RESUMEN
Carbon dioxide (CO2) is the major greenhouse gas and also an abundant and renewable carbon resource. Therefore, its chemical conversion and utilization are of great attraction for sustainable development. Especially, reductive conversion of CO2 with energy input has become a current hotspot due to its ability to access fuels and various important chemicals. Nowadays, the controllable CO2 hydrogenation to formic acid and alcohols using sustainable H2 resources has been regarded as an appealing solution to hydrogen storage and CO2 accumulation. In addition, photocatalytic CO2 reduction to CO also provides a potential way to utilize this greenhouse gas efficiently. Besides direct CO2 hydrogenation, CO2 reductive functionalization integrates CO2 reduction with subsequent C-X (X = N, S, C, O) bond formation and indirect transformation strategies, enlarging the diverse products derived from CO2 and promoting CO2 reductive conversion into a new stage. In this Perspective, the progress and challenges of CO2 reductive conversion, including hydrogenation, reductive functionalization, photocatalytic reduction, and photocatalytic reductive functionalization are summarized and discussed along with the key issues and future trends/directions in this field. We hope this Perspective can evoke intense interest and inspire much innovation in the promise of CO2 valorization.
RESUMEN
Invited for the cover of this issue is the group of Liang-Nian He at Nankai University. The image depicts that 2D ultrathin metal organic layers (MOLs) with bis-metallic catalytic sites make an efficient photocatalyst resulting in efficient and selective visible-light-driven CO2 reduction. Read the full text of the article at 10.1002/chem.202201767.
RESUMEN
As novel generated 2D materials, metal-organic layers (MOLs) have recently emerged as a potential platform for photocatalytic CO2 reduction reaction (PCO2 RR). Such 2D structures negate the blemish of low-density catalytic sites and low electron transmission efficiency on the surface of metal organic frameworks (MOFs), while retaining the advantage of low expenditure when using earth-abundant metal nodes and meritorious applicability in the PCO2 RR. Herein, it is reported that the 2D ultrathin layer material with bis-metallic catalytic sites (Ni-O metal node and the Ni-N metal site) from bidentate ligand 2,2'-bipyridine-5,5'-dicarboxylate (H2 bpydc) and nickel(II) remarkably boosts the visible light-driven PCO2 RR performance with a CO yield of 2400â mmol g-1 for 18â h and a selectivity up to 99 %. Consequently, the effects of morphology, catalytic sites and intrinsic properties on PCO2 RR efficiency have been investigated in detail. In this context, the ultrathin layer structure has been elucidated as the key point to facilitate electron transfer efficiency. Notably, the bis-metallic catalytic sites with reasonable distance between two adjacent metals presumably induce synergistic effect and offer a guiding ideology for further designing high performance photocatalysts.
RESUMEN
Several boron-containing small molecules have been approved by the US FDA to treat human diseases. We explored potential applications of boron-containing compounds in modern agriculture by pursuing multiple research and development programs. Here, we report a novel series of multi-substitution benzoxaboroles (1-36), a compound class that we recently reported as targeting geranylgeranyl transferase I (GGTase I) and thereby inhibiting protein prenylation (Kim et al., 2020). These compounds were designed, synthesized, and tested against the agriculturally important fungal pathogens Mycosphaerella fijiensis and Colletotrichum sublineolum in a structure-activity relationship (SAR) study. Compounds 13, 28, 30, 34 and 36 were identified as active leads with excellent antifungal MIC95 values in the range of 1.56-3.13 ppm against M. fijiensis and 0.78-3.13 ppm against C. sublineolum.
Asunto(s)
Antifúngicos/farmacología , Ascomicetos/efectos de los fármacos , Compuestos de Boro/farmacología , Colletotrichum/efectos de los fármacos , Fungicidas Industriales/farmacología , Agricultura , Transferasas Alquil y Aril/antagonistas & inhibidores , Transferasas Alquil y Aril/metabolismo , Antifúngicos/síntesis química , Antifúngicos/química , Ascomicetos/metabolismo , Compuestos de Boro/síntesis química , Compuestos de Boro/química , Colletotrichum/metabolismo , Relación Dosis-Respuesta a Droga , Fungicidas Industriales/síntesis química , Fungicidas Industriales/química , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Recent development of benzoxaborole-based chemistry gave rise to a collection of compounds with great potential in targeting diverse infectious diseases, including human African Trypanosomiasis (HAT), a devastating neglected tropical disease. However, further medicinal development is largely restricted by a lack of insight into mechanism of action (MoA) in pathogenic kinetoplastids. We adopted a multidisciplinary approach, combining a high-throughput forward genetic screen with functional group focused chemical biological, structural biology and biochemical analyses, to tackle the complex MoAs of benzoxaboroles in Trypanosoma brucei. We describe an oxidative enzymatic pathway composed of host semicarbazide-sensitive amine oxidase and a trypanosomal aldehyde dehydrogenase TbALDH3. Two sequential reactions through this pathway serve as the key underlying mechanism for activating a series of 4-aminomethylphenoxy-benzoxaboroles as potent trypanocides; the methylamine parental compounds as pro-drugs are transformed first into intermediate aldehyde metabolites, and further into the carboxylate metabolites as effective forms. Moreover, comparative biochemical and crystallographic analyses elucidated the catalytic specificity of TbALDH3 towards the benzaldehyde benzoxaborole metabolites as xenogeneic substrates. Overall, this work proposes a novel drug activation mechanism dependent on both host and parasite metabolism of primary amine containing molecules, which contributes a new perspective to our understanding of the benzoxaborole MoA, and could be further exploited to improve the therapeutic index of antimicrobial compounds.
Asunto(s)
Aldehído Deshidrogenasa/metabolismo , Amina Oxidasa (conteniendo Cobre)/metabolismo , Compuestos de Boro/metabolismo , Modelos Biológicos , Profármacos/metabolismo , Tripanocidas/metabolismo , Trypanosoma brucei brucei/enzimología , Activación Metabólica , Aldehído Deshidrogenasa/antagonistas & inhibidores , Aldehído Deshidrogenasa/química , Aldehído Deshidrogenasa/genética , Aldehído Oxidorreductasas/antagonistas & inhibidores , Aldehído Oxidorreductasas/química , Aldehído Oxidorreductasas/genética , Aldehído Oxidorreductasas/metabolismo , Amina Oxidasa (conteniendo Cobre)/antagonistas & inhibidores , Amina Oxidasa (conteniendo Cobre)/química , Amina Oxidasa (conteniendo Cobre)/genética , Sustitución de Aminoácidos , Animales , Compuestos de Boro/química , Compuestos de Boro/farmacología , Resistencia a Medicamentos , Ensayos Analíticos de Alto Rendimiento , Humanos , Estructura Molecular , Mutación , Filogenia , Profármacos/química , Profármacos/farmacología , Dominios y Motivos de Interacción de Proteínas , Interferencia de ARN , Ratas , Proteínas Recombinantes de Fusión/química , Proteínas Recombinantes de Fusión/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Relación Estructura-Actividad , Tripanocidas/química , Tripanocidas/farmacología , Trypanosoma brucei brucei/efectos de los fármacos , Trypanosoma brucei brucei/fisiologíaRESUMEN
Novel l-valinate amide benzoxaboroles and analogues were designed and synthesized for a structure-activity-relationship (SAR) investigation to optimize the growth inhibitory activity against Trypanosoma congolense (T. congolense) and Trypanosoma vivax (T. vivax) parasites. The study identified 4-fluorobenzyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-l-valinate (5, AN11736), which showed IC50 values of 0.15â¯nM against T. congolense and 1.3â¯nM against T. vivax, and demonstrated 100% efficacy with a single dose of 10â¯mg/kg against both T. congolense and T. vivax in mouse models of infection (IP dosing) and in the target animal, cattle, dosed intramuscularly. AN11736 has been advanced to early development studies.
Asunto(s)
Antiprotozoarios/síntesis química , Compuestos de Boro/síntesis química , Tripanosomiasis Africana/tratamiento farmacológico , Valina/análogos & derivados , Animales , Antiprotozoarios/farmacología , Antiprotozoarios/uso terapéutico , Compuestos de Boro/farmacología , Compuestos de Boro/uso terapéutico , Bovinos , Ratones , Relación Estructura-Actividad , Trypanosoma congolense/efectos de los fármacos , Trypanosoma vivax/efectos de los fármacos , Tripanosomiasis Africana/patología , Tripanosomiasis Africana/veterinaria , Valina/síntesis química , Valina/farmacología , Valina/uso terapéuticoRESUMEN
We identified a novel 6-benzyl ether benzoxaborole with potent activity against Mycobacterium tuberculosis The compound had an MIC of 2 µM in liquid medium. The compound was also able to prevent growth on solid medium at 0.8 µM and was active against intracellular bacteria (50% inhibitory concentration [IC50] = 3.6 µM) without cytotoxicity against eukaryotic cells (IC50 > 100 µM). We isolated resistant mutants (MIC ≥ 100 µM), which had mutations in Rv1683, Rv3068c, and Rv0047c.
Asunto(s)
Antituberculosos/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Tuberculosis Pulmonar/tratamiento farmacológico , Antituberculosos/efectos adversos , Línea Celular Tumoral , Farmacorresistencia Bacteriana/genética , Células Hep G2 , Humanos , Pruebas de Sensibilidad Microbiana , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/crecimiento & desarrollo , Tuberculosis Resistente a Múltiples Medicamentos/microbiología , Tuberculosis Pulmonar/microbiologíaRESUMEN
There is a need for new antimalarials, ideally with novel mechanisms of action. Benzoxaboroles have been shown to be active against bacteria, fungi, and trypanosomes. Therefore, we investigated the antimalarial activity and mechanism of action of 3-aminomethyl benzoxaboroles against Plasmodium falciparum Two 3-aminomethyl compounds, AN6426 and AN8432, demonstrated good potency against cultured multidrug-resistant (W2 strain) P. falciparum (50% inhibitory concentration [IC50] of 310 nM and 490 nM, respectively) and efficacy against murine Plasmodium berghei infection when administered orally once daily for 4 days (90% effective dose [ED90], 7.4 and 16.2 mg/kg of body weight, respectively). To characterize mechanisms of action, we selected parasites with decreased drug sensitivity by culturing with stepwise increases in concentration of AN6426. Resistant clones were characterized by whole-genome sequencing. Three generations of resistant parasites had polymorphisms in the predicted editing domain of the gene encoding a P. falciparum leucyl-tRNA synthetase (LeuRS; PF3D7_0622800) and in another gene (PF3D7_1218100), which encodes a protein of unknown function. Solution of the structure of the P. falciparum LeuRS editing domain suggested key roles for mutated residues in LeuRS editing. Short incubations with AN6426 and AN8432, unlike artemisinin, caused dose-dependent inhibition of [(14)C]leucine incorporation by cultured wild-type, but not resistant, parasites. The growth of resistant, but not wild-type, parasites was impaired in the presence of the unnatural amino acid norvaline, consistent with a loss of LeuRS editing activity in resistant parasites. In summary, the benzoxaboroles AN6426 and AN8432 offer effective antimalarial activity and act, at least in part, against a novel target, the editing domain of P. falciparum LeuRS.
Asunto(s)
Antimaláricos/farmacología , Leucina-ARNt Ligasa/metabolismo , Malaria Falciparum/tratamiento farmacológico , Plasmodium falciparum/efectos de los fármacos , Compuestos de Boro/farmacología , Resistencia a Medicamentos/efectos de los fármacos , Concentración 50 Inhibidora , Malaria Falciparum/parasitología , Plasmodium falciparum/metabolismoRESUMEN
Novel isoxazoline amide benzoxaboroles were designed and synthesized to optimize the ectoparasiticide activity of this chemistry series against ticks and fleas. The study identified an orally bioavailable molecule, (S)-N-((1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)methyl)-2-methyl-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzamide (23), with a favorable pharmacodynamics profile in dogs (Cmax=7.42ng/mL; Tmax=26.0h; terminal half-life t1/2=127h). Compound 23, a development candidate, demonstrated 100% therapeutic effectiveness within 24h of treatment, with residual efficacy of 97% against American dog ticks (Dermacentor variabilis) on day 30 and 98% against cat fleas (Ctenocephalides felis) on day 32 after a single oral dose at 25mg/kg in dogs.
Asunto(s)
Amidas/farmacología , Antiparasitarios/farmacología , Compuestos de Boro/farmacología , Ctenocephalides/efectos de los fármacos , Dermacentor/efectos de los fármacos , Infestaciones Ectoparasitarias/tratamiento farmacológico , Isoxazoles/farmacología , Administración Oral , Amidas/administración & dosificación , Amidas/química , Animales , Antiparasitarios/administración & dosificación , Antiparasitarios/química , Compuestos de Boro/administración & dosificación , Compuestos de Boro/química , Gatos , Perros , Relación Dosis-Respuesta a Droga , Infestaciones Ectoparasitarias/parasitología , Isoxazoles/administración & dosificación , Isoxazoles/química , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Relación Estructura-ActividadRESUMEN
A novel series of isoxazoline benzoxaborole small molecules was designed and synthesized for a structure-activity relationship (SAR) investigation to assess the ectoparasiticide activity against ticks and fleas. The study identified an orally bioavailable molecule, (S)-3,3-dimethyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-ol (38, AN8030), which was long lasting in dogs (t1/2=22 days). Compound 38 demonstrated 97.6% therapeutic effectiveness within 24 h of treatment, with residual efficacy of 95.3% against American dog ticks (Dermacentor variabilis) on day 30% and 100% against cat fleas (Ctenocephalides felis) on day 32 after a single oral dose at 50 mg/kg in dogs.
Asunto(s)
Compuestos de Boro/química , Enfermedades de los Perros/tratamiento farmacológico , Descubrimiento de Drogas , Infestaciones Ectoparasitarias/tratamiento farmacológico , Isoxazoles/síntesis química , Administración Oral , Animales , Compuestos de Boro/administración & dosificación , Compuestos de Boro/farmacología , Enfermedades de los Perros/parasitología , Perros , Isoxazoles/administración & dosificación , Isoxazoles/química , Isoxazoles/farmacología , Estructura Molecular , Relación Estructura-Actividad , Factores de TiempoRESUMEN
Designing earth-abundant metal complexes as efficient molecular photocatalysts for visible light-driven CO2 reduction is a key challenge in artificial photosynthesis. Here, we demonstrated the first example of a mononuclear iron pyridine-thiolate complex that functions both as a photosensitizer and catalyst for CO2 reduction. This single-component bifunctional molecular photocatalyst efficiently reduced CO2 to formate and CO with a total turnover number (TON) of 46 and turnover frequency (TOF) of 11.5â h-1 in 4â h under visible light irradiation. Notably, the quantum yield was determined to be 8.4 % for the generation of formate and CO at 400â nm. Quenching experiments indicate that high photocatalytic activity is mainly attributed to the rapid intramolecular quenching protocol. The mechanism investigation by DFT calculation and electrochemical studies revealed that the protonation of Febpy(pyS)2 is indispensable step for photocatalytic CO2 reduction.
RESUMEN
Gram-negative bacteria cause approximately 70% of the infections in intensive care units. A growing number of bacterial isolates responsible for these infections are resistant to currently available antibiotics and to many in development. Most agents under development are modifications of existing drug classes, which only partially overcome existing resistance mechanisms. Therefore, new classes of Gram-negative antibacterials with truly novel modes of action are needed to circumvent these existing resistance mechanisms. We have previously identified a new a way to inhibit an aminoacyl-tRNA synthetase, leucyl-tRNA synthetase (LeuRS), in fungi via the oxaborole tRNA trapping (OBORT) mechanism. Herein, we show how we have modified the OBORT mechanism using a structure-guided approach to develop a new boron-based antibiotic class, the aminomethylbenzoxaboroles, which inhibit bacterial leucyl-tRNA synthetase and have activity against Gram-negative bacteria by largely evading the main efflux mechanisms in Escherichia coli and Pseudomonas aeruginosa. The lead analogue, AN3365, is active against Gram-negative bacteria, including Enterobacteriaceae bearing NDM-1 and KPC carbapenemases, as well as P. aeruginosa. This novel boron-based antibacterial, AN3365, has good mouse pharmacokinetics and was efficacious against E. coli and P. aeruginosa in murine thigh infection models, which suggest that this novel class of antibacterials has the potential to address this unmet medical need.
Asunto(s)
Aminoacil-ARNt Sintetasas/antagonistas & inhibidores , Antibacterianos/farmacología , Compuestos de Boro/farmacología , Escherichia coli/efectos de los fármacos , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Pseudomonas aeruginosa/efectos de los fármacos , Aminoacil-ARNt Sintetasas/metabolismo , Animales , Antibacterianos/síntesis química , Antibacterianos/farmacocinética , Proteínas Bacterianas/antagonistas & inhibidores , Proteínas Bacterianas/metabolismo , Compuestos de Boro/síntesis química , Compuestos de Boro/farmacocinética , Cristalografía por Rayos X , Descubrimiento de Drogas , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Escherichia coli/enzimología , Femenino , Infecciones por Bacterias Gramnegativas/microbiología , Humanos , Leucina/metabolismo , Ratones , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Pseudomonas aeruginosa/enzimología , Relación Estructura-Actividad , Muslo/microbiología , Inhibidores de beta-Lactamasas , beta-Lactamasas/metabolismoRESUMEN
Benzoxaboroles are a novel class of drug-like compounds that have been rich sources of novel inhibitors for various enzymes and of new drugs. While examining benzoxaborole activity in phenotypic screens, our attention was attracted by the (aminomethylphenoxy)benzoxaborole family, which potently inhibited Toll-like receptor-stimulated cytokine secretion from leukocytes. After considering their structure-activity relationships and the central role of kinases in leukocyte biology, we performed a kinome-wide screen to investigate the members of the (aminomethylphenoxy)benzoxaborole family. This technique identified Rho-activated kinase (ROCK) as a target. We showed competitive behavior, with respect to ATP, and then determined the ROCK2-drug cocrystal structure. The drug occupies the ATP site in which the oxaborole moiety provides hydrogen bond donors and acceptors to the hinge, and the aminomethyl group interacts with the magnesium/ATP-interacting aspartic acid common to protein kinases. The series exhibits excellent selectivity against most of the kinome, with greater than 15-fold selectivity against the next best member of the AGC protein kinase subfamily. Medicinal chemistry efforts with structure-based design resulted in a compound with a Ki of 170 nM. Cellular studies revealed strong enzyme inhibition rank correlation with suppression of intracellular phosphorylation of a ROCK substrate. The biochemical potencies of these compounds also translated to functional activity, causing smooth muscle relaxation in rat aorta and guinea pig trachea. The series exhibited oral availability and one member reduced rat blood pressure, consistent with ROCK's role in smooth muscle contraction. Thus, the benzoxaborole moiety represents a novel hinge-binding kinase scaffold that may have potential for therapeutic use.
Asunto(s)
Compuestos de Boro/metabolismo , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Quinasas Asociadas a rho/antagonistas & inhibidores , Quinasas Asociadas a rho/metabolismo , Animales , Aorta Torácica/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Citocinas/sangre , Humanos , Células Jurkat , Modelos Moleculares , Contracción Muscular/efectos de los fármacos , Relajación Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Miocitos del Músculo Liso/efectos de los fármacos , Fosforilación , Inhibidores de Proteínas Quinasas/química , Proteína Fosfatasa 1/metabolismo , Ratas , Ratas Endogámicas SHR , Ratas Sprague-Dawley , Relación Estructura-Actividad , Tráquea/efectos de los fármacos , Quinasas Asociadas a rho/genéticaRESUMEN
A series of novel 6-(aminomethylphenoxy)benzoxaborole analogs was synthesized for the investigation of the structure-activity relationship of the inhibition of TNF-alpha, IL-1beta, and IL-6, from lipopolysaccharide stimulated peripheral blood mononuclear cells. Compounds 9d and 9e showed potent activity against all three cytokines with IC50 values between 33 and 83nM. Chloro substituted analog 9e (AN3485) is considered to be a promising lead for novel anti-inflammatory agent with a favorable pharmacokinetic profile.
Asunto(s)
Antiinflamatorios/química , Benzoxazoles/química , Compuestos de Boro/química , Compuestos Bicíclicos Heterocíclicos con Puentes/metabolismo , Animales , Antiinflamatorios/metabolismo , Antiinflamatorios/farmacocinética , Compuestos de Boro/metabolismo , Compuestos de Boro/farmacocinética , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacocinética , Semivida , Humanos , Interleucina-1beta/antagonistas & inhibidores , Interleucina-1beta/metabolismo , Interleucina-6/antagonistas & inhibidores , Interleucina-6/metabolismo , Cinética , Leucocitos Mononucleares/efectos de los fármacos , Lipopolisacáridos/toxicidad , Ratones , Unión Proteica , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
We have designed and synthesized a novel class of compounds based on fluoroquinolone antibacterial prototype. The design concept involved the replacement of the 3-carboxylic acid in ciprofloxacin with an oxaborole-fused ring as an acid-mimicking group. The synthetic method employed in this work provides a good example of incorporating boron atom in complex molecules with multiple functional groups. The antibacterial activity of the newly synthesized compounds has been evaluated.
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Compuestos de Boro/síntesis química , Compuestos de Boro/farmacología , Fluoroquinolonas/síntesis química , Fluoroquinolonas/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Ciprofloxacina/química , Ciprofloxacina/farmacología , Relación Estructura-ActividadRESUMEN
Structure-activity relationships of 6-(benzoylamino)benzoxaborole analogs were investigated for the inhibition of TNF-α, IL-1ß, and IL-6 from lipopolysaccharide stimulated peripheral blood mononuclear cells. Compound 1q showed potent activity against all three cytokines with IC50 values between 0.19 and 0.50µM, inhibited LPS-induced TNF-α and IL-6 elevation in mice and improved collagen-induced arthritis in mice. Compound 1q (AN4161) is considered to be a promising lead for novel anti-inflammatory agent with an excellent pharmacokinetic profile.
Asunto(s)
Antiinflamatorios/química , Antiinflamatorios/uso terapéutico , Artritis Experimental/tratamiento farmacológico , Derivados del Benceno/química , Derivados del Benceno/uso terapéutico , Compuestos de Boro/química , Compuestos de Boro/uso terapéutico , Animales , Antiinflamatorios/farmacocinética , Antiinflamatorios/farmacología , Derivados del Benceno/farmacocinética , Derivados del Benceno/farmacología , Compuestos de Boro/farmacocinética , Compuestos de Boro/farmacología , Interleucina-1beta/inmunología , Interleucina-6/inmunología , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/inmunología , Lipopolisacáridos/inmunología , Ratones , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
BACKGROUND: Prion diseases are a group of degenerative nerve diseases that are caused by infectious prion proteins or gene mutations. In humans, prion diseases result from mutations in the prion protein gene (PRNP). Only a limited number of cases involving a specific PRNP mutation at codon 196 (E196A) have been reported. The coexistence of Korsakoff syndrome in patients with Creutzfeldt-Jakob disease (CJD) caused by E196A mutation has not been documented in the existing literature. CASE SUMMARY: A 61-year-old Chinese man initially presented with Korsakoff syndrome, followed by rapid-onset dementia, visual hallucinations, akinetic mutism, myoclonus, and hyperthermia. The patient had no significant personal or familial medical history. Magnetic resonance imaging of the brain revealed extensive hyperintense signals in the cortex, while positron emission tomography/computed tomography showed a diffuse reduction in cerebral cortex metabolism. Routine biochemical and microorganism testing of the cerebrospinal fluid (CSF) yielded normal results. Tests for thyroid function, human immunodeficiency virus, syphilis, vitamin B1 and B12 levels, and autoimmune rheumatic disorders were normal. Blood and CSF tests for autoimmune encephalitis and autoantibody-associated paraneoplastic syndrome yielded negative results. A test for 14-3-3 protein in the CSF yielded negative results. Whole-genome sequencing revealed a disease-causing mutation in PRNP. The patient succumbed to the illness 11 months after the initial symptom onset. CONCLUSION: Korsakoff syndrome, typically associated with alcohol intoxication, also manifests in CJD patients. Individuals with CJD along with PRNP E196A mutation may present with Korsakoff syndrome.
RESUMEN
A series of new boron-containing benzoxaborole compounds was designed and synthesized for a continuing structure-activity relationship (SAR) investigation to assess the antimalarial activity changes derived from side-chain structural variation, substituent modification on the benzene ring and removal of boron from five-membered oxaborole ring. This SAR study demonstrated that boron is required for the antimalarial activity, and discovered that three fluoro-substituted 7-(2-carboxyethyl)-1,3-dihydro-1-hydroxy-2,1-benzoxaboroles (9, 14 and 20) have excellent potencies (IC(50) 0.026-0.209 µM) against Plasmodium falciparum.
Asunto(s)
Antimaláricos/síntesis química , Antimaláricos/farmacología , Compuestos de Boro/síntesis química , Compuestos de Boro/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Flúor/química , Plasmodium falciparum/efectos de los fármacos , Antimaláricos/química , Antimaláricos/toxicidad , Compuestos de Boro/química , Compuestos de Boro/toxicidad , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Compuestos Bicíclicos Heterocíclicos con Puentes/toxicidad , Supervivencia Celular/efectos de los fármacos , Células HeLa , Humanos , Concentración 50 Inhibidora , Células Jurkat , Estructura Molecular , Relación Estructura-ActividadRESUMEN
A novel series of P3 oxo-modified macrocyclic hepatitis C virus NS3/4A serine protease inhibitor was designed, synthesized and biologically evaluated. The hydroxy-substituted inhibitor 10 demonstrated high potency in genotype 1a and 1b replicon and in the panel of HCV protease mutants. Interestingly, the t-butyl carbonate analog 9c, while not the most potent one in this series, exhibited a virtually flat potency profile in the panel of HCV protease mutants, thus providing opportunity for further optimization.
Asunto(s)
Descubrimiento de Drogas , Hepacivirus/efectos de los fármacos , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Ciclopropanos , Hepacivirus/genética , Humanos , Hidroxilación , Concentración 50 Inhibidora , Isoindoles , Lactamas/química , Lactamas/farmacología , Lactamas Macrocíclicas , Estructura Molecular , Mutación , Prolina/análogos & derivados , Inhibidores de Proteasas/química , Sulfonamidas/química , Sulfonamidas/farmacologíaRESUMEN
We have synthesized and evaluated a series of novel HCV NS3 protease inhibitors with various P4 capping groups, which include urea, carbamate, methoxy-carboxamide, cyclic carbamate and amide, pyruvic amide, oxamate, oxalamide and cyanoguanidine. Most of these compounds are remarkably potent, exhibiting single-digit to sub-nanomolar activity in the enzyme assay and cell-based replicon assay. Selected compounds were also evaluated in the protease-inhibitor-resistant mutant transient replicon assay, and they were found to show quite different potency profiles against a panel of HCV protease-inhibitor-resistant mutants.