Oxime derivatives with larvicidal activity against Aedes aegypti L.

Oximes containing secondary metabolites constitute an important group of bioactive compounds and have been described and frequently updated in the literature due to their pharmacological properties. Thus, the aim of this study was to evaluate the larvicidal activity of a series of fourteen structurally related [1,4]-Benzoquinone mono-oximes on third-instar Aedes aegypti larvae and to investigate structure-activity relationships (SAR) of these compounds. Results of larvicidal assay revealed that all oximes were found to have larvicidal activity. Compound 2,6-dimethyl-[1,4]-benzoquinone oxime tosylate (11) was the most bioactive (LC50 = 9.858 ppm), followed by 2-methyl-[1,4]-benzoquinone oxime tosylate (9) (LC50 = 14.450 ppm). [1,4]-benzoquinone oxime (1) exhibited the lowest potency, with an LC50 = 121.181 ppm. The molecular characteristics which may help to understand the assayed compounds larvicidal activity were identified. SAR indicates that the addition of alkyl groups attached to the ring, number, position in the unsaturated cyclic structure, and size of these groups influence the larvicidal activity. Moreover, the lipophilicity seems to play an important role in increasing the larvicidal effect, because, in general, tosyl-containing products were more potent than products containing free OH.

Synthesis of new chlorin†e6 trimethyl and protoporphyrin†IX dimethyl ester derivatives and their photophysical and electrochemical characterizations.

In view of increasing demands for efficient photosensitizers for photodynamic therapy (PDT), we herein report the synthesis and photophysical characterizations of new chlorin e6 trimethyl ester and protoporphyrin IX dimethyl ester dyads as free bases and Zn(II) complexes. The synthesis of these molecules linked at the ß-pyrrolic positions to pyrano[3,2-c]coumarin, pyrano[3,2-c]quinolinone, and pyrano[3,2-c]naphthoquinone moieties was performed by using the domino Knoevenagel hetero Diels-Alder reaction. The α-methylenechromanes, α-methylenequinoline, and ortho-quinone methides were generated in situ from a Knoevenagel reaction of 4-hydroxycoumarin, 4-hydroxy-6-methylcoumarin, 4-hydroxy-N-methylquinolinone, and 2-hydroxy-1,4-naphthoquinone, respectively, with paraformaldehyde in dioxane. All the dyads as free bases and as Zn(II) complexes were obtained in high yields. All new compounds were fully characterized by 1D and 2D NMR techniques, UV/Vis spectroscopy, and HRMS. Their photophysical properties were evaluated by measuring the fluorescence quantum yield, the singlet oxygen quantum yield by luminescence detection, and also the triplet lifetimes were correlated by flash photolysis and intersystem crossing (ISC) rates. The fluorescence lifetimes were measured by a time-correlated single photon count (TCSPC) method, fluorescence decay associated spectra (FDAS), and anisotropy measurements. Magnetic circular dichroism (MCD) and circular dichroism (CD) spectra were recorded for one Zn(II) complex in order to obtain information, respectively, on the electronic and conformational states, and interpretation of these spectra was enhanced by molecular orbital (MO) calculations. Electrochemical studies of the Zn(II) complexes were also carried out to gain insights into their behavior for such applications.

Photobiological characteristics of chlorophyll a derivatives as microbial PDT agents.

Chlorin-e6 (chl-e6) and a hydrogenated derivative (chl-e6H) were semi-synthesized, and their photophysical properties and photodynamic activity against Escherichia coli, Staphylococcus aureus and Candida albicans evaluated. Methyl pheophorbide-a (Mepheo-a) was obtained from S. maxima using methanolic extraction with acid catalysis (CH3OH­H2SO4). Chlorin-e6 was prepared from Mepheo-a by basic hydrolysis with H2O­acetone and NaOH. Hydrogenated Chlorin-e6 was synthesized by a similar procedure starting from the hydrogenated methyl pheophorbide-a (Mepheo-aH). Photophysical studies were performed in order to determine the singlet oxygen quantum yield of chl-e6H which is higher than that of chl-e6. The microorganism inactivation of chl-e6 and chl-e6H was investigated at two concentrations and three fluence levels. Both chl-e6 and chl-e6H showed microorganism inactivation against Gram-positive bacteria and a fungus.

Larvicidal activity of para-benzoquinones.

Plant products may be alternative sources of mosquito larval control agents, since they constitute a rich source of bioactive compounds that are biodegradable into nontoxic products. It has been reported that quinones and derivatives present toxic activity against mosquito larvae Aedes aegypti. Therefore, these facts led us to investigate the larvicidal potential of six structurally related para-benzoquinones against A. aegypti L. (Culicidae) larvae, the vector of dengue fever. All the para-benzoquinones were found to have larvicidal effect. The unsubstituted para-benzoquinone was the compound that exhibited the lowest potency, while 2-isopropyl-para-benzoquinone was the most bioactive. In general, the presence of alkyl groups results in more potent compounds. In addition, the number, position, and size of these groups modulate the potency of the compounds. The experimental results showed that by appropriate structural modification of para-benzoquinones, it may be possible to develop novel insecticidal compounds with potential use to control A. aegypti population.

Phototoxicity in a laryngeal cancer cell line enhanced by a targeting amphiphilic chlorin photosensitizer.

BACKGROUND: Photodynamic therapy (PDT) has been established in several countries as an alternative therapy for the treatment of various malignancies. This therapy involves the incorporation of a photosensitizer (PS) that is activated by visible light and form reactive oxygen species leading to target cell death by apoptosis or necrosis. Previously, our group has demonstrated that CHL-T (semi-synthesized from chlorophyll a and containing a linked solubilizing group TRISMA®) presented a pronounced potential to induce death in HeLa cell line after PDT. In the present study, besides confirm the high cytotoxicity in another cell line, we have further investigated the cell death mechanisms caused by CHL-T as a photosensitizer in laryngeal carcinoma cells. METHODS: Cells were exposed to different concentrations of three photosensitizers, namely, hypericin (HY), unmodified chlorin (CHL) and a synthesized amphiphilic chlorin derivative (CHL-T). PSs accumulation and localization were accessed by fluorescence assays. Photosensitization was induced at 6Jcm-2 using red LEDs (630±10nm). Viability was assessed by mitochondrial function (MTT); whereas apoptosis/necrosis was evaluated by fluorescence microscopy and flow cytometry. Expression of pro-apoptotic p53 protein was studied by Western blot. RESULTS AND CONCLUSIONS: All PS showed similar localization profile in the HEp-2 cells. The use of CHL-T increased the percentage of apoptotic cells and also p53 expression in comparison with the use of HY and CHL as photosensitizers. This study shows a significant effect of CHLT associated with red light (630±10nm and 18mWcm-2) irradiation on a cancer cell line, indicating the potential of this amphiphilic chlorin in enhancing the therapeutic effectiveness of Photodynamic Therapy (PDT).

Antimicrobial Photodynamic Therapy against Endodontic Enterococcus faecalis and Candida albicans Mono and Mixed Biofilms in the Presence of Photosensitizers: A Comparative Study with Classical Endodontic Irrigants.

Endodontic biofilms eradication from the infected root canal system remains as the primary focus in endodontic field. In this study, it was assessed the efficacy of antimicrobial Photodynamic Therapy (aPDT) with the Zn(II)chlorin e6 methyl ester (Zn(II)e6Me) activated by red light against monospecies and mixed biofilms of Enterococcus faecalis and Candida albicans. The results were compared with the ones obtained with Rose Bengal (RB), Toluidine Blue-O (TBO), the synthetic tetracationic porphyrin (TMPyP) as well as classical endodontic irrigants (3% NaOCl, 17% EDTA and 2% CHX). The antimicrobial efficacy of aPDT toward monospecies and mixed biofilms was quantified resorting to safranin red method. The changes of biofilm organization and of cellular ultrastructure were evaluated through several microscopy techniques (light, laser confocal and transmission electron microscopy). Zn(II)e6Me once activated with light for 60 or 90 s was able to remove around 60% of the biofilm's biomass. It was more efficient than TBO and RB and showed similar efficiency to TMPyP and classical irrigants, CHX and EDTA. As desirable in a PS, Zn(II)e6Me in the dark showed smaller activity than TMPyP. Only NaOCl revealed higher efficiency, with 70-90% of the biofilm's biomass removal. The organization of biofilms and the normal microbial cell ultrastructure were extensively damaged by the presence of Zn(II)e6Me. aPDT with Zn(II)e6Me showed to be an efficient antimicrobial strategy deserving further studies leading to a future clinical usage in endodontic disinfection.

Anticonvulsant activity of thymoquinone and its structural analogues

It has been widely reported that the crude oil of Nigella sativa L., Ranunculaceae, seeds and its major chemical component thymoquinone present anticonvulsant activity. These facts led us to verify the pharmacological potential of five structurally related para-benzoquinones on the pentylenotetrazol-induced seizures model, and establish the structural characteristics that influence the anticonvulsant activity of thymoquinone. The unsubstituted para-benzoquinone was the compound that exhibited the highest potency, while 2-methyl-p-benzoquinone was inactive. It was found that the presence of alkyl groups attached to the ring influence the pharmacological activity of the para-benzoquinones. In addition, the number, position, and size of these groups change the anticonvulsant potency of the compounds.