RESUMEN
We designed and synthesized a series of symmetric bis-6-amidino-benzothiazole derivatives with aliphatic central units and evaluated their efficacy against bloodstream forms of the African trypanosome Trypanosoma brucei. Of these, a dicationic benzothiazole compound (9a) exhibited sub-nanomolar in vitro potency with remarkable selectivity over mammalian cells (>26,000-fold). Unsubstituted 5-amidine groups and a cyclohexyl spacer were the crucial determinants of trypanocidal activity. In all cases, mice treated with a single dose of 20 mg kg-1 were cured of stage 1 trypanosomiasis. The compound displayed a favorable in vitro ADME profile, with the exception of low membrane permeability. However, we found evidence that uptake by T. brucei is mediated by endocytosis, a process that results in lysosomal sequestration. The compound was also active in low nanomolar concentrations against cultured asexual forms of the malaria parasite Plasmodium falciparum. Therefore, 9a has exquisite cross-species efficacy and represents a lead compound with considerable therapeutic potential.
Asunto(s)
Tripanocidas , Trypanosoma brucei brucei , Trypanosoma , Tripanosomiasis Africana , Tripanosomiasis , Ratones , Animales , Tripanosomiasis Africana/tratamiento farmacológico , Tripanosomiasis Africana/parasitología , Tripanosomiasis/tratamiento farmacológico , Benzotiazoles/farmacología , Benzotiazoles/uso terapéutico , Tripanocidas/farmacología , Tripanocidas/uso terapéutico , MamíferosRESUMEN
A series of tetrahydropyrimidinyl-substituted benzimidazoles attached to various aliphatic or aromatic residues via phenoxymethylene were synthesised to investigate their antibacterial activities against selected Gram-positive and Gram-negative bacteria. The influence of the type of substituent at the C-3 and C-4 positions of the phenoxymethylene linker on the antibacterial activity was observed, showing that the aromatic moiety improved the antibacterial potency. Of all the evaluated compounds, benzoyl-substituted benzimidazole derivative 15a was the most active compound, particularly against the Gram-negative pathogens E. coli (MIC = 1 µg mL-1) and M. catarrhalis (MIC = 2 µg mL-1). Compound 15a also exhibited the most promising antibacterial activity against sensitive and resistant strains of S. pyogenes (MIC = 2 µg mL-1). Significant stabilization effects and positive induced CD bands strongly support the binding of the most biologically active benzimidazoles inside the minor grooves of AT-rich DNA, in line with docking studies. The predicted physico-chemical and ADME properties lie within drug-like space except for low membrane permeability, which needs further optimization. Our findings encourage further development of novel structurally related 5(6)-tetrahydropyrimidinyl substituted benzimidazoles in order to optimize their antibacterial effect against common respiratory pathogens.
RESUMEN
Interleukin 17 (IL-17) cytokines promote inflammatory pathophysiology in many autoimmune diseases, including psoriasis, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease. Such broad involvement of IL-17 in various autoimmune diseases makes it an ideal target for drug discovery. Psoriasis is a chronic inflammatory disease characterized by numerous defective components of the immune system. Significantly higher levels of IL-17A have been noticed in lesions of psoriatic patients, if compared to non-lesion parts. Therefore, this paper is focused on the macrolide inspired macrocycles as potential IL-17A/IL-17RA modulators and covers the molecular design, synthesis, and in vitro profiling. Macrocycles are designed to diversify and enrich chemical space through different ring sizes and a variety of three-dimensional shapes. Inhibitors in the nM range were identified in both target-based and phenotypic assays. In vitro ADME as well as in vivo PK properties are reported.
Asunto(s)
Antiinflamatorios/farmacología , Interleucina-17/antagonistas & inhibidores , Compuestos Macrocíclicos/farmacología , Unión Proteica/efectos de los fármacos , Receptores de Interleucina-17/antagonistas & inhibidores , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/metabolismo , Humanos , Interleucina-17/metabolismo , Compuestos Macrocíclicos/síntesis química , Compuestos Macrocíclicos/metabolismo , Masculino , Ratones , Simulación del Acoplamiento Molecular , Estructura Molecular , Receptores de Interleucina-17/metabolismo , Relación Estructura-Actividad , Células THP-1RESUMEN
Novel imidazoline benzimidazole derivatives containing diversely substituted phenoxy moieties were synthesized with the aim of evaluating their antitrypanosomal activity, DNA/RNA binding affinity and in vitro ADME properties. The presence of the diethylaminoethyl subunit in 18a-18c led to enhanced antitrypanosomal potency, particularly for 18a and 18c, which contain unsubstituted and methoxy-substituted phenoxy moieties. They were found to be > 2-fold more potent against African trypanosomes than nifurtimox. Fluorescence and CD spectroscopy, thermal denaturation assays and computational analysis indicated a preference of 18a-18c toward AT-rich DNA and their minor groove binding mode. Replacement of the amidine group with less basic and ionisable nitrogen-containing moieties failed to improve membrane permeability of the investigated compounds. Due to structural diversification, the compounds displayed a range of physico-chemical features resulting in variable in vitro ADME properties, leaving space for further optimization of the biological profiles.
Asunto(s)
Bencimidazoles/síntesis química , Bencimidazoles/farmacología , ADN/metabolismo , Diseño de Fármacos , Imidazolinas/química , ARN/metabolismo , Trypanosoma/efectos de los fármacos , Antiprotozoarios/síntesis química , Antiprotozoarios/química , Antiprotozoarios/metabolismo , Antiprotozoarios/farmacología , Bencimidazoles/química , Bencimidazoles/metabolismo , Técnicas de Química SintéticaRESUMEN
The human histone demethylases of the KDM4 family have been related to diseases such as prostate and breast cancer. Majority of currently known inhibitors suffer from the low permeability and low selectivity between the enzyme isoforms. In this study, toxoflavin motif was used to design and synthesize new KDM4C inhibitors with improved biological activity and in vitro ADME properties. Inhibitors displayed good passive cellular permeability and metabolic stability. However, diminishing of redox liability and consequently non-specific influence on cell viability still remains a challenge.
Asunto(s)
Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Histona Demetilasas con Dominio de Jumonji/antagonistas & inhibidores , Pirimidinonas/farmacología , Triazinas/farmacología , Células A549 , Animales , Perros , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Histona Demetilasas con Dominio de Jumonji/metabolismo , Células de Riñón Canino Madin Darby , Ratones , Microsomas Hepáticos/química , Microsomas Hepáticos/metabolismo , Estructura Molecular , Pirimidinonas/síntesis química , Pirimidinonas/química , Teoría Cuántica , Relación Estructura-Actividad , Triazinas/síntesis química , Triazinas/químicaRESUMEN
This chapter will discuss the recent literature of macrocycles and drug-like property space moving beyond the rule of five (bRo5). Trends in chemical classes that fall within this definition are discussed and the impact of the latest technologies in the field assessed. The physicochemical properties, which have provided both successes and challenges, especially in scale-up, are discussed. A recent patent literature is reviewed and the chapter concludes with a perspective on the future of macrocyclic drug discovery.
Asunto(s)
Descubrimiento de Drogas , Compuestos Macrocíclicos/farmacología , Antiinfecciosos/síntesis química , Antiinfecciosos/química , Antiinfecciosos/farmacología , Humanos , Compuestos Macrocíclicos/síntesis química , Compuestos Macrocíclicos/química , Estructura Molecular , Relación Estructura-ActividadRESUMEN
A series of novel amidino 2-substituted benzimidazoles linked to 1,4-disubstituted 1,2,3-triazoles were synthesized by implementation of microwave and ultrasound irradiation in click reaction and subsequent condensation of thus obtained 4-(1,2,3-triazol-1-yl)benzaldehyde with o-phenylenediamines. In vitro antiproliferative screening of compounds performed on human cancer cell lines revealed that p-chlorophenyl-substituted 1,2,3-triazolyl N-isopropylamidine 10c and benzyl-substituted 1,2,3-triazolyl imidazoline 11f benzimidazoles had selective and potent cytostatic activities in the low nM range against non-small cell lung cancer cell line A549, which could be attributed to induction of apoptosis and primary necrosis. Additional Western blot analyses showed different mechanisms of cytostatic activity between compounds 10c and 11f that could be associated with the nature of aromatic substituent at 1-(1,2,3-triazolyl) and amidino moiety at C-5 position of benzimidazole ring. Specifically, compound 11f abrogated the activity of several protein kinases including TGM2, CDK9, SK1 and p38 MAPK, whereas compound 10c did not have profound effect on the activities of CDK9 and TGM2, but instead showed moderate downregulation of SK1 activity concomitant with a significant reduction in p38 MAPK. Further in silico structural analysis demonstrated that compound 11f bound slightly better to the ATP binding site of p38 MAPK compared to 10c, which correlated well with observed stronger decrement in the expression level of phospho-p38 MAPK elicited by 11f in comparison with 10c.
Asunto(s)
Amidinas/farmacología , Antineoplásicos/farmacología , Bencimidazoles/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Diseño de Fármacos , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Amidinas/síntesis química , Amidinas/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Bencimidazoles/síntesis química , Bencimidazoles/química , Carcinoma de Pulmón de Células no Pequeñas/patología , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Neoplasias Pulmonares/patología , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Proteínas Quinasas , Relación Estructura-Actividad , Triazoles/química , Triazoles/farmacologíaRESUMEN
Novel halogenated purines and pseudopurines with diverse aryl-substituted 1,2,3-triazoles were prepared. While p-(trifluoromethyl)-substituted 1,2,3-triazole in N-9 alkylated purine and 3-deazapurine was critical for strong albeit unselective activity on pancreatic adenocarcinoma cells CFPAC-1,1-(p-fluorophenyl)-1,2,3-triazole derivative of 7-deazapurine showed selective cytostatic effect on metastatic colon cancer cells SW620. Importantly, 1-(p-chlorophenyl)-1,2,3-triazole-tagged benzimidazole displayed the most pronounced and highly selective inhibitory effect in nM range on non-small cell lung cancer A549. This compound revealed to target molecular processes at the extracellular side and inside the plasma membrane regulated by GPLD1 and growth factor receptors PDGFR and IGF-1R leading to the inhibition of cell proliferation and induction of apoptosis mediated by p38 MAP kinase and NF-κB, respectively. Further optimisation of this compound as to reduce its toxicity in normal cells may lead to the development of novel agent effective against lung cancer.
Asunto(s)
Antineoplásicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Citostáticos/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Purinas/farmacología , Bibliotecas de Moléculas Pequeñas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Carcinoma de Pulmón de Células no Pequeñas/patología , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Citostáticos/síntesis química , Citostáticos/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Neoplasias Pulmonares/patología , Modelos Moleculares , Estructura Molecular , Purinas/síntesis química , Purinas/química , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/química , Relación Estructura-Actividad , Triazoles/química , Triazoles/farmacologíaRESUMEN
The aim of this study was to investigate lipophilicity and cellular accumulation of rationally designed azithromycin and clarithromycin derivatives at the molecular level. The effect of substitution site and substituent properties on a global physico-chemical profile and cellular accumulation of investigated compounds was studied using calculated structural parameters as well as experimentally determined lipophilicity. In silico models based on the 3D structure of molecules were generated to investigate conformational effect on studied properties and to enable prediction of lipophilicity and cellular accumulation for this class of molecules based on non-empirical parameters. The applicability of developed models was explored on a validation and test sets and compared with previously developed empirical models.
Asunto(s)
Antibacterianos/química , Antibacterianos/farmacocinética , Azitromicina/análogos & derivados , Azitromicina/farmacocinética , Claritromicina/análogos & derivados , Claritromicina/farmacocinética , Humanos , Modelos Biológicos , Modelos Químicos , Conformación Molecular , Simulación de Dinámica MolecularRESUMEN
Benzimidazo[1,2-a]quinolines and benzo[b]thieno[2,3-b]pyrido[1,2-a]benzimidazoles with amino chains on the different positions have been evaluated by 2D and 3D assays on the human breast cancer cells. Pentacyclic derivatives were synthesized by microwave assisted amination to study the influence of the thiophene substructure on antitumor activity in comparison to tetracyclic analogues. The results obtained from 2D assay reveals that the antitumor activity is strongly dependent on the nature and position of amino chains. Tetracyclic derivatives displayed selective activity on SK-BR-3 with the 2-amino substituted derivatives as the most active ones while pentacyclic derivatives 6-16 and 21-25 showed more pronounced activity on T-47D. The evaluation of antitumor activity in the 3D assay pointed out that some of the tetracyclic and pentacyclic amino substituted derivatives showed selective activity on the MDA-MB-231 cell line. Influence of physico-chemical properties of the compounds on antiproliferative activity have been investigated by multivariate statistical methods. As a measure of lipophilicity, experimental Chrom LogD values have been determined and number of structural parameters have been calculated for investigated compounds. Main factors contributing to the antiproliferative effect for both 2D and 3D cell cultures are found to be basicity, lipophilicity, molecular weight and number of H-bond donors.
Asunto(s)
Bencimidazoles/farmacología , Bencimidazoles/síntesis química , Bencimidazoles/química , Ácidos Carboxílicos/química , Técnicas de Cultivo de Célula , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Simulación por Computador , Doxorrubicina/química , Doxorrubicina/farmacología , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Análisis Multivariante , Piridonas/química , Relación Estructura-ActividadRESUMEN
Macrolones are a new class of antimicrobial compounds consisting of a macrolide scaffold linked to a 4-quinolone-3-carboxylic acid moiety via C(4â³) position of a macrolide. As macrolides are known to possess favorable pharmacokinetic properties by accumulating in inflammatory cells, in this study we determined the intensity of accumulation in human polymorphonuclear leukocytes (PMNs) of 57 compounds of the macrolone class and analyzed the relationship between the molecular structure and this cellular pharmacokinetic property. Accumulation of macrolones ranged from 0 to 5.5-fold higher than the standard macrolide azithromycin. Distinct structural features in all three considered molecule parts: the macrolide scaffold, quinolone moiety and the linker, affect cellular accumulation. Interestingly, while the parent macrolide, azithromycin, accumulates approximately 3-fold more than clarithromycin, among macrolones all clarithromycin derivatives accumulated in PMNs significantly more than their azithromycin counterparts. Modeling cellular accumulation of macrolones with simple molecular descriptors, as well as with the measured octanol-water distribution coefficient, revealed that the number of hydrogen bond donors and secondary amide groups negatively contribute to macrolone accumulation, while lipophilicity makes a positive contribution.
Asunto(s)
Antibacterianos/química , Antibacterianos/farmacología , Macrólidos/química , Macrólidos/farmacología , Neutrófilos/metabolismo , Células Cultivadas , Humanos , Relación Estructura-ActividadRESUMEN
Macrolide antibiotics, like erythromycin, clarithromycin, and azithromycin, possess anti-inflammatory properties. These properties are considered fundamental to the efficacy of these three macrolides in the treatment of chronic inflammatory diseases like diffuse panbronchiolitis and cystic fibrosis. However, long-term treatment with macrolide antibiotics presents a considerable risk for promotion of bacterial resistance. We have examined antibacterial and anti-inflammatory effects of a novel macrolide class: N'-substituted 2'-O,3'-N-carbonimidoyl bridged erythromycin-derived 14- and 15-membered macrolides. A small focused library was prepared, and compounds without antimicrobial activity, which inhibited IL-6 production, were selected. Data analysis led to a statistical model that could be used for the design of novel anti-inflammatory macrolides. The most promising compound from this library retained the anti-inflammatory activity observed with azithromycin in lipopolysaccharide-induced pulmonary neutrophilia in vivo. Importantly, this study strongly suggests that antimicrobial and anti-inflammatory activities of macrolides are independent and can be separated, which raises development plausibility of novel anti-inflammatory therapeutics.
Asunto(s)
Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Eritromicina/análogos & derivados , Interleucina-6/antagonistas & inhibidores , Macrólidos/química , Macrólidos/farmacología , Animales , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Antiinflamatorios no Esteroideos/síntesis química , Azitromicina/farmacología , Azitromicina/uso terapéutico , Bronquiolitis/tratamiento farmacológico , Líquido del Lavado Bronquioalveolar/inmunología , Línea Celular , Claritromicina/farmacología , Claritromicina/uso terapéutico , Fibrosis Quística/tratamiento farmacológico , Interacciones Farmacológicas/inmunología , Farmacorresistencia Bacteriana/inmunología , Eritromicina/farmacología , Eritromicina/uso terapéutico , Infecciones por Haemophilus/tratamiento farmacológico , Haemophilus influenzae/efectos de los fármacos , Humanos , Lipopolisacáridos/administración & dosificación , Lipopolisacáridos/efectos adversos , Pulmón/inmunología , Macrólidos/síntesis química , Masculino , Ratones , Ratones Endogámicos BALB C , Pruebas de Sensibilidad Microbiana , Moraxella catarrhalis/efectos de los fármacos , Neutrófilos/inmunología , Ratas , Ratas Sprague-Dawley , Streptococcus/efectos de los fármacosRESUMEN
Macrolides are stereospecific macrolactones of high molecular weights. Herein, 600 mostly semisynthetic macrolides are compared with 50,000 small non-macrolide synthetic molecules in terms of measured physicochemical properties in order to assess the drug-likeness and developability chances of macrolides. The pre-selected set of diverse macrolides is comprised mostly of derivatives of clarithromycin and azithromycin cores. Lipophilicity (CHI logD), affinity for immobilized artificial membranes (CHI IAM), human serum albumin (HSA) and α(1)-acid glycoprotein (AGP) plasma protein bindings (PPB), DMSO precipitative solubility as well as artificial membrane permeability (AMP) have been determined by high-throughput screening methods. It has been found that macrolides and small molecules have similar lipophilicity profiles, though macrolides show weaker PPB and have better solubility than small discovery molecules. However, macrolides are poorly permeable and have high affinity for immobilized artificial membranes signifying their strong interaction with biological phospholipids. In order to retain the drug-like profile, the design of novel macrolide molecules should be focused on optimisation of macrolide cores, that is macrolactone moiety with sugars and other small substituents avoiding large substituents and flexible linkers such as in conjugate derivatives.
Asunto(s)
Fenómenos Químicos , Macrólidos/química , Macrólidos/metabolismo , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/metabolismo , Dimetilsulfóxido/química , Humanos , Enlace de Hidrógeno , Interacciones Hidrofóbicas e Hidrofílicas , Orosomucoide/metabolismo , Permeabilidad , Albúmina Sérica/metabolismo , SolubilidadRESUMEN
A set of novel macrolones containing the flexible C8 basic linker and quinolone 3-(2'-hydroxyethyl)carboxamido group has been prepared and structurally characterized by NMR and IR spectroscopy, mass spectrometry and molecular modeling. The new compounds were evaluated in vitro against a panel of erythromycin-susceptible and erythromycin-resistant Gram-positive and Gram-negative bacterial strains. Compared to azithromycin, most of the compounds exhibited improved in vitro potency against the key respiratory pathogens.
Asunto(s)
Antibacterianos/síntesis química , Azitromicina/análogos & derivados , Macrólidos/síntesis química , Quinolonas/síntesis química , Antibacterianos/química , Azitromicina/síntesis química , Humanos , Macrólidos/química , Espectroscopía de Resonancia Magnética , Pruebas de Sensibilidad Microbiana , Quinolonas/química , Relación Estructura-ActividadRESUMEN
Some macrolide antibiotics were reported to inhibit interleukin-6 (IL6) and prostaglandin-E2 (PGE(2)) production by bacterial lipopolysaccharide (LPS) stimulated J774A.1 cells. Macrolides are also known to accumulate in cells and some were proven inducers of phospholipidosis. In the present study, with a set of 18 mainly 14- and 15-membered macrolides, we have investigated whether these macrolide induced phenomena in J774A.1 cells are connected. In LPS-stimulated J774A.1 cells, the extent of inhibition of proinflammatory markers (IL6 and PGE(2)) by macrolides significantly correlated with their extent of accumulation in cells, as well as with the induction of phospholipidosis, and cytotoxic effects in prolonged culture (with correlation coefficients (R) ranging from 0.78 to 0.93). The effects observed were related to macrolide binding to phospholipids (CHI IAM), number of positively charged centres, and were inversely proportional to the number of hydrogen bond donors. Similar interdependence of effects was obtained with chloroquine and amiodarone, whereas for dexamethasone and indomethacin these effects were not linked. The observed macrolide induced phenomena in J774A.1 cells were reversible and elimination of the macrolides from the culture media prevented phospholipidosis and the development of cytotoxicity in long-term cultures. Based on comparison with known clinical data, we conclude that LPS-stimulated J774A.1 cells in presented experimental setup are not a representative cellular model for the evaluation of macrolide anti-inflammatory potential in clinical trials. Nevertheless, our study shows that, at least in in vitro models, binding to biological membranes may be the crucial factor of macrolide mechanism of action.
Asunto(s)
Antibacterianos/inmunología , Antiinflamatorios/inmunología , Macrólidos/inmunología , Fosfolípidos/metabolismo , Animales , Antibacterianos/farmacocinética , Antibacterianos/farmacología , Antiinflamatorios/farmacocinética , Antiinflamatorios/farmacología , Sitios de Unión , Línea Celular , Permeabilidad de la Membrana Celular , Supervivencia Celular/efectos de los fármacos , Dinoprostona/inmunología , Interleucina-6/inmunología , Lipopolisacáridos/inmunología , Macrólidos/farmacocinética , Macrólidos/farmacología , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/metabolismo , RatonesRESUMEN
Macrolides with 14- and 15-membered ring are characterized by high and extensive tissue distribution, as well as good cellular accumulation and retention. Since macrolide structures do not fit the Lipinski rule of five, macrolide pharmacokinetic properties cannot be successfully predicted by common models based on data for small molecules. Here we describe the development of the first models for macrolide cellular pharmacokinetics. By comparison of cellular accumulation and retention in six human primary cell cultures of leukocytic and lung origin, as well as in lung carcinoma cell line NCI-H292, this cell line was found to be an adequate representative cell type for modeling macrolide cellular pharmacokinetics. Accumulation and retention in the NCI-H292 cells, as well as various physicochemical properties, were determined for a set of 48 rationally designed basic macrolide compounds. Classification models for predicting macrolide cellular accumulation and retention were developed using relatively easily determined and conceptually simple descriptors: experimentally determined physicochemical parameters ChromlogD and CHI IAM, as well as a calculated number of positively charged atoms (POS). The models were further tested and improved by addition of 37 structurally diverse macrolide molecules.
Asunto(s)
Macrólidos/farmacocinética , Modelos Biológicos , Línea Celular Tumoral , Fenómenos Químicos , Humanos , Leucocitos/citología , Leucocitos/metabolismo , Pulmón/citología , Pulmón/metabolismo , Neoplasias Pulmonares , Macrólidos/química , Cultivo Primario de Células , Mucosa Respiratoria/citología , Mucosa Respiratoria/metabolismo , Relación Estructura-ActividadRESUMEN
A series of novel ureas and thioureas of 3-decladinosyl-3-hydroxy 15-membered azalides, were discovered, structurally characterized and biologically evaluated. They have shown good antibacterial activity against selected Gram-positive and Gram-negative bacterial strains. These include Nâ³ substituted 9a-(N'-carbamoyl-γ-aminopropyl)- (6a,c), 9a-(N'-thiocarbamoyl-γ-aminopropyl)- (7a,e), 9a-[N'-(ß-cyanoethyl)-N'-(carbamoyl-γ-aminopropyl)]- (9a-c, 9g) 9a-[N'-(ß-cyanoethyl)-N'-(thiocarbamoyl-γ-aminopropyl)]-derivatives (10d-f) of 5-O-desosaminyl-9-deoxo-9-dihydro-9a-aza-9a-homoerythronolide A (3). Among the synthesized compounds thiourea 7a and urea 9b have shown substantially improved activity comparable to azithromycin (1) and significantly better activity than the 3-decladinosyl-azithromycin (2) and the parent 3-cladinosyl analogues against efflux-mediated resistant S. pneumoniae.
Asunto(s)
Antibacterianos/química , Antibacterianos/farmacología , Streptococcus pneumoniae/efectos de los fármacos , Tiourea/química , Tiourea/farmacología , Urea/química , Urea/farmacología , Bacterias/efectos de los fármacos , Infecciones Bacterianas/tratamiento farmacológico , Farmacorresistencia Bacteriana , Humanos , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Infecciones Neumocócicas/tratamiento farmacológicoRESUMEN
Tyrosine phosphorylation represents a unique signaling process that controls metabolic pathways, cell activation, growth and differentiation, membrane transport, apoptosis, neural, and other functions. We present here the three-dimensional structure of Fyn tyrosine kinase, a Src-family enzyme involved in T-cell receptor signal transduction. The structure of Fyn was modeled for homology using the Sybyl-Composer suite of programs for modeling. Procheck and Prosa II programs showed the high quality of the obtained three-dimensional model. Rosmarinic acid, a secondary metabolite of herbal plants, was discovered as a new Fyn kinase inhibitor using immunochemical and in silico methods. Two possible binding modes of rosmarinic acid were evaluated here, i.e., near to or in the ATP-binding site of kinase domain of Fyn. Enzyme kinetic experiments revealed that Fyn is inhibited by a linear-mixed noncompetitive mechanism of inhibition by rosmarinic acid. This indicates that rosmarinic acid binds to the second "non-ATP" binding site of the Fyn tyrosine kinase.
Asunto(s)
Cinamatos/química , Depsidos/química , Proteínas Proto-Oncogénicas c-fyn/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-fyn/química , Secuencia de Aminoácidos , Sitios de Unión , Humanos , Cinética , Modelos Moleculares , Datos de Secuencia Molecular , Unión Proteica , Conformación Proteica , Homología de Secuencia de Aminoácido , Ácido RosmarínicoRESUMEN
The three-dimensional structures of oleandomycin (1) and its derivatives oleandomycin-9-oxime (2) and 10,11-anhydrooleandomycin (3) were determined in different solvents by the combined use of NMR and molecular modeling methods. The experimental NMR data were compared with the results of molecular modeling and known crystal structures of the related molecules. It was shown that the dominant conformation of the lactone ring is the folded-out conformation with some amounts of the folded-in one depending on the solvent and temperature, while desosamine and cladinose sugars adopt the usual chair conformations. Modeling calculations provided evidence for conformational changes in the upper lactone region as well. Saturation transfer difference (STD) NMR experiments have provided information on the binding epitopes of 1-3 in complexes with E. coli ribosomes. The obtained molecular surfaces in close contact with ribosomes were compared with recently available 3D structures of the related macrolide-ribosome complexes, and the observed differences were discussed. The knowledge gained from this study can serve as a platform for the design of novel macrolides with an improved biological profile.
Asunto(s)
Macrólidos/farmacocinética , Espectroscopía de Resonancia Magnética/métodos , Oleandomicina/análogos & derivados , Ribosomas/metabolismo , Antibacterianos , Sitios de Unión , Macrólidos/química , Modelos Moleculares , Conformación Molecular , Oleandomicina/química , Oleandomicina/farmacocinética , SolventesRESUMEN
In this Article we present enthalpies of fusion and melting points obtained from new thermochemical measurements of tris(acetylacetonato)metal(III), M(acac)(3), complexes (M = Fe, Al, Cr, Mn, Co) using differential scanning calorimetry (DSC) and evaluate them in relation to their different values found in the literature. An enthalpy of fusion of 27.67 kJ mol(-)(1) was derived for Mn(acac)(3) from a symmetrical DSC thermogram captured for the first time. The enthalpy value was indirectly confirmed with the solubility measurements of Mn(acac)(3) in acetylacetone. A hypothesis has been stated that the enthalpy of fusion and the potential energy of M(acac)(3) in the crystal state may be related. To calculate molecular in-crystal potential energy, in this Article we proposed a molecular mechanics model for the M(acac)(3) class of compounds. Nine X-ray crystal structures of M(acac)(3) complexes (M = Fe, Al, V, Mn, Co, Cr, Sc) were included in the modeling. The conformational potential energy was minimized for a molecule surrounded by other molecules in the crystal lattice. The partial charges from two schemes, the electrostatic potential (ESP) fit and the natural population analysis (NPA), were used to construct two types of force fields to examine which force field type would yield a better fit with the experimental thermal properties. The final force fields were named FF-ESP and FF-NPA. Both force field sets reproduced well the experimental crystal data of nine M(acac)(3) complexes as well as of tris(3-methyl-2,4-pentanedionato-O,O')cobalt(III). Only in-crystal potential energies derived by FF-NPA yielded a significant correlation (correlation coefficient R = -0.71) with the measured enthalpies of fusion. The enthalpy of fusion for Co(acac)(3) could not be determined experimentally because of simultaneous decomposition and fusion, and it is predicted to be 33.2 kJ mol(-)(1) from the correlation regression line.