet oxygen quantum yield (Φ_Δ=0.86–0.89) as a result of their di‐α‐substitution. They became slightly aggregated in water with 0.05 % Cremophor EL, but they could still generate singlet oxygen effectively. The antimicrobial photodynamic activities of these compounds were then examined against various bacterial strains, including the Gram‐positive methicillin‐sensitive Staphylococcus aureus ATCC 25923 and methicillin‐resistant Staphylococcus aureus ATCC BAA‐43, and the Gram‐negative Escherichia coli ATCC 35218 and Pseudomonas aeruginosa ATCC 27853. Generally, the dyes were much more potent toward the Gram‐positive bacteria. Only 15 to 90 nM of these photosensitizers was required to induce a 4 log reduction in the cell viability of the strains. For Escherichia coli, the photocytotoxicity increased with the length of the oligolysine chain. The octalysine derivative showed the highest potency with a 4 log reduction concentration of 0.8 μM . Pseudomonas aeruginosa was most resistant to the photodynamic treatment. The potency of the tetralysine derivative toward a series of clinical strains of Staphylococcus aureus was also examined and found to be comparable with that toward the nonclinical counterparts. Moreover, the efficacy of these compounds in photodynamic inactivation of viruses was also examined. They were highly photocytotoxic against the enveloped viruses influenza A virus (H1N1) and herpes simplex virus type 1 (HSV1), but exhibited no significant cytotoxicity against the nonenveloped viruses adenovirus type 3 (Ad3) or coxsackievirus (Cox B1). The octalysine derivative also showed the highest potency with an IC₅₀ value of 0.05 nM for the two enveloped viruses.     

Photophysical properties and antibacterial activity of meso-substituted cationic porphyrins

A series of derivatives of 5,10,15,20-tetrakis-(4-N-methylpyridyl)-porphine, where one N-methyl group was replaced by a hydrocarbon chain ranging from C6 to C22, were characterized for their photophysical and photosensitizing properties. The absorption and fluorescence features of the various compounds in neutral aqueous solutions were typical of largely monomeric porphyrins, with the exception of the C22 derivative, which appeared to be extensively aggregated. This was confirmed by the very low triplet quantum yield and lifetime of the C22 derivative as compared with 0.2-0.7 quantum yields and 88-167 micros lifetimes for the other porphyrins. The photophysical properties and photosensitizing activity toward N-acetyl-L-tryptophanamide of the C22 porphyrin became comparable to those typical of the other derivatives in 2% aqueous sodium dodecyl sulfate, where the C22 compound is fully monomerized. All the porphyrin derivatives exhibited at micromolar concentrations photoinactivation activity against both Staphylococcus aureus and Escherichia coli, even though the gram-negative bacteria were markedly less photosensitive. The photosensitizing efficiency was influenced by (1) the amount of cell-bound porphyrin, which increased with increasing length of the hydrocarbon chain; and (2) the tendency to undergo partial aggregation in the cell, which seems to be especially important for the C22 derivative.     

New Thiophene Derivatives as Antimicrobial Agents

Phenacylbromide derivatives constitute a multilateral group of precursors for the synthesis of numerous heterocycles of organic compounds. Briefly, 5‐(2‐bromo‐acetyl)‐substituted‐thiophene derivative has been used as a synthon for synthesis of new thiophene‐containing compounds through the reaction with nucleophilic nitrogen compounds and thioamides. The suggested structures of the newly synthesized thiophene compounds were confirmed and assured with different spectroscopic tools and with CHN elemental analysis. Additionally, the antimicrobial activity of these thiophene compounds was recorded to investigate their potency against various types of bacteria and fungi. Results showed that these compounds exhibit significant inhibitory activity against the growth of tested bacterial and fungal strains and that some derivatives were more potent than the employed reference drugs.     

Silylation Improves the Photodynamic Activity of Tetraphenylporphyrin Derivatives In Vitro and In Vivo

The effects of silyl and hydrophilic groups on the photodynamic properties of tetraphenylporphyrin (TPP) derivatives have been studied in vitro and in vivo. Silylation led to an improvement in the quantum yield of singlet oxygen sensitization for both sulfo and carboxy derivatives, although the silylation did not affect other photophysical properties. Silylation also improved the cellular uptake efficiency for both sulfo and carboxy derivatives, enhancing the in vitro photodynamic activity of the photosensitizer in U251 human glioma cells. The carboxy derivative (SiTPPC₄) was found to show higher cellular uptake efficiency and in vitro photodynamic activity than the corresponding sulfo derivative (SiTPPS₄), which indicates that the carboxy group is a more promising hydrophilic group than the sulfo group in the silylated porphyrin. SiTPPC₄ was found to show high selective accumulation efficiency in tumors, although almost no tumor selectivity was observed for the nonsilylated porphyrin. The concentration of SiTPPC₄ in tumors was 13 times higher than that in muscle 12 h after drug administration. We also studied tumor response after treatment and found that silylation enhanced in vivo photodynamic activity significantly. SiTPPC₄ shows higher photodynamic activity than NPe6 with white light irradiation.     

Cationic Hypericin Derivatives as Novel Agents with Photobactericidal Activity: Synthesis and Photodynamic Inactivation of Propionibacterium acnes

The present communication describes for the first time the synthesis and preliminary testing of two cationic hypericin derivatives. Uncharged hypericin derivatives with ω , ω '-attached C₂-linkers leading to a pyridyl or a 4-dimethylaminophenyl residue were prepared and subsequently quaternized by means of iodomethane. Photobactericidal activity was assessed using Propionibacterium acnes . The quaternary N , N , N -trimethyl-anilinium derivative displayed a pronounced photodynamic inactivation of the bacteria at low incubation concentrations (<100 n m ) and a short incubation time (1 h) after illumination with yellow light (590 nm, 20 J cm⁻²), whereas the photobactericidal efficacy of the N -methyl-pyridinium derivative was negligible under identical experimental conditions.     

Influence of Side‐Chain Composition on Polythiophene Properties and Supramolecular Assembly of Anionic Polythiophene Derivatives

A series of 10 polythiophene derivatives is reported, in which each polymer has a different percentage of carboxylic acid‐bearing repeat units. The properties of these polymers are explored under acidic conditions, where the carboxylic acid moieties remain neutral, and under basic conditions, where the carboxylic acid units become anionic carboxylates. The properties that are examined for both solutions and films include UV–vis absorption spectroscopy, photoluminescence spectroscopy, and red‐edge optical band gaps. All the properties studied are strongly dependent both on protonation state and percentage of carboxylic acid/carboxylate side chains along the polymer backbone. The anionic form of each polythiophene derivative was also used in layer‐by‐layer film deposition with a cationic phosphonium polyelectrolyte. The film growth process was studied by spectroscopic techniques to assess the influence of side‐chain composition on the film growth and optical properties. © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019     

PHOTOACTIVE METHYLENE BLUE DYE DERIVATIVES SUITABLE FOR COUPLING TO PROTEIN

Methylene blue is a very strong photoactive dye that has an absorption peak (668 nm) that corresponds well to a popular low-cost diode laser. However, it has not been used in photodynamic tumor therapy and immunodiagnostics because it cannot be covalently coupled to protein. Therefore, methylene blue derivatives having a succinimido or maleimido functional group were synthesized and coupled to antibody, serum albumin and transfemn proteins. Incorporation of dye into antibody protein at high ratios (more than three per molecule) caused precipitation and loss of antibody activity. Inclusion of one or more carboxylic acid residues in the methylene blue derivative before coupling to protein alleviated the precipitation problem, and up to 36 methylene blue dye molecules could be attached to an antibody fragment using bovine serum protein as a carrier. Methylene blue derivatives and protein complexes formed from them oxidized luminol when stimulated with red light. The new dye conjugates were used in an optically pumped chemiluminescence immunoassay for α-fetoprotein. These compounds and techniques should also be useful for photodynamic tumor therapy where it is desired to attach a red-absorbing photoactive dye to antibody protein.     

Calix[4]arene based 1,3,4-oxadiazole and thiadiazole derivatives: design, synthesis, and biological evaluation

In the present investigation, we describe some novel calixarene based heterocyclic compounds (5a-5i) in which 1,3,4-oxadiazole and 1,3,4-thiadiazole derivatives have been coupled with 5,11,17,23-tetra-tert-butyl-25,27-bis(chlorocarbonyl-methoxy)-26,28-dihydroxy calix[4]arene. All the newly synthesized calixarene based heterocyclic compounds have been characterized by elemental analysis and various spectroscopic methods like FTIR, (1)H NMR, (13)C NMR, and FAB-MS. All the final scaffolds have been subjected to antioxidant activity, in vitro antimicrobial screening against two gram (+ve) bacteria (S. aureus, S. pyogenes), two gram (-ve) bacteria (E. coli, P. aeruginosa) and two fungal strains (C. albicans, A. clavatus) and also have been screened for their antitubercular activity against Mycobacterium tuberculosis H(37)Rv.