RESUMEN
As part of Drugs for Neglected Diseases initiative's lead optimization program for the development of new chemical entities to treat visceral leishmaniasis (VL), a series of aminothiazoles were synthesized and screened for in vitro efficacy, solubility and microsomal stability. The primary aim of identifying a lead structure with sub-micromolar activity was achieved. Out of 43 compounds synthesized, 16 compounds showed in vitro activity at less than 1 µM against VL. Compound 32 showed excellent antileishmanial potency (IC50 = 3 nM) and had all the acceptable properties except for metabolic instability. Blocking the metabolic soft spots in compound 32, where the 4-methoxy pyridine substituent was replaced by 5-ethoxy group, led to compound 36 (IC50 = 280 nM) with improved stability. To understand the disposition of 36, in vivo pharmacokinetic study was conducted in a mouse model. Compound 36 showed high clearance (91 mL/min/kg); short half-life (0.48 h) after intravenous administration (1 mg/kg) and exposure (AUC0-24) following oral administration was 362 ng h/mL with absolute bioavailability of 8%. To summarize, 43 analogs were synthesized out of which 15 compounds showed very potent sub-nanomolar efficacy in in vitro systems but the liability of metabolic instability seemed to be the major challenge for this chemical class and remains to be addressed.
Asunto(s)
Antiprotozoarios/farmacología , Leishmania donovani/efectos de los fármacos , Leishmaniasis/tratamiento farmacológico , Tiazoles/farmacología , Administración Oral , Animales , Antiprotozoarios/administración & dosificación , Antiprotozoarios/química , Línea Celular , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Células KB , Leishmaniasis/parasitología , Masculino , Ratones , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Relación Estructura-Actividad , Tiazoles/administración & dosificación , Tiazoles/químicaRESUMEN
An analogous library of 2-substituted quinoline compounds was synthesized with the aim to identify a potential drug candidate to treat visceral leishmaniasis. These molecules were tested for their in vitro and in vivo biological activity against Leishmania donovani. Metabolic stability of these compounds was also improved through the introduction of halogen substituents. Compound (26g), found to be the most active; exhibited an IC50 value of 0.2 µM and >180 fold selectivity. The hydrochloride salt of (26g) showed 84.26 ± 4.44 percent inhibition at 50 mg/kg × 5 days (twice daily, oral route) dose in L. donovani/hamster model. The efficacy was well correlated with the PK data observed which indicating that the compound is well distributed.
Asunto(s)
Antiprotozoarios/farmacología , Diseño de Fármacos , Leishmania donovani/efectos de los fármacos , Leishmaniasis Visceral/tratamiento farmacológico , Quinolinas/farmacología , Animales , Antiprotozoarios/administración & dosificación , Antiprotozoarios/síntesis química , Línea Celular , Cricetinae , Modelos Animales de Enfermedad , Leishmaniasis Visceral/parasitología , Macrófagos/efectos de los fármacos , Macrófagos/parasitología , Masculino , Ratones , Pruebas de Sensibilidad Parasitaria , Quinolinas/administración & dosificación , Quinolinas/síntesis químicaRESUMEN
Treatment of 1,6-anhydrosugars with commercially available bis(trimethylsilyl) sulfide in the presence of trimethylsilyl triflate led to the formation of α-glycosyl thiols. All the reactions were highly stereoselective and afforded the α-glycosyl thiols in good to excellent yields. By this procedure, a variety of 1,6-anhydrosugars, differing in their sugar units, glycosidic linkages, and protecting group pattern, were converted smoothly into the corresponding α-glycosyl thiols, which could be of great utility in thioglycoside chemistry. It is noteworthy that 1,6-anhydrosugars carrying the 2-O-acyl group and 1,6-anhydrosugar-containing oligosaccharides could also be ring-opened stereospecifically under the same conditions to give rise to the corresponding 1-thiosugars in high yields. Thus, a very concise and efficient access to α-glycosyl thiols of great value was established.
Asunto(s)
Biomimética/métodos , Glicósidos/síntesis química , Compuestos de Sulfhidrilo/síntesis química , Conformación de Carbohidratos , Técnicas de Química Sintética , Espectroscopía de Resonancia Magnética , Oligosacáridos/química , Estereoisomerismo , Compuestos de Trimetilsililo/químicaRESUMEN
The acid-catalyzed reaction of 1,2-anhydro-3,4,6-tri-O-benzyl-α-d-glucopyranose (7) as glycosyl donor with bis-trimethylsilyl sulfide as acceptor affords the α-thiol. Hence, this sterically hindered S-nucleophile as acceptor should provide with O-glycosyl trichloroacetimidates as glycosyl donors that have nonparticipating groups at C-2, glycosylthiols with the thiol group in axial position. This was confirmed for various donors (4, 16-19) with the exception of the corresponding mannosyl donor (20). However, powerful participating groups at C-2 of the donor (23-28) governed the anomeric selectivity.
Asunto(s)
Compuestos de Sulfhidrilo/síntesis química , Compuestos de Sulfhidrilo/farmacologíaRESUMEN
Acid-base catalyzed glycosyl donor and then glycosyl acceptor activation with phenylboron difluoride or diphenylboron fluoride permits hydrogen bond mediated intramolecular S(N)2-type glycosidation in generally high anomeric selectivity.
Asunto(s)
Glicósidos/síntesis química , Catálisis , Glicósidos/química , Enlace de Hidrógeno , Estructura MolecularRESUMEN
Activation of CD1d-restricted invariant NKT (iNKT) cells with the glycolipid α-galactosylceramide (α-GalCer) confers protection against disease in murine models, however, clinical trials in humans have had limited impact. We synthesized a novel thioglycoside analogue of α-GalCer, denoted α-S-GalCer, and tested its efficacy for stimulating human iNKT cells in vitro. α-S-GalCer stimulated cytokine release by iNKT cells in a CD1d-dependent manner and primed CD1d(+) target cells for lysis. α-S-GalCer-stimulated iNKT cells induced maturation of monocyte-derived dendritic cells into antigen-presenting cells that released IL-12 and small amounts of IL-10. The nature and potency of α-S-GalCer and α-GalCer in human iNKT cell activation were similar. However, in contrast to α-GalCer, α-S-GalCer did not activate murine iNKT cells in vivo. Because of its enhanced stability in biological systems, α-S-GalCer may be superior to α-GalCer as a parent compound for developing adjuvant therapies for humans.
Asunto(s)
Galactosilceramidas/inmunología , Activación de Linfocitos/inmunología , Células T Asesinas Naturales/inmunología , Tiogalactósidos/inmunología , Tioglicósidos/inmunología , Animales , Células Presentadoras de Antígenos/inmunología , Células Presentadoras de Antígenos/metabolismo , Antígenos CD1d/inmunología , Línea Celular , Células Cultivadas , Citotoxicidad Inmunológica/efectos de los fármacos , Citotoxicidad Inmunológica/inmunología , Células Dendríticas/efectos de los fármacos , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Galactosilceramidas/química , Galactosilceramidas/farmacología , Células HeLa , Humanos , Interferón gamma/sangre , Interferón gamma/inmunología , Interferón gamma/metabolismo , Interleucina-10/inmunología , Interleucina-10/metabolismo , Interleucina-12/inmunología , Interleucina-12/metabolismo , Interleucina-4/sangre , Interleucina-4/inmunología , Interleucina-4/metabolismo , Activación de Linfocitos/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Estructura Molecular , Células T Asesinas Naturales/efectos de los fármacos , Células T Asesinas Naturales/metabolismo , Tiogalactósidos/química , Tiogalactósidos/farmacología , Tioglicósidos/química , Tioglicósidos/farmacologíaRESUMEN
The first total synthesis of a thioglycoside analogue of KRN7000, a potential immunostimulant, is described. Two key intermediates are alpha-galactosyl thiol 4 and phytosphingosine derivative 5, which were both prepared from D-galactose.
Asunto(s)
Adyuvantes Inmunológicos/síntesis química , Galactosilceramidas/síntesis química , Tioglicósidos/química , Adyuvantes Inmunológicos/química , Galactosa/química , Galactosilceramidas/química , Estructura Molecular , Compuestos de Sulfhidrilo/químicaRESUMEN
The glycosylation of 3,5-O-di-tert-butylsilylene-protected d-thioarabinofuranosides with a range of glycosyl acceptors using NIS/AgOTf as promoters proceeded in a stereoselective manner to give the corresponding beta-D-arabinofuranosides in high yields.
Asunto(s)
Arabinosa/síntesis química , Arabinosa/química , Secuencia de Carbohidratos , Glicosilación , Estereoisomerismo , Especificidad por SustratoRESUMEN
A new simple method for the synthesis of alpha-glycosyl thiols is described. Ring-opening of 1,6-anhydrosugars with commercially available bis(trimethylsilyl)sulfide under the action of catalytic amounts of TMSOTf smoothly afforded alpha-glycosyl thiols in very high yields and in a stereospecific way.