Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 29
Filtrar
1.
Eur J Med Chem ; 269: 116292, 2024 Apr 05.
Artículo en Inglés | MEDLINE | ID: mdl-38479168

RESUMEN

Selective inhibitors of DYRK1A are of interest for the treatment of cancer, Type 2 diabetes and neurological disorders. Optimization of imidazo [1,2-b]pyridazine fragment 1 through structure-activity relationship exploration and in silico drug design efforts led to the discovery of compound 17 as a potent cellular inhibitor of DYRK1A with selectivity over much of the kinome. The binding mode of compound 17 was elucidated with X-ray crystallography, facilitating the rational design of compound 29, an imidazo [1,2-b]pyridazine with improved kinase selectivity with respect to closely related CLK kinases.


Asunto(s)
Diabetes Mellitus Tipo 2 , Yohexol/análogos & derivados , Piridazinas , Humanos , Quinasas DyrK , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/química , Relación Estructura-Actividad , Piridazinas/química
2.
Sci Adv ; 7(16)2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33853786

RESUMEN

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) macrodomain within the nonstructural protein 3 counteracts host-mediated antiviral adenosine diphosphate-ribosylation signaling. This enzyme is a promising antiviral target because catalytic mutations render viruses nonpathogenic. Here, we report a massive crystallographic screening and computational docking effort, identifying new chemical matter primarily targeting the active site of the macrodomain. Crystallographic screening of 2533 diverse fragments resulted in 214 unique macrodomain-binders. An additional 60 molecules were selected from docking more than 20 million fragments, of which 20 were crystallographically confirmed. X-ray data collection to ultra-high resolution and at physiological temperature enabled assessment of the conformational heterogeneity around the active site. Several fragment hits were confirmed by solution binding using three biophysical techniques (differential scanning fluorimetry, homogeneous time-resolved fluorescence, and isothermal titration calorimetry). The 234 fragment structures explore a wide range of chemotypes and provide starting points for development of potent SARS-CoV-2 macrodomain inhibitors.


Asunto(s)
Dominio Catalítico/fisiología , Unión Proteica/fisiología , Proteínas no Estructurales Virales/metabolismo , Dominio Catalítico/genética , Cristalografía por Rayos X , Humanos , Modelos Moleculares , Simulación del Acoplamiento Molecular , Conformación Proteica , SARS-CoV-2/genética , SARS-CoV-2/fisiología , Proteínas no Estructurales Virales/genética , Tratamiento Farmacológico de COVID-19
3.
bioRxiv ; 2020 Nov 24.
Artículo en Inglés | MEDLINE | ID: mdl-33269349

RESUMEN

The SARS-CoV-2 macrodomain (Mac1) within the non-structural protein 3 (Nsp3) counteracts host-mediated antiviral ADP-ribosylation signalling. This enzyme is a promising antiviral target because catalytic mutations render viruses non-pathogenic. Here, we report a massive crystallographic screening and computational docking effort, identifying new chemical matter primarily targeting the active site of the macrodomain. Crystallographic screening of diverse fragment libraries resulted in 214 unique macrodomain-binding fragments, out of 2,683 screened. An additional 60 molecules were selected from docking over 20 million fragments, of which 20 were crystallographically confirmed. X-ray data collection to ultra-high resolution and at physiological temperature enabled assessment of the conformational heterogeneity around the active site. Several crystallographic and docking fragment hits were validated for solution binding using three biophysical techniques (DSF, HTRF, ITC). Overall, the 234 fragment structures presented explore a wide range of chemotypes and provide starting points for development of potent SARS-CoV-2 macrodomain inhibitors.

4.
ChemMedChem ; 15(13): 1200-1215, 2020 07 03.
Artículo en Inglés | MEDLINE | ID: mdl-32358915

RESUMEN

Water networks within kinase inhibitor design and more widely within drug discovery are generally poorly understood. The successful targeting of these networks prospectively has great promise for all facets of inhibitor design, including potency and selectivity for the target. Herein, we describe the design and testing of a targeted library of 4-anilinoquin(az)olines for use as inhibitors of cyclin G-associated kinase (GAK). GAK cellular target engagement assays, ATP binding-site modelling and extensive water mapping provide a clear route to access potent inhibitors for GAK and beyond.


Asunto(s)
Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Quinazolinas/farmacología , Agua/química , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Células HEK293 , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/metabolismo , Quinazolinas/síntesis química , Quinazolinas/química , Relación Estructura-Actividad
5.
ChemMedChem ; 15(1): 26-49, 2020 01 07.
Artículo en Inglés | MEDLINE | ID: mdl-31675459

RESUMEN

The 4-anilinoquinoline and 4-anilinoquinazoline ring systems have been the focus of significant efforts in prior kinase drug discovery programs, which have led to approved medicines. Broad kinome profiles of these compounds have now been assessed with the advent of advanced screening technologies. These ring systems, while originally designed for specific targets including epidermal growth factor receptor (EGFR), but actually display a number of potent collateral kinase targets, some of which have been associated with negative clinical outcomes. We have designed and synthesized a series of 4-anilinoquin(az)olines in order to better understand the structure-activity relationships of three main collateral kinase targets of quin(az)oline-based kinase inhibitors: cyclin G associated kinase (GAK), STE20-like serine/threonine-protein kinase (SLK) and serine/threonine-protein kinase 10 (STK10). This was achieved through a series of quantitative structure-activity relationship (QSAR) analysis, water mapping of the kinase ATP binding sites and extensive small-molecule X-ray structural analysis.


Asunto(s)
Compuestos de Anilina/química , Diseño de Fármacos , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Relación Estructura-Actividad Cuantitativa , Quinazolinas/química , Adenosina Trifosfato/química , Adenosina Trifosfato/metabolismo , Compuestos de Anilina/metabolismo , Sitios de Unión , Dominio Catalítico , Cristalografía por Rayos X , Humanos , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Cinética , Conformación Molecular , Simulación del Acoplamiento Molecular , Unión Proteica , Inhibidores de Proteínas Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Quinazolinas/metabolismo , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/metabolismo
6.
Molecules ; 24(22)2019 Nov 06.
Artículo en Inglés | MEDLINE | ID: mdl-31698822

RESUMEN

SGC-GAK-1 (1) is a potent, selective, cell-active chemical probe for cyclin G-associated kinase (GAK). However, 1 was rapidly metabolized in mouse liver microsomes by cytochrome P450-mediated oxidation, displaying rapid clearance in liver microsomes and in mice, which limited its utility in in vivo studies. Chemical modifications of 1 that improved metabolic stability, generally resulted in decreased GAK potency. The best analog in terms of GAK activity in cells was 6-bromo-N-(1H-indazol-6-yl)quinolin-4-amine (35) (IC50 = 1.4 µM), showing improved stability in liver microsomes while still maintaining a narrow spectrum activity across the kinome. As an alternative to scaffold modifications we also explored the use of the broad-spectrum cytochrome P450 inhibitor 1-aminobenzotriazole (ABT) to decrease intrinsic clearance of aminoquinoline GAK inhibitors. Taken together, these approaches point towards the development of an in vivo chemical probe for the dark kinase GAK.


Asunto(s)
Proteínas Quinasas Dependientes de GMP Cíclico/química , Análisis por Conglomerados , Proteínas Quinasas Dependientes de GMP Cíclico/antagonistas & inhibidores , Modelos Moleculares , Estructura Molecular , Conformación Proteica , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Relación Estructura-Actividad
7.
J Org Chem ; 84(21): 14187-14201, 2019 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-31460764

RESUMEN

A one-pot and modular approach to the synthesis of 2,4(5)-disubstituted imidazoles was developed based on ketone oxidation, employing catalytic HBr and DMSO, followed by imidazole condensation with aldehydes. This methodology afforded twenty-nine disubstituted NH-imidazoles (23%-85% yield). A three-step synthesis of 20 kinase inhibitors was achieved by employing this oxidation-condensation protocol, followed by bromination and Suzuki coupling in the imidazole ring to yield trisubstituted NH-imidazoles (23%-69%, three steps). This approach was also employed in the synthesis of known inhibitor GSK3037619A.


Asunto(s)
Aldehídos/química , Imidazoles/química , Imidazoles/síntesis química , Cetonas/química , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/síntesis química , Oxidación-Reducción
8.
Eur J Med Chem ; 177: 316-337, 2019 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-31158747

RESUMEN

Residues in the histone substrate binding sites that differ between the KDM4 and KDM5 subfamilies were identified. Subsequently, a C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one series was designed to rationally exploit these residue differences between the histone substrate binding sites in order to improve affinity for the KDM4-subfamily over KDM5-subfamily enzymes. In particular, residues E169 and V313 (KDM4A numbering) were targeted. Additionally, conformational restriction of the flexible pyridopyrimidinone C8-substituent was investigated. These approaches yielded potent and cell-penetrant dual KDM4/5-subfamily inhibitors including 19a (KDM4A and KDM5B Ki = 0.004 and 0.007 µM, respectively). Compound cellular profiling in two orthogonal target engagement assays revealed a significant reduction from biochemical to cell-based activity across multiple analogues; this decrease was shown to be consistent with 2OG competition, and suggests that sub-nanomolar biochemical potency will be required with C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one compounds to achieve sub-micromolar target inhibition in cells.


Asunto(s)
Inhibidores Enzimáticos/farmacología , Histona Demetilasas con Dominio de Jumonji/antagonistas & inhibidores , Piridinas/farmacología , Pirimidinonas/farmacología , Línea Celular Tumoral , Cristalografía por Rayos X , Ensayos de Selección de Medicamentos Antitumorales/métodos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Histona Demetilasas con Dominio de Jumonji/química , Histona Demetilasas con Dominio de Jumonji/metabolismo , Estructura Molecular , Unión Proteica , Piridinas/síntesis química , Piridinas/química , Piridinas/metabolismo , Pirimidinonas/síntesis química , Pirimidinonas/química , Pirimidinonas/metabolismo , Relación Estructura-Actividad
9.
J Med Chem ; 62(5): 2830-2836, 2019 03 14.
Artículo en Inglés | MEDLINE | ID: mdl-30768268

RESUMEN

We describe SGC-GAK-1 (11), a potent, selective, and cell-active inhibitor of cyclin G-associated kinase (GAK), together with a structurally related negative control SGC-GAK-1N (14). 11 was highly selective in an in vitro kinome-wide screen, but cellular engagement assays defined RIPK2 as a collateral target. We identified 18 as a potent RIPK2 inhibitor lacking GAK activity. Together, this chemical probe set can be used to interrogate GAK cellular biology.


Asunto(s)
Ciclina G/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Sondas Moleculares/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Células HEK293 , Humanos , Masculino
10.
Cell Rep ; 26(1): 79-93.e8, 2019 01 02.
Artículo en Inglés | MEDLINE | ID: mdl-30605688

RESUMEN

ß-Catenin-dependent WNT signal transduction governs development, tissue homeostasis, and a vast array of human diseases. Signal propagation through a WNT-Frizzled/LRP receptor complex requires proteins necessary for clathrin-mediated endocytosis (CME). Paradoxically, CME also negatively regulates WNT signaling through internalization and degradation of the receptor complex. Here, using a gain-of-function screen of the human kinome, we report that the AP2 associated kinase 1 (AAK1), a known CME enhancer, inhibits WNT signaling. Reciprocally, AAK1 genetic silencing or its pharmacological inhibition using a potent and selective inhibitor activates WNT signaling. Mechanistically, we show that AAK1 promotes clearance of LRP6 from the plasma membrane to suppress the WNT pathway. Time-course experiments support a transcription-uncoupled, WNT-driven negative feedback loop; prolonged WNT treatment drives AAK1-dependent phosphorylation of AP2M1, clathrin-coated pit maturation, and endocytosis of LRP6. We propose that, following WNT receptor activation, increased AAK1 function and CME limits WNT signaling longevity.


Asunto(s)
Clatrina/metabolismo , Endocitosis/fisiología , Proteína-6 Relacionada a Receptor de Lipoproteína de Baja Densidad/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Wnt/metabolismo , Vía de Señalización Wnt/fisiología , Animales , Retroalimentación Fisiológica , Células HEK293 , Humanos , Masculino , Ratones , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores
11.
Org Biomol Chem ; 16(2): 336, 2018 01 03.
Artículo en Inglés | MEDLINE | ID: mdl-29256564

RESUMEN

Correction for 'Synthesis of kinase inhibitors containing a pentafluorosulfanyl moiety' by Supojjanee Sansook et al., Org. Biomol. Chem., 2017, 15, 8655-8660.

12.
ChemMedChem ; 13(1): 48-66, 2018 01 08.
Artículo en Inglés | MEDLINE | ID: mdl-29072804

RESUMEN

4-Anilinoquinolines were identified as potent and narrow-spectrum inhibitors of the cyclin G associated kinase (GAK), an important regulator of viral and bacterial entry into host cells. Optimization of the 4-anilino group and the 6,7-quinoline substituents produced GAK inhibitors with nanomolar activity, over 50 000-fold selectivity relative to other members of the numb-associated kinase (NAK) subfamily, and a compound (6,7-dimethoxy-N-(3,4,5-trimethoxyphenyl)quinolin-4-amine; 49) with a narrow-spectrum kinome profile. These compounds may be useful tools to explore the therapeutic potential of GAK in prevention of a broad range of infectious and systemic diseases.


Asunto(s)
Compuestos de Anilina/química , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/metabolismo , Quinazolinas/química , Compuestos de Anilina/metabolismo , Compuestos de Anilina/farmacología , Sitios de Unión , Dominio Catalítico , Diseño de Fármacos , Endocitosis/efectos de los fármacos , Humanos , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Cinética , Simulación del Acoplamiento Molecular , Unión Proteica , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Quinazolinas/metabolismo , Quinazolinas/farmacología , Relación Estructura-Actividad , Virus/patogenicidad
13.
Org Biomol Chem ; 15(40): 8655-8660, 2017 Oct 18.
Artículo en Inglés | MEDLINE | ID: mdl-28984325

RESUMEN

A series of 3-methylidene-1H-indol-2(3H)-ones substituted with a 5- or 6-pentafluorosulfanyl group has been synthesized by a Knoevenagel condensation reaction of SF5-substituted oxindoles with a range of aldehydes. The resulting products were characterized by X-ray crystallography studies and were tested for biological activity versus a panel of cell lines and protein kinases. Some exhibited single digit nM activity.


Asunto(s)
Fluoruros/farmacología , Indoles/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas/metabolismo , Compuestos de Azufre/farmacología , Línea Celular , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Fluoruros/síntesis química , Fluoruros/química , Humanos , Indoles/síntesis química , Indoles/química , Modelos Moleculares , Estructura Molecular , Oxindoles , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Relación Estructura-Actividad , Compuestos de Azufre/síntesis química , Compuestos de Azufre/química
14.
ACS Chem Biol ; 12(11): 2730-2736, 2017 11 17.
Artículo en Inglés | MEDLINE | ID: mdl-29043777

RESUMEN

ATAD2 (ANCCA) is an epigenetic regulator and transcriptional cofactor, whose overexpression has been linked to the progress of various cancer types. Here, we report a DNA-encoded library screen leading to the discovery of BAY-850, a potent and isoform selective inhibitor that specifically induces ATAD2 bromodomain dimerization and prevents interactions with acetylated histones in vitro, as well as with chromatin in cells. These features qualify BAY-850 as a chemical probe to explore ATAD2 biology.


Asunto(s)
ATPasas Asociadas con Actividades Celulares Diversas/antagonistas & inhibidores , ATPasas Asociadas con Actividades Celulares Diversas/metabolismo , Proteínas de Unión al ADN/antagonistas & inhibidores , Proteínas de Unión al ADN/metabolismo , Sondas Moleculares/química , Sondas Moleculares/farmacología , Mapas de Interacción de Proteínas/efectos de los fármacos , Multimerización de Proteína/efectos de los fármacos , ATPasas Asociadas con Actividades Celulares Diversas/química , Línea Celular Tumoral , Cromatina/metabolismo , Proteínas de Unión al ADN/química , Descubrimiento de Drogas , Histonas/metabolismo , Humanos , Ligandos , Modelos Moleculares , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/química , Isoformas de Proteínas/metabolismo
15.
Angew Chem Int Ed Engl ; 56(22): 6264-6267, 2017 05 22.
Artículo en Inglés | MEDLINE | ID: mdl-28267269

RESUMEN

Described herein is the preparation of oxalyl boronate building blocks and their application for the construction of heterocycles. The oxalyl unit, readily accessible through commercially available starting materials, enables a modular approach for the synthesis of imidazoles. A variety of aromatic, heteroaromatic, and alkyl carboxaldehydes were condensed with oxalyl boronates to afford substituted boryl imidazoles in a regiocontrolled fashion. Subsequent palladium-catalyzed cross-coupling with haloarenes furnished the desired trisubstituted imidazole scaffolds. To demonstrate the utility of these scaffolds, potent inhibitors of the serine/threonine-protein kinase STK10 were synthesized.


Asunto(s)
Ácidos Borónicos/química , Imidazoles/síntesis química , Catálisis , Estructura Molecular , Paladio/química , Estereoisomerismo
16.
J Med Chem ; 59(4): 1388-409, 2016 Feb 25.
Artículo en Inglés | MEDLINE | ID: mdl-26741168

RESUMEN

We report the discovery of N-substituted 4-(pyridin-2-yl)thiazole-2-amine derivatives and their subsequent optimization, guided by structure-based design, to give 8-(1H-pyrazol-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-ones, a series of potent JmjC histone N-methyl lysine demethylase (KDM) inhibitors which bind to Fe(II) in the active site. Substitution from C4 of the pyrazole moiety allows access to the histone peptide substrate binding site; incorporation of a conformationally constrained 4-phenylpiperidine linker gives derivatives such as 54j and 54k which demonstrate equipotent activity versus the KDM4 (JMJD2) and KDM5 (JARID1) subfamily demethylases, selectivity over representative exemplars of the KDM2, KDM3, and KDM6 subfamilies, cellular permeability in the Caco-2 assay, and, for 54k, inhibition of H3K9Me3 and H3K4Me3 demethylation in a cell-based assay.


Asunto(s)
Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Histona Demetilasas con Dominio de Jumonji/antagonistas & inhibidores , Proteínas Nucleares/antagonistas & inhibidores , Pirimidinonas/química , Pirimidinonas/farmacología , Proteínas Represoras/antagonistas & inhibidores , Células CACO-2 , Permeabilidad de la Membrana Celular , Inhibidores Enzimáticos/farmacocinética , Humanos , Histona Demetilasas con Dominio de Jumonji/química , Histona Demetilasas con Dominio de Jumonji/metabolismo , Proteínas Nucleares/química , Proteínas Nucleares/metabolismo , Pirimidinonas/farmacocinética , Proteínas Represoras/química , Proteínas Represoras/metabolismo
17.
Angew Chem Int Ed Engl ; 54(21): 6217-21, 2015 May 18.
Artículo en Inglés | MEDLINE | ID: mdl-25864491

RESUMEN

The bromodomain-containing proteins BRD9 and BRD7 are part of the human SWI/SNF chromatin-remodeling complexes BAF and PBAF. To date, no selective inhibitor for BRD7/9 has been reported despite its potential value as a biological tool or as a lead for future therapeutics. The quinolone-fused lactam LP99 is now reported as the first potent and selective inhibitor of the BRD7 and BRD9 bromodomains. Development of LP99 from a fragment hit was expedited through balancing structure-based inhibitor design and biophysical characterization against tractable chemical synthesis: Complexity-building nitro-Mannich/lactamization cascade processes allowed for early structure-activity relationship studies whereas an enantioselective organocatalytic nitro-Mannich reaction enabled the synthesis of the lead scaffold in enantioenriched form and on scale. This epigenetic probe was shown to inhibit the association of BRD7 and BRD9 to acetylated histones in vitro and in cells. Moreover, LP99 was used to demonstrate that BRD7/9 plays a role in regulating pro-inflammatory cytokine secretion.


Asunto(s)
Proteínas Cromosómicas no Histona/antagonistas & inhibidores , Descubrimiento de Drogas , Lactamas/química , Lactamas/farmacología , Factores de Transcripción/antagonistas & inhibidores , Proteínas Cromosómicas no Histona/química , Proteínas Cromosómicas no Histona/metabolismo , Humanos , Modelos Moleculares , Factores de Transcripción/química , Factores de Transcripción/metabolismo
18.
Angew Chem Weinheim Bergstr Ger ; 127(21): 6315-6319, 2015 May 18.
Artículo en Inglés | MEDLINE | ID: mdl-27346896

RESUMEN

The bromodomain-containing proteins BRD9 and BRD7 are part of the human SWI/SNF chromatin-remodeling complexes BAF and PBAF. To date, no selective inhibitor for BRD7/9 has been reported despite its potential value as a biological tool or as a lead for future therapeutics. The quinolone-fused lactam LP99 is now reported as the first potent and selective inhibitor of the BRD7 and BRD9 bromodomains. Development of LP99 from a fragment hit was expedited through balancing structure-based inhibitor design and biophysical characterization against tractable chemical synthesis: Complexity-building nitro-Mannich/lactamization cascade processes allowed for early structure-activity relationship studies whereas an enantioselective organocatalytic nitro-Mannich reaction enabled the synthesis of the lead scaffold in enantioenriched form and on scale. This epigenetic probe was shown to inhibit the association of BRD7 and BRD9 to acetylated histones in vitro and in cells. Moreover, LP99 was used to demonstrate that BRD7/9 plays a role in regulating pro-inflammatory cytokine secretion.

19.
Bioorg Med Chem Lett ; 24(17): 4215-22, 2014 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-25086682

RESUMEN

A series of dual-targeting, alcohol-containing benzothiazoles has been identified with superior antibacterial activity and drug-like properties. Early lead benzothiazoles containing carboxylic acid moieties showed efficacy in a well-established in vivo model, but inferior drug-like properties demanded modifications of functionality capable of demonstrating superior efficacy. Eliminating the acid group in favor of hydrophilic alcohol moieties at C(5), as well as incorporating solubilizing groups at the C(7) position of the core ring provided potent, broad-spectrum Gram-positive antibacterial activity, lower protein binding, and markedly improved efficacy in vivo.


Asunto(s)
Antibacterianos/farmacología , Benzotiazoles/química , Benzotiazoles/farmacología , ADN Bacteriano/química , ADN Bacteriano/efectos de los fármacos , ADN Superhelicoidal/efectos de los fármacos , Haemophilus influenzae/efectos de los fármacos , Alcoholes/química , Antibacterianos/síntesis química , Antibacterianos/química , Benzotiazoles/síntesis química , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Staphylococcus , Relación Estructura-Actividad
20.
Bioorg Med Chem Lett ; 24(1): 353-9, 2014 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-24287381

RESUMEN

The design, synthesis and structure-activity relationships of a series of oxazole-benzamide inhibitors of the essential bacterial cell division protein FtsZ are described. Compounds had potent anti-staphylococcal activity and inhibited the cytokinesis of the clinically-significant bacterial pathogen Staphylococcus aureus. Selected analogues possessing a 5-halo oxazole also inhibited a strain of S. aureus harbouring the glycine-to-alanine amino acid substitution at residue 196 of FtsZ which conferred resistance to previously reported inhibitors in the series. Substitutions to the pseudo-benzylic carbon of the scaffold improved the pharmacokinetic properties by increasing metabolic stability and provided a mechanism for creating pro-drugs. Combining multiple substitutions based on the findings reported in this study has provided small-molecule inhibitors of FtsZ with enhanced in vitro and in vivo antibacterial efficacy.


Asunto(s)
Antibacterianos/farmacología , Proteínas Bacterianas/antagonistas & inhibidores , Benzamidas/farmacología , Proteínas del Citoesqueleto/antagonistas & inhibidores , Diseño de Fármacos , Oxazoles/farmacología , Staphylococcus aureus/efectos de los fármacos , Antibacterianos/síntesis química , Antibacterianos/química , Benzamidas/química , Relación Dosis-Respuesta a Droga , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Oxazoles/química , Staphylococcus aureus/química , Relación Estructura-Actividad
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA