RESUMO
Trichomoniasis, caused by the protozoan Trichomonas vaginalis, is the most prevalent non-viral sexually transmitted infection that affects over 170 million people worldwide. The only type of drug recommended for the therapeutic control of trichomoniasis is the 5-nitroimidazoles, although there have been reports of some undesirable side effects and clinical resistance. Hence, the need for the search for new tricomonicidal agents is necessary. In a previous work, we demonstrated that two 2-amino-4-aryl thiazole derivatives (ATZ-1 and ATZ-2) possess a portent antigiardial effect. In the current paper, we investigated the in vitro antitrichomonal activity of these thiazole compounds. Both ATZ-1 and ATZ-2 reduced the viability and growth of parasites in a dose-dependent manner, with an IC50 value of 0.15 µg/mL and 0.18 µg/mL, respectively. Furthermore, both thiazole compounds were able to decrease the proteolytic activity in T. vaginalis trophozoites compared with untreated parasites. Interestingly, a full proteolytic inhibition profile was observed in the 50-kDa region which was associated with the decreased expression of the gene that codes for the trichomonad protease TvMP50. The docking simulations predicted strong interactions of the thiazole compounds in the TvMP50 protease's active site, suggesting a possible role as protease inhibitors. Our results demonstrate the potential of 2-amino-4-aryl thiazole derivatives as trichomonicidal compounds and could be, mechanistically, involved in the inhibition of key trichomonad proteases.
Assuntos
Antitricômonas/farmacologia , Inibidores de Proteases/farmacologia , Tiazóis/farmacologia , Tricomoníase/tratamento farmacológico , Trichomonas vaginalis/efeitos dos fármacos , Humanos , Testes de Sensibilidade Parasitária , Tricomoníase/parasitologiaRESUMO
The present paper sought to investigate the in vitro and in vivo anti-inflammatory effects of the methanolic extract (ME), hexane-ethyl acetate fraction E (FE) found in Chrysophyllum cainito fruits (CCF), as well the lupeol acetate (LA) obtained from FE on lipopolysaccharide (LPS)-stimulated mouse peritoneal macrophages. The macrophages were treated with ME, FE or LA at various concentrations and the viability of cells was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide method. Production of pro-inflammatory (IL-1ß, IL-6, and TNF-α) and anti-inflammatory (IL-10) cytokines, as well as the nitric oxide (NO) and hydrogen peroxide (H2O2) levels was determined using macrophages treated with ME, FE or LA at various concentrations and stimulated with LPS as an in vitro model. Afterwards, we evaluated the anti-inflammatory effects in vivo using the TPA-induced ear edema and carrageenan-induced paw edema tests in mice and production of inflammatory mediators was estimated in serum samples. The results showed that the ME, FE and LA from fruits, FE and LA were able to trigger an inhibition in NO and H2O2 levels, as well as IL-1ß, IL-6, and TNF-α released by macrophages in a concentration-dependent manner. LA from C. cainito fruits was found to significantly attenuate carrageenan-induced paw edema and TPA-induced ear edema. Therefore, the results suggest ME, FE and LA isolated from C. cainito fruits have anti-inflammatory effects on macrophages without affecting cell viability.
Assuntos
Anti-Inflamatórios/farmacologia , Inflamação/tratamento farmacológico , Extratos Vegetais/farmacologia , Sapotaceae/química , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/isolamento & purificação , Carragenina , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Edema/tratamento farmacológico , Frutas , Inflamação/patologia , Lipopolissacarídeos , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Extratos Vegetais/administração & dosagemRESUMO
The aim of the present work was to apply a validated methodology for the detection of organochlorine pesticides in Didelphis virginiana (Virginia opossum) serum samples collected in Yucatan, Mexico. Recent studies performed to investigate the presence of Organochlorines (OCLs) in water, human blood and milk, and animal tissues from Yucatan have shown that the OCLs concentrations are high and can be associated with potential human health risk. Since opossum is considered an important synanthropic species in Yucatan, 40 opossum serum samples were analyzed by gas chromatography with electron capture detector. The most common OCLs found in opossum sera were lindanes, chlordanes, drines, and endosulfan. Heptachlor, heptachlor epoxide, and lindanes were found at the highest concentrations, while dichlorodiphenyl trichloroethane and its metabolites were found at the lowest concentrations in the samples. The good linearity, precision, and accuracy obtained in the evaluated parameters in the extraction and chromatographic methods support its application for the monitoring of OCLs pesticides in populations of opossums and other wild species in Yucatan.
Assuntos
Didelphis/sangue , Monitoramento Ambiental , Hidrocarbonetos Clorados/sangue , Praguicidas/sangue , Animais , Cromatografia Gasosa , DDT/sangue , Endossulfano/sangue , Heptacloro/sangue , Hidrocarbonetos Clorados/química , México , Praguicidas/químicaRESUMO
Mechanistic theoretical studies about the feasibility of the traditional proposed mechanism of formation for icetexane diterpene dimer grandione were assessed using density functional method at the M06-2X/6-31G(d,p) level of theory. Bulk water solvent effects were taken into account implicitly using the polarizable continuum model (SCI-PCM). The results were compared with the selectivity found in the biomimetic synthesis performed by experimental research groups. The relative free energy calculation shows that the one-step H-DA formation mechanism nominated in the literature is not a viable mechanism. We found that an alternative competing Tandem pathway is consistent with the experimental trends. Thus, our results suggested that the compound grandione is formed via a H-DA/retro-Claisen rearrangement and not by the traditional H-DA mechanism proposed early in the experimental studies. The H-DA initial step produce a biecyclic adduct followed by a domino retro-Claisen rearrangement that releases the energy strain of the bicyclic intermediary. Steric issues and hyperconjugation interactions are the mainly factors driving the reaction nature and the selectivity in the formation reaction. Finally, the enzymatic assistance for dimer formation was analyzed in terms of the calculated transition state energy barrier.
Assuntos
Diterpenos/química , Diterpenos/síntese química , Modelos QuímicosRESUMO
Herein we describe a salicylaldehyde-annulation reaction as a plug and play toolkit to diversify the complexity of naturally occurring ketones. The protocol entails the transformation of the polycyclic natural ketone into its propargyl vinyl ether derivative (two synthetic steps) and its microwave-assisted imidazole-catalyzed domino rearrangement to generate the salicylaldehyde ring. This annexed unit allows further synthetic transformations: e.g., the installation of a pharmacophore module to generate natural product-pharmacophore hybrids endowed with unknown biological (pharmaceutical) annotations.
RESUMO
The biogenetic origin of triterpene dimers from the Celastraceae family has been proposed as assisted hetero-Diels-Alder reaction (HDA). In this work, computational calculation of HDA between natural quinonemethides (tingenone and isopristimerol) and hypothetical orthoquinones has been performed at the M06-2X/6-31G(d) level of theory. We have located all the HDA transition states supporting the biogenetic route via HDA cycloadditions. We found that all reactions take place through a concerted inverse electron demand and asynchronous mechanism. The enzymatic assistance for dimer formation was analyzed in terms of the calculated transition state energy barrier.
Assuntos
Vias Biossintéticas , Quinonas/metabolismo , Triterpenos/metabolismo , Reação de Cicloadição , Modelos Biológicos , Modelos Químicos , Plantas/metabolismo , Teoria QuânticaRESUMO
Four new diterpenes, crossogumerins A-D (1-4) along with six known ones (5-10) were isolated from the root bark of Crossopetalum gaumeri, an endemic medicinal plant from the Yucatan Peninsula. Their structures were elucidated on the basis of 1D and 2D NMR techniques, including HMQC, HMBC, and ROESY experiments. Compounds 1-5, 8-10 were evaluated for cytotoxicity against HeLa (carcinoma of the cervix) and Hep-2 (lung carcinoma) human tumor cells lines and against normal Vero cells (African green monkey kidney) in lag and log phase of growth. Podocarpane diterpenes, crossogumerin B (2) and nimbiol (10), exhibited the highest activity against HeLa cells (IC50 values of 3.1 and 8.1 µM, respectively), but also selectivity on Vero cells (SI 22.6 and 7.5, respectively). The preliminary SAR studies suggest that an epoxy moiety in ring B and a hydrogen bond-donor group strategically positioned in the diterpene core are important requirements for cytotoxicity and selectivity.
Assuntos
Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Celastraceae/química , Diterpenos/química , Diterpenos/farmacologia , Animais , Antineoplásicos Fitogênicos/isolamento & purificação , Linhagem Celular Tumoral , Chlorocebus aethiops , Diterpenos/isolamento & purificação , Células HeLa , Humanos , Neoplasias/tratamento farmacológico , Raízes de Plantas/química , Células VeroRESUMO
The title compound, (C9H9N2S)2[PdCl4], consists of two monoprotonated 2-amino-4-phenyl-1,3-thia-zole molecules and one tetra-chlorido-palladate anion. The organic molecules exhibit a dihedral angle between the main rings planes of 31.82â (9)°. In the anion, the Pd(II) atom is located on a crystallographic centre of symmetry with a square-planar geometry. In the crystal, the anions and cations are connected through bifurcated N-Hâ¯Cl hydrogen bonds, and these inter-actions lead to hydrogen-bonded tapes of cations and anions along [100].
RESUMO
In this study, twenty-four organic extracts from six marine sponge species, collected at shallows of Yucatan, Mexico, were evaluated against Giardia lamblia trophozoites and Vero cells. The dichloromethane and hexane extracts of Haliclona tubifera exhibited the highest antigiardiasic activity (IC50 = 1.00 and 2.11 µg/mL, respectively), as well as high selectivity (SI = 41.8 and > 47.4, respectively), while ethyl acetate and methanol extracts of Cinachyrella alloclada, and methanol extract of Suberites aurantiaca showed moderate activity. Contrastingly, the extracts of Halichondria magniculosa and Oceanapia nodosa were considered non actives. Consequently, the dichloromethane extract of H. tubifera were subject to an exploratory chemical study, isolating cholesterol, two benzaldehyde derivatives, three benzoic acid derivatives, cytosine, and thymine.
Assuntos
Giardia lamblia , Haliclona , Chlorocebus aethiops , Animais , México , Metanol , Cloreto de Metileno , Células VeroRESUMO
The n â π* interactions were studied in amides and thioamides systems models, through the analysis of the electron density topology along with the Natural Bonding Orbital (NBO) approach. The effect of the dispersion terms was assessed using different DFT functionals. The NBO, independent gradient model (IGM), and the analysis of the reduced density gradient outcomes show that dispersion forces play a significant role in the strength of n â π* interactions. The IGM results indicate that δg height values for n â π* interactions do not extend beyond 0.025. All the methods used in this work predict that n â π* interaction between pairs of thioamides is stronger than those between amides. However, the electron density topology-based methods were not able to replicate the trends in the relative force of this interaction found in the experimental and NBO results.
RESUMO
The energy change on each Occupied Molecular Orbital as a function of rotation about the C-C bond in ethane was studied using the B3LYP, mPWB95 functional and MP2 methods with different basis sets. Also, the effect of the ZPE on rotational barrier was analyzed. We have found that σ and π energies contribution stabilize a staggered conformation. The σ(s) molecular orbital stabilizes the staggered conformation while the stabilizes the eclipsed conformation and destabilize the staggered conformation. The π(z) and molecular orbitals stabilize both the eclipsed and staggered conformations, which are destabilized by the π(v) and molecular orbitals. The results show that the method of calculation has the effect of changing the behavior of the energy change in each Occupied Molecular Orbital energy as a function of the angle of rotation about the C-C bond in ethane. Finally, we found that if the molecular orbital energy contribution is deleted from the rotational energy, an inversion in conformational preference occurs.
Assuntos
Etano/química , Modelos MolecularesRESUMO
A series of 15 novel 1,3-thiazole amide derivatives of the pentacyclic triterpene Ochraceolide A (1) was synthesized, characterized, and evaluated in vitro against three human cancer cell lines (MCF-7, MDA-MB-231 and SiHa) and a normal cell line (Vero). Synthetic derivatives were obtained by acylation of the 2-aminothiazole triterpene 2, previously reported. Remarkably, the 5-nitrofuramide derivative (2o) showed better cytotoxic and antiproliferative activity than compound 2 and the other derivatives against the three cancer cell lines with CC50 and IC50 values of 1.6-12.7 µM. Furthermore, butyramide derivative (2c) was approximately 25 times more selective than 2, as well as 3.4 times more selective than Docetaxel, against SiHa cells in the cytotoxic assay, while the phenyl amide derivatives were inactive against the three cancer cell lines.
Assuntos
Antineoplásicos , Triterpenos , Amidas/farmacologia , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Relação Estrutura-Atividade , Tiazóis/farmacologia , Triterpenos/farmacologiaRESUMO
Acrolein dimerization is a intriguing case since the reaction does not occur to form the electronically preferred regioisomeric adduct. Various explanations have been suggested to rationalize this experimental regioselectivity, however, none of these arguments had been convincing enough. In this work, the hetero Diels-Alder acrolein dimerization was theoretically investigated using DFT and MP2 methods. The influence of nucleophilic/electrophilic interactions and non-covalent interactions (NCI) in the regiospecificity of the reaction were analyzed. Our results show that the NCI at the transition state are the key factor controlling the regiospecificity in this reaction. Besides, we found that the choice of calculation method can have an effect on the prediction of the mechanism in the reaction, as all DFT methods forecast a one-step hetero Diels-Alder acrolein dimerization, while MP2 predicts a stepwise description for the lower energy reaction channel.
RESUMO
This study aimed to evaluate the in vitro activity of extracts of two marine sponge species, occurring in the shallows of the Yucatan peninsula coast, on two cancer and one normal mammalian cell lines. Hexane, dichloromethane, ethyl acetate and methanol extracts of Halichondria magniconulosa and Halichondria melanadocia were screened for their cytotoxic activity against hormone-dependent breast cancer (MCF-7) and human cervix cancer (SiHa) cell lines. The ethyl acetate extract of H. magniconulosa exhibited significant cytotoxicity against MCF-7 cells to a CC50 of 0.8 µg/mL, as well as high selectivity (SI = 24.5). On the other hand, SiHa cells were moderately sensitive to the dichloromethane and ethyl acetate extracts of the same species. (CC50 = 34.9 and 31.5 µg/mL, respectively). None of the extracts of H. melanadocia were considered active due their CC50's were ranged from 59.0 to 94.5 µg/mL.
Assuntos
Antineoplásicos , Neoplasias da Mama , Poríferos , Animais , Antineoplásicos/farmacologia , Feminino , Humanos , México , Extratos Vegetais/farmacologiaRESUMO
Two crystallographically independent mol-ecules (A and B) are present in the asymmetric unit of the title compound, C11H9IN2OS, which differ mainly in the dihedral angle between the phenyl and thia-zole rings [38.94â (16) and 32.12â (15)°, respectively]. In the crystal, the mol-ecules form â¯Aâ¯Bâ¯Aâ¯B⯠chains along the [001] and [010] directions through moderate N-Hâ¯O hydrogen bonds and C-Hâ¯π inter-actions, respectively. The overall three-dimensional network is formed by Iâ¯I and Iâ¯S inter-actions. Hirshfeld surface analysis indicates that the most important contributions to the crystal packing are from Hâ¯C/Câ¯H (26.2%), Hâ¯H (20.9%), Hâ¯I/Iâ¯H (19.4%) and Hâ¯O/Oâ¯H (6.8%) inter-actions.
RESUMO
Micromycetes from unexplored sources represent an opportunity to discover novel natural products to control insect pests. With this aim, a strain of Acremonium masseei CICY026 isolated from a tropical sinkhole was identified, cultured on fermented rice, and its ethyl acetate extract (EAE) was evaluated against three serious phytophagous insects (Bemisia tabaci, Myzus persicae, and Rhopalosiphum padi). DNA from A. masseei CICY026 was used to confirm its identity. EAE caused settling inhibition (SI) of M. persicae and R. padi (67.5% and 75.3%, respectively). Bioassay-guided fractionation of the active EAE led to the isolation of a novel metabolite, named hexahydroacremonintriol (1), and of acremonin A glucoside (2). The structures of 1 and 2 were determined using IR, one- and two-dimensional NMR, HRMS, and confirmed by theoretical data. The aphid M. persicae was noticeably sensitive to 1 and 2 (SI: 55.6% and 67.2%, respectively), whereas R. padi was only slightly affected by 1 (SI: 59%). This new knowledge about mycobiota from these special sinkhole ecosystems will inform the development of new biorational pesticides.
RESUMO
Stem bark of Hippocratea excelsa afforded six pentacyclic triterpenes, five oleanane and one ursane types. They were identified as 11beta,21beta-dihydroxy-olean-12-ene-3-one (2), 3alpha,11alpha,21beta-trihydroxy-olean-12-ene (3), 3alpha,21beta-dihydroxy-11alpha-methoxy-olean-12-ene (4), 3alpha,21beta-dihydroxy-olean-9(11),12-diene (5), 3alpha,21beta-dihydroxy-olean-12-ene (6) and 3alpha,21beta-dihydroxy-11alpha-methoxy-urs-12-ene, isolated as its diacetate derivative (7), as well as 3alpha,21beta-dihydroxy-olean-12-ene (1) previously isolated from the root bark. The known alpha- and beta-amyrin, oleanoic and ursolic acids, trans-polyisoprene, and the ubiquitous beta-sitosterol were also isolated. Structures were elucidated on the basis of spectroscopic analyses, including homo- and heteronuclear correlation NMR experiments (COSY, ROESY, HSQC and HMBC) and comparison with literature data. The antigiardial activity of compounds 2-5 was not significant.
Assuntos
Hippocrateaceae/química , Ácido Oleanólico/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/isolamento & purificação , Triterpenos Pentacíclicos/química , Triterpenos Pentacíclicos/isolamento & purificação , Casca de Planta/química , Triterpenos/química , Triterpenos/isolamento & purificação , Ácido UrsólicoRESUMO
A new ent-kaurane diterpene glycoside identified as (-)19-beta-D-glucopyranosyl 6,7-dihydroxy kaurenoate, was isolated from the seeds of Pithecellobium albicans. The structure of the new compound was established by spectral data.
Assuntos
Diterpenos do Tipo Caurano/química , Fabaceae/química , Folhas de Planta/química , Sementes/química , Estrutura MolecularRESUMO
Methanol extracts of leaves, roots and bark of Senna racemosa (Mill.) H.S. Irwin & Barneby (syn. Cassia racemosa Mill.) were tested for antiprotozooal activity against Giardia intestinalis and Entamoeba histolytica. All of the tested extracts showed good activity against both protozoa species. Extracts from stem bark and leaves were most active, with an IC(50) of 2.10 microg/mL for Giardia intestinalis and 3.87 microg/mL for Entamoeba histolytica. Of the previously isolated compounds from Senna racemosa, the piperidine alkaloid cassine had greater activity against Giardia intestinalis with an IC(50) of 3.28 microg/mL and chrysophanol, a 1,8-dihydroxy-anthraquinone, was the most active agent against Entamoeba histolytica, with an IC(50) of 6.21 microg/mL.
Assuntos
Antraquinonas/farmacologia , Antiprotozoários/farmacologia , Cetonas/farmacologia , Piperidinas/farmacologia , Senna/química , Animais , Antraquinonas/química , Antraquinonas/isolamento & purificação , Entamoeba histolytica/efeitos dos fármacos , Giardia lamblia/efeitos dos fármacos , Cetonas/química , Cetonas/isolamento & purificação , Metronidazol/farmacologia , Piperidinas/química , Piperidinas/isolamento & purificação , Casca de Planta/química , Extratos Vegetais/farmacologia , Folhas de Planta/química , Caules de Planta/químicaRESUMO
The title compound, C30H44O3 [systematic name: 6aR,6â bR,8aS,9aR,12aR,14bR)-4,4,6a,6;b,8a,14b-hexa-methyl-12-methyl-eneicosa-hydro-3H-phenanthro[1',2':6,7]indeno-[2,1-b]furan-3,11(2H)-dione], is a triterpene lactone, which was isolated from di-chloro-methane extract of Elaeodendron trichotomum (Turcz.) Lundell (celastraceae) stem bark. The compound has a lupane skeleton and consists of four fused six-membered rings and two five-membered rings. In the crystal, mol-ecules are linked by weak C-Hâ¯O hydrogen bonds into a three-dimensional network. The configuration of ochraceolide A was proposed based on analogue compounds which belong to the lupane type.