RESUMO
A series of novel 2-arylmethoxy-4-(2-fluoromethyl-biphenyl-3-ylmethoxy) benzylamine derivatives was designed, synthesized, and evaluated for their antitumor effects as PD-1/PD-L1 inhibitors both in vitro and in vivo. Firstly, the ability of these compounds to block the PD-1/PD-L1 immune checkpoint was assessed using the homogeneous time-resolved fluorescence (HTRF) assay. Two of the compounds can strongly block the PD-1/PD-L1 interaction, with IC50 values of less than 10 nM, notably, compound HD10 exhibited significant clinical potential by inhibiting the PD-1/PD-L1 interaction with an IC50 value of 3.1 nM. Further microscale thermophoresis (MST) analysis demonstrated that HD10 had strong interaction with PD-L1 protein. Co-crystal structure (2.7 Å) analysis of HD10 in complex with the PD-L1 protein revealed a strong affinity between the compound and the target PD-L1 dimer. This provides a solid theoretical basis for further in vitro and in vivo studies. Next, a typical cell-based experiment demonstrated that HD10 could remarkably prevent the interaction of hPD-1 293 T cells from human recombinant PD-L1 protein, effectively restoring T cell function, and promoting IFN-γ secretion in a dose-dependent manner. Moreover, HD10 was effective in suppressing tumor growth (TGI = 57.31 %) in a PD-1/PD-L1 humanized mouse model without obvious toxicity. Flow cytometry, qPCR, and immunohistochemistry data suggested that HD10 inhibits tumor growth by activating the immune system in vivo. Based on these results, it seems likely that HD10 is a promising clinical candidate that should be further investigated.
Assuntos
Antineoplásicos , Antígeno B7-H1 , Benzilaminas , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Receptor de Morte Celular Programada 1 , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismo , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Animais , Camundongos , Relação Estrutura-Atividade , Benzilaminas/farmacologia , Benzilaminas/química , Benzilaminas/síntese química , Estrutura Molecular , Relação Dose-Resposta a Droga , Proliferação de Células/efeitos dos fármacos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/síntese química , Inibidores de Checkpoint Imunológico/química , Linhagem Celular Tumoral , Feminino , Modelos MolecularesRESUMO
A series of 23 novel benzylamines was synthesized by reductive amination from halogen-substituted 3- and 4-benzyloxybenzaldehyde derivatives and 6-methylhept-2-yl amine or n-octylamine. The antimycotic activity of the resulting amines was evaluated in a microdilution assay against the apathogenic yeast Yarrowia lipolytica as test microorganism. Promising compounds were also tested against human pathogenic Candida species. The influence of halogen substituents at the benzyl ether side chain was studied in this screening, as well as the influence of the branched side chain of (±)-6-methylhept-2-yl amine in comparison with the n-octyl side chain.
Assuntos
Antifúngicos , Benzilaminas , Testes de Sensibilidade Microbiana , Antifúngicos/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Benzilaminas/farmacologia , Benzilaminas/química , Benzilaminas/síntese química , Relação Estrutura-Atividade , Candida/efeitos dos fármacos , Estrutura Molecular , Yarrowia/efeitos dos fármacos , Humanos , Relação Dose-Resposta a DrogaRESUMO
17ß-Hydroxysteroid dehydrogenase type 3 (17ß-HSD3) is expressed at high levels in testes and seminal vesicles; it is also present in prostate tissue and involved in gonadal and non-gonadal testosterone biosynthesis. The enzyme is membrane-bound, and a crystal structure is not yet available. Selective aryl benzylamine-based inhibitors were designed and synthesised as potential agents for prostate cancer therapeutics through structure-based design, using a previously built homology model with docking studies. Potent, selective, low nanomolar IC50 17ß-HSD3 inhibitors were discovered using N-(2-([2-(4-chlorophenoxy)phenylamino]methyl)phenyl)acetamide (1). The most potent compounds have IC50 values of approximately 75 nM. Compound 29, N-[2-(1-Acetylpiperidin-4-ylamino)benzyl]-N-[2-(4-chlorophenoxy)phenyl]acetamide, has an IC50 of 76 nM, while compound 30, N-(2-(1-[2-(4-chlorophenoxy)-phenylamino]ethyl)phenyl)acetamide, has an IC50 of 74 nM. Racemic C-allyl derivative 26 (IC50 of 520 nM) was easily formed from 1 in good yield and, to determine binding directionality, its enantiomers were separated by chiral chromatography. Absolute configuration was determined using single crystal X-ray crystallography. Only the S-(+)-enantiomer (32) was active with an IC50 of 370 nM. Binding directionality was predictable through our in silico docking studies, giving confidence to our model. Importantly, all novel inhibitors are selective over the type 2 isozyme of 17ß-HSD2 and show <20% inhibition when tested at 10 µM. Lead compounds from this series are worthy of further optimisation and development as inhibitors of testosterone production by 17ß-HSD3 and as inhibitors of prostate cancer cell growth.
Assuntos
17-Hidroxiesteroide Desidrogenases/química , Benzilaminas/química , Neoplasias da Próstata/tratamento farmacológico , 17-Hidroxiesteroide Desidrogenases/antagonistas & inibidores , 17-Hidroxiesteroide Desidrogenases/ultraestrutura , Benzilaminas/síntese química , Benzilaminas/farmacologia , Linhagem Celular Tumoral , Cristalografia por Raios X , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Concentração Inibidora 50 , Masculino , Simulação de Acoplamento Molecular , Próstata/efeitos dos fármacos , Próstata/metabolismo , Neoplasias da Próstata/patologia , Relação Estrutura-Atividade , Testosterona/biossínteseRESUMO
A series of novel urea, sulfamide and N,N-dipropargyl substituted benzylamines were synthesized from dihydrochalcones. The synthesized compounds were evaluated for their cholinesterases and carbonic anhydrase inhibitory actions. The known dihydrochalcones were converted into four new benzylamines via reductive amination. N,N-Dipropargylamines, ureas and sulfamides were synthesized following the reactions of benzylamines with propargyl bromide, N,N-dimethyl sulfamoyl chloride and N,N-dimethyl carbamoyl chloride. The novel substituted benzylamines derived from dihydrochalcones were evaluated against some enzymes such as human erythrocyte carbonic anhydrase I and II isoenzymes (hCA I and hCA II), acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The novel substituted benzylamines derived from dihydrochalcones exhibited Ki values in the range of 0.121-1.007 nM on hCA I, and 0.077-0.487 nM on hCA II closely related to several pathological processes. On the other hand, Ki values were found in the range of 0.112-0.558 nM on AChE, 0.061-0.388 nM on BChE. As a result, novel substituted benzylamines derived from dihydrochalcones showed potent inhibitory profiles against indicated metabolic enzymes. In addition, Induced-Fit Docking (IFD) simulations and ADME prediction studies have also been carried out to elucidate the inhibition mechanisms and drug-likeness of the synthesized compounds. Therefore, these results can make significant contributions to the treatment of some global diseases, especially Alzheimer's diseases and glaucoma, and the development of new drugs.
Assuntos
Benzilaminas/farmacologia , Inibidores da Anidrase Carbônica/farmacologia , Chalconas/farmacologia , Inibidores da Colinesterase/farmacologia , Acetilcolinesterase/metabolismo , Animais , Benzilaminas/síntese química , Benzilaminas/química , Butirilcolinesterase/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Anidrases Carbônicas/metabolismo , Chalconas/química , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Electrophorus , Cavalos , Humanos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Up to date, the current clinical practice employs only symptomatic treatments for management of Parkinson's disease (PD) but unable to stop disease progression. The discovery of new chemical entities endowed with potent and selective human monoamine oxidase B (hMAO-B) inhibitory activity is a clinically relevant subject. Herein, a structural optimization strategy for safinamide (a well-known second generation hMAO-B inhibitor) afforded a series of thirty-six safinamide-derived new analogs (4aa-bj). Most compounds showed promising inhibitory activities against hMAO-B (>70% inhibition at a single dose concentration of 10 µM), with no apparent effect on hMAO-A at 100 µM. Moreover, while six compounds (4ak, 4as, 4az, 4be, 4bg, and 4bi) exhibited potent double-digit nanomolar activities over hMAO-B with IC50 values of 29.5, 42.2, 22.3, 18.8, 42.2, and 33.9 nM, respectively, three derivatives (4aq, 4at, and 4bf), possessing the same carboxamide moiety (2-pyrazinyl), showed the most potent single-digit nanomolar activities (IC50 = 9.7, 5.1, and 3.9 nM, respectively). Compound 4bf revealed an excellent selectivity index (SI > 25641) with a 29-fold increase compared to safinamide (SI > 892). A structure activity relationship along with molecular docking simulations provided insights into enzyme - inhibitor interactions and a rational for the observed activity. In an in vivo MPTP-induced mouse model of PD, oral administration of compound 4bf significantly protected nigrostriatal dopaminergic neurons as revealed by tyrosine hydroxylase staining and prevented MPTP-induced Parkinsonism as revealed by motor behavioral assays. Accordingly, we present compound 4bf as a novel, highly potent, and selective hMAO-B inhibitor with an effective therapeutic profile for relieving PD.
Assuntos
Alanina/análogos & derivados , Benzilaminas/farmacologia , Descoberta de Drogas , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/tratamento farmacológico , Alanina/síntese química , Alanina/química , Alanina/farmacologia , Benzilaminas/síntese química , Benzilaminas/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Doença de Parkinson/metabolismo , Relação Estrutura-AtividadeRESUMO
Parkinson's disease (PD) is one of the most common age-related neurodegenerative diseases. Inhibition of monoamine oxidase-B (MAO-B), which is mainly found in the glial cells of the brain, may lead to an elevated level of dopamine (DA) in patients. MAO-B inhibitors have been used extensively for patients with PD. However, the discovery of the selective MAO-B inhibitor is still a challenge. In this study, a computational strategy was designed for the rapid discovery of selective MAO-B inhibitors. A series of (S)-2-(benzylamino)propanamide derivatives were designed. In vitro biological evaluations revealed that (S)-1-(4-((3-fluorobenzyl)oxy)benzyl)azetidine-2-carboxamide (C3) was more potent and selective than safinamide, a promising drug for regulating MAO-B. Further studies revealed that the selectivity mechanism of C3 was due to the steric clash caused by the residue difference of Phe208 (MAO-A) and Ile199 (MAO-B). Animal studies showed that compound C3 could inhibit cerebral MAO-B activity and alleviate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neuronal loss.
Assuntos
Amidas/uso terapêutico , Benzilaminas/uso terapêutico , Inibidores da Monoaminoxidase/uso terapêutico , Monoaminoxidase/metabolismo , Doença de Parkinson Secundária/tratamento farmacológico , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Alanina/análogos & derivados , Alanina/metabolismo , Amidas/síntese química , Amidas/metabolismo , Animais , Benzilaminas/síntese química , Benzilaminas/metabolismo , Sítios de Ligação , Neurônios Dopaminérgicos/efeitos dos fármacos , Desenho de Fármacos , Humanos , Masculino , Camundongos Endogâmicos ICR , Simulação de Acoplamento Molecular , Estrutura Molecular , Monoaminoxidase/química , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/metabolismo , Doença de Parkinson Secundária/induzido quimicamente , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
Prions are misfolded proteins involved in neurodegenerative diseases of high interest in veterinary and public health. In this work, we report the chemical space exploration around the anti-prion compound BB 0300674 in order to gain an understanding of its Structure Activity Relationships (SARs). A series of 43 novel analogues, based on four different chemical clusters, were synthetized and tested against PrPSc and mutant PrP toxicity assays. From this biological screening, two compounds (59 and 65) emerged with a 10-fold improvement in anti-prion activity compared with the initial lead compound, presenting at the same time interesting cell viability.
Assuntos
Benzilaminas/química , Proteínas PrPSc/metabolismo , Animais , Benzilaminas/síntese química , Benzilaminas/farmacologia , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Células HEK293 , Humanos , Camundongos , Mutagênese , Proteínas PrPSc/antagonistas & inibidores , Proteínas PrPSc/genética , Relação Estrutura-AtividadeRESUMO
Disulfide bond formation is a critical post-translational modification of newly synthesized polypeptides in the oxidizing environment of the endoplasmic reticulum and is mediated by protein disulfide isomerase (PDIA1). In this study, we report a series of α-aminobenzylphenol analogues as potent PDI inhibitors. The lead compound, AS15, is a covalent nanomolar inhibitor of PDI, and the combination of AS15 analogues with glutathione synthesis inhibitor buthionine sulfoximine (BSO) leads to synergistic cell growth inhibition. Using nascent RNA sequencing, we show that an AS15 analogue triggers the unfolded protein response in glioblastoma cells. A BODIPY-labeled analogue binds proteins including PDIA1, suggesting that the compounds are cell-permeable and reach the intended target. Taken together, these findings demonstrate an extensive biochemical characterization of a novel series of highly potent reactive small molecules that covalently bind to PDI.
Assuntos
Benzilaminas/farmacologia , Inibidores Enzimáticos/farmacologia , Fenóis/farmacologia , Isomerases de Dissulfetos de Proteínas/antagonistas & inibidores , Benzilaminas/síntese química , Benzilaminas/metabolismo , Linhagem Celular Tumoral , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Glutationa/metabolismo , Humanos , Estrutura Molecular , Fenóis/síntese química , Fenóis/metabolismo , Relação Estrutura-Atividade , Resposta a Proteínas não Dobradas/efeitos dos fármacosRESUMO
The remarkable effects exhibited by classical psychedelics in recent clinical trials have spawned considerable interest in 5-HT2A receptor (5-HT2AR) activation as a treatment strategy for several psychiatric/cognitive disorders. In this study we have continued our development of 25CN-NBOH, one of the most 5-HT2AR-selective agonists reported to date, as a pharmacological tool for exploration of 5-HT2AR expression and functions. The importance of the 2' and 3' positions in 25CN-NBOH as structural hotspots for its 5-HT2AR activity was investigated by synthesis and pharmacological characterization of six novel analogs at 5-HT2AR and 5-HT2CR in binding and functional assays. While the 5-HT2AR activity of 25CN-NBOH was retained in 3'-methyl, 2',3'-chroman, 2',3'-dihydrofuran and 2',3'-furan analogs, the 3'-methoxy and 3'-ethyl analogs displayed substantially lower binding affinities and agonist potencies than 25CN-NBOH. Interestingly, the 2',3'-substitution pattern was also a key determinant of agonist efficacy, as all six analogs exhibited low-efficacy partial agonism or de facto antagonism at the 5-HT2AR in the functional assays. Systemic administration of 25CN-NBOH and its close structural analog 25CN-NBMD induced robust head-twitch response in mice, a well-established behavioural effect of 5-HT2AR activation in vivo, and 25CN-NBOH mediated robust reductions in the activity of mice in an anxiety-related marble burying assay, which supports the proposed beneficial effects of 5-HT2AR activation on disorders characterized by cognitive rigidity. Finally, tritiated 25CN-NBOH exhibited high 5-HT2AR binding affinity (KD ~1 nM) and selectivity against 5-HT2BR and 5-HT2CR in equilibrium and kinetic binding studies of the recombinant receptors, and in concordance [3H]25CN-NBOH displayed substantial specific, ketanserin-sensitive binding to cortex and small levels of binding to choroid plexus in rat brain slices in autoradiography studies. In conclusion, this work delineates the subtle molecular determinants of the 5-HT2AR activity in 25CN-NBOH, substantiates the potential in this compound and its analogs as tools for in vivo studies of the 5-HT2AR, and introduces a novel selective agonist radioligand as another potentially valuable tool for future explorations of this receptor.
Assuntos
Benzofuranos/farmacologia , Benzilaminas/farmacologia , Alucinógenos/farmacologia , Nitrilas/farmacologia , Receptor 5-HT2A de Serotonina/metabolismo , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Animais , Benzofuranos/síntese química , Benzilaminas/síntese química , Sítios de Ligação , Cerebelo/diagnóstico por imagem , Cerebelo/efeitos dos fármacos , Cerebelo/metabolismo , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Plexo Corióideo/diagnóstico por imagem , Plexo Corióideo/efeitos dos fármacos , Plexo Corióideo/metabolismo , Feminino , Células HEK293 , Alucinógenos/síntese química , Humanos , Cinética , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nitrilas/síntese química , Ligação Proteica , Ratos , Ratos Long-Evans , Agonistas do Receptor 5-HT2 de Serotonina/síntese química , Relação Estrutura-AtividadeRESUMO
The isoquinolinequinone (IQQ) pharmacophore is a privileged framework in known cytotoxic natural product families, caulibugulones and mansouramycins. Exploiting both families as a chemical starting point, we report on the structured development of an IQQ N-oxide anticancer framework which exhibits growth inhibition in the nM range across melanoma, ovarian and leukaemia cancer cell lines. A new lead compound (16, R6 = benzyl, R7 = H) exhibits nM GI50 values against 31/57 human tumour cell lines screened as part of the NCI60 panel and shows activity against doxorubicin resistant tumour cell lines. An electrochemical study highlights a correlation between electropositivity of the IQQ N-oxide framework and cytotoxicity. Adduct binding to sulfur based biological nucleophiles glutathione and cysteine was observed in vitro. This new framework possesses significant anticancer potential.
Assuntos
Antineoplásicos/farmacologia , Óxidos N-Cíclicos/farmacologia , Isoquinolinas/farmacologia , Quinonas/farmacologia , Antineoplásicos/síntese química , Benzilaminas/síntese química , Benzilaminas/farmacologia , Linhagem Celular Tumoral , Óxidos N-Cíclicos/síntese química , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Isoquinolinas/síntese química , Quinonas/síntese químicaRESUMO
Transforming growth factor-ß (TGF-ß) plays an important role in regulating epithelial to mesenchymal transition (EMT) and the TGF-ß signaling pathway is a potential target for therapeutic intervention in the development of many diseases, such as fibrosis and cancer. Most currently available inhibitors of TGF-ß signaling function as TGF-ß receptor I (TßR-I) kinase inhibitors, however, such kinase inhibitors often lack specificity. In the present study, we targeted the extracellular protein binding domain of the TGF-ß receptor II (TßR-II) to interfere with the protein-protein interactions (PPIs) between TGF-ß and its receptors. One compound, CJJ300, inhibited TGF-ß signaling by disrupting the formation of the TGF-ß-TßR-I-TßR-II signaling complex. Treatment of A549 cells with CJJ300 resulted in the inhibition of downstream signaling events such as the phosphorylation of key factors along the TGF-ß pathway and the induction of EMT markers. Concomitant with these effects, CJJ300 significantly inhibited cell migration. The present study describes for the first time a designed molecule that can regulate TGF-ß-induced signaling and EMT by interfering with the PPIs required for the formation of the TGF-ß signaling complex. Therefore, CJJ300 can be an important lead compound with which to study TGF-ß signaling and to design more potent TGF-ß signaling antagonists.
Assuntos
Benzilaminas/farmacologia , Ligação Proteica/efeitos dos fármacos , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Células A549 , Benzilaminas/síntese química , Movimento Celular/efeitos dos fármacos , Desenho de Fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Ligantes , Simulação de Acoplamento Molecular , Transdução de Sinais/efeitos dos fármacosRESUMO
We report the first preparation of a monoclonal antibody (mAb) that can immobilize a palladium (Pd)-complex. The allylic amination reaction using a supramolecular catalyst consisting of the Pd-complex and mAb selectively gives the (R)-enantiomer product with an enantiomeric excess (ee) of 98 ± 2%. This is in sharp contrast to the reaction catalyzed by a conventional Pd-catalyst (ee < 2%).
Assuntos
Anticorpos Monoclonais/química , Complexos de Coordenação/química , Paládio/química , Compostos Alílicos/síntese química , Compostos Alílicos/química , Aminação , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/metabolismo , Benzilaminas/síntese química , Benzilaminas/química , Catálise , Bovinos , Complexos de Coordenação/imunologia , Complexos de Coordenação/metabolismo , Reações Cruzadas/imunologia , Feminino , Gastrópodes/química , Hemocianinas/química , Camundongos Endogâmicos BALB C , Ligação Proteica , Ródio/química , Soroalbumina Bovina/química , Estereoisomerismo , Água/químicaRESUMO
Intrinsically disordered proteins are an emerging class of proteins without a folded structure and currently disorder-based drug targeting remains a challenge. p53 is the principal regulator of cell division and growth whereas MDM2 consists its main negative regulator. The MDM2-p53 recognition is a dynamic and multistage process that amongst other, employs the dissociation of a transient α-helical N-terminal ''lid'' segment of MDM2 from the proximity of the p53-complementary interface. Several small molecule inhibitors have been reported to inhibit the formation of the p53-MDM2 complex with the vast majority mimicking the p53 residues Phe19, Trp23 and Leu26. Recently, we have described the transit from the 3-point to 4-point pharmacophore model stabilizing this intrinsically disordered N-terminus by increasing the binding affinity by a factor of 3. Therefore, we performed a thorough SAR analysis, including chiral separation of key compound which was evaluated by FP and 2D NMR. Finally, p53-specific anti-cancer activity towards p53-wild-type cancer cells was observed for several representative compounds.
Assuntos
Antineoplásicos/farmacologia , Proteínas Intrinsicamente Desordenadas/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Proteína Supressora de Tumor p53/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Benzilaminas/síntese química , Benzilaminas/química , Benzilaminas/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cianetos/síntese química , Cianetos/química , Cianetos/farmacologia , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Formiatos/síntese química , Formiatos/química , Formiatos/farmacologia , Humanos , Indóis/síntese química , Indóis/química , Indóis/farmacologia , Proteínas Intrinsicamente Desordenadas/química , Proteínas Intrinsicamente Desordenadas/metabolismo , Estrutura Molecular , Proteínas Proto-Oncogênicas c-mdm2/química , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Relação Estrutura-Atividade , Proteína Supressora de Tumor p53/química , Proteína Supressora de Tumor p53/metabolismoRESUMO
Discovery of antimicrobial agents with a novel model of action is in urgent need for the clinical management of multidrug-resistant bacterial infections. Recently, we reported the identification of a first-in-class bacterial ribosomal RNA synthesis inhibitor, which interrupted the interaction between the bacterial transcription factor NusB and NusE. In this study, a series of diaryl derivatives were rationally designed and synthesized based on the previously established pharmacophore model. Inhibitory activity against the NusB-NusE binding, circular dichroism of compound treated NusB, antimicrobial activity, cytotoxicity, hemolytic property and cell permeability using Caco-2â¯cells were measured. Structure-activity relationship and quantitative structure-activity relationship were also concluded and discussed. Some of the derivatives demonstrated improved antimicrobial activity than the hit compound against a panel of clinically important pathogens, lowering the minimum inhibition concentration to 1-2⯵g/mL against Staphylococcus aureus, including clinical strains of methicillin-resistant Staphylococcus aureus at a level comparable to some of the marketed antibiotics. Given the improved antimicrobial activity, specific inhibition of target protein-protein interaction and promising pharmacokinetic properties without significant cytotoxicity, this series of diaryl compounds have high potentials and deserve for further studies towards a new class of antimicrobial agents in the future.
Assuntos
Compostos de Anilina/farmacologia , Antibacterianos/farmacologia , Benzilaminas/farmacologia , Ligação Proteica/efeitos dos fármacos , Bases de Schiff/farmacologia , Compostos de Anilina/síntese química , Compostos de Anilina/química , Compostos de Anilina/toxicidade , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/toxicidade , Proteínas de Bactérias/metabolismo , Benzilaminas/síntese química , Benzilaminas/química , Benzilaminas/toxicidade , Células CACO-2 , Desenho de Fármacos , Eritrócitos/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Células HeLa , Hemólise/efeitos dos fármacos , Humanos , Queratinócitos/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Bases de Schiff/síntese química , Bases de Schiff/química , Bases de Schiff/toxicidade , Relação Estrutura-Atividade , Fatores de Transcrição/metabolismoRESUMO
Complement factor D (FD), a highly specific S1 serine protease, plays a central role in the amplification of the alternative complement pathway (AP) of the innate immune system. Dysregulation of AP activity predisposes individuals to diverse disorders such as age-related macular degeneration, atypical hemolytic uremic syndrome, membranoproliferative glomerulonephritis type II, and paroxysmal nocturnal hemoglobinuria. Previously, we have reported the screening efforts and identification of reversible benzylamine-based FD inhibitors (1 and 2) binding to the open active conformation of FD. In continuation of our drug discovery program, we designed compounds applying structure-based approaches to improve interactions with FD and gain selectivity against S1 serine proteases. We report herein the design, synthesis, and medicinal chemistry optimization of the benzylamine series culminating in the discovery of 12, an orally bioavailable and selective FD inhibitor. 12 demonstrated systemic suppression of AP activation in a lipopolysaccharide-induced AP activation model as well as local ocular suppression in intravitreal injection-induced AP activation model in mice expressing human FD.
Assuntos
Benzilaminas/farmacologia , Via Alternativa do Complemento/efeitos dos fármacos , Inibidores de Serina Proteinase/farmacologia , Animais , Benzilaminas/síntese química , Benzilaminas/metabolismo , Sítios de Ligação , Fator D do Complemento/antagonistas & inibidores , Fator D do Complemento/química , Fator D do Complemento/metabolismo , Cães , Desenho de Fármacos , Humanos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Simulação de Acoplamento Molecular , Conformação Proteica , Ratos , Inibidores de Serina Proteinase/síntese química , Inibidores de Serina Proteinase/metabolismoRESUMO
Growing evidence confirms the potential of PDE4 inhibitors for the treatment of Parkinson's disease. Our reported PDE4 inhibitors FCPR16 and FCPR03 have displayed neuroprotective effects in SH-SY5Y cells, but have very low oral bioavailability. To access analogues with improved bioavailability, a new series of arylbenzylamine derivatives were designed and synthesized. Preliminary screening results of the series showed that arylbenzylamine derivatives bearing a pyridin-3-amine side chain displayed good inhibitory activities against human PDE4B1 and PDE4D7 isoforms. Moreover, kinetic studies revealed that the most potent compounds 11r and 11s with mid-nanomolar IC50 values partially bind to PDE4B1 (Imaxâ¯=â¯93% and 90% respectively). Molecular docking results revealed the possible interactions of compounds 11r and 11s with upstream conserved region 2 (UCR2) of PDE4B1, which illuminate possible reasons for their partial inhibition against PDE4. Using a cell-based model of PD, compounds 11r and 11s were found to alleviate cellular apoptosis in SH-SY5Y cells induced by MPP+ (1-methyl-4-phenylpyridinium), with this neuroprotective effect being greater than PDE4 inhibitor rolipram. Furthermore, compound 11r displayed nearly sevenfold oral bioavailability (8.20%) than FCPR03 (1.23%).
Assuntos
Benzilaminas/farmacologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Descoberta de Drogas , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/tratamento farmacológico , Inibidores da Fosfodiesterase 4/farmacologia , Animais , Benzilaminas/síntese química , Benzilaminas/química , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Inibidores da Fosfodiesterase 4/síntese química , Inibidores da Fosfodiesterase 4/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
We previously reported that a lipophilic N-(4'-hydroxy-3',5'-di-tert-butylbenzyl) derivative (1) of the voltage-gated sodium channel blocker mexiletine, was a more potent sodium channel blocker inâ vitro and inâ vivo. We demonstrate that replacing the chiral methylethylene linker between the amine and di-tert-butylphenol with an achiral 1,3-propylene linker (to give (2)) maintains potency inâ vitro. We synthesized 25 analogues bearing the 1,3-propylene linker and found that minor structural changes resulted in pronounced changes in state dependence of blocking human NaV 1.2 and 1.6 channels by high-throughput patch-clamp analysis. Compared to mexiletine, compounds 1 and 2 are highly selective NaV 1.2 inhibitors and >500 times less potent in inhibiting NaV 1.6 channels. On the other hand, a derivative (compound 4) bearing 2,6-dimethoxy groups in place of the 2,6-dimethyl groups found in mexiletine was found to be the most potent inhibitor, but is nonselective against both channels in the tonic, frequency-dependent and inactivated states. In a kindled mouse model of refractory epilepsy, compound 2 inhibited seizures induced by 6â Hz 44â mA electrical stimulation with an IC50 value of 49.9±1.6â mg kg-1 . As established sodium channel blockers do not suppress seizures in this mouse model, this indicates that 2 could be a promising candidate for treating pharmaco-resistant epilepsy.
Assuntos
Benzilaminas/síntese química , Convulsões/tratamento farmacológico , Bloqueadores do Canal de Sódio Disparado por Voltagem/síntese química , Canais de Sódio Disparados por Voltagem/metabolismo , Animais , Benzilaminas/metabolismo , Estabilidade de Medicamentos , Estimulação Elétrica , Humanos , Mexiletina/metabolismo , Camundongos , Estrutura Molecular , Técnicas de Patch-Clamp/métodos , Relação Estrutura-Atividade , Bloqueadores do Canal de Sódio Disparado por Voltagem/metabolismoRESUMO
Inspite of progress made for the discovery of novel antiepileptic drugs, epilepsy remains an unmet medical need. We synthesized nine trifluoromethylated enaminone derivatives and tested them for their anticonvulsant activity using maximal electroshock seizure (MES) test, subcutaneous pentylenetetrazole (scPTZ) test, and rotorod test for neurotoxicity. Among the compounds tested 3-(4-fluoro-3-(trifluomethyl)benzylamino)-5-(trifluoromethyl)cyclohex-2-enone (4f) showed ED50 of 23.47â¯mg/kg, when given orally to rats, 3-(4-chlorophenylamino)-5-(trifluoromethyl)cyclohex-2-enone (5a), which was previously reported by us but for which no quantitative data was available at the time, exhibited an ED50 of 62.39â¯mg/kg. Under the same conditions commercially available carbamazepine showed an ED50 of 28.20â¯mg/kg. There were no neurotoxicity observed upto a dose of 300â¯mg/kg for all the tested compounds. Compounds 4f and 5a represent good lead compounds for further development.
Assuntos
Anticonvulsivantes/farmacologia , Benzilaminas/farmacologia , Cicloexanonas/farmacologia , Cicloexilaminas/farmacologia , Hidrocarbonetos Fluorados/farmacologia , Convulsões/prevenção & controle , Animais , Anticonvulsivantes/síntese química , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/toxicidade , Benzilaminas/síntese química , Benzilaminas/farmacocinética , Benzilaminas/toxicidade , Simulação por Computador , Cicloexanonas/síntese química , Cicloexanonas/farmacocinética , Cicloexanonas/toxicidade , Cicloexilaminas/síntese química , Cicloexilaminas/farmacocinética , Cicloexilaminas/toxicidade , Desenho de Fármacos , Hidrocarbonetos Fluorados/síntese química , Hidrocarbonetos Fluorados/farmacocinética , Hidrocarbonetos Fluorados/toxicidade , Masculino , Camundongos , Estrutura Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
Herein, we present a method for the preparation of supramolecular polymers with tunable fluorescence via the combination of metal-ligand coordination and phenanthrene-21-crown-7 (P21C7)-based host-guest interactions. A suite of rhomboidal metallacycles with different substituents were prepared via the coordination-driven self-assembly of a P21C7-based 60° diplatinum(II) acceptor and 120° dipyridyl donors. Upon variation of the substituents on the dipyridyl donors, the metallacycles exhibit emission wavelengths spanning the visible region (λmax = 427-593 nm). Metallacycle-cored supramolecular polymers were obtained via host-guest interactions between bis-ammonium salts and P21C7. The supramolecular polymers exhibit emission wavelengths similar to those of the individual metallacycles and higher fluorescent efficiency in solution and thin films. Utilizing a yellow-emitting supramolecular polymer thin film with high quantum yield (0.22), a white-light-emitting LED was fabricated by painting the thin film onto an ultraviolet LED. This study presents an efficient approach for tuning the properties of fluorescent supramolecular polymers and the potential of the metallacycle-cored supramolecular polymers as a platform for the fabrication of light-emitting materials with good processability and tunability.
Assuntos
Complexos de Coordenação/química , Éteres de Coroa/química , Corantes Fluorescentes/química , Fenantrenos/química , Polímeros/química , Benzilaminas/síntese química , Benzilaminas/química , Complexos de Coordenação/síntese química , Éteres de Coroa/síntese química , Fluorescência , Corantes Fluorescentes/síntese química , Estrutura Molecular , Fenantrenos/síntese química , Platina/química , Polímeros/síntese química , SolubilidadeRESUMO
Based on the potential role of Na-K-Cl cotransporters (NKCCs) in epileptic seizures, the loop diuretic bumetanide, which blocks the NKCC1 isoforms NKCC1 and NKCC2, has been tested as an adjunct with phenobarbital to suppress seizures. However, because of its physicochemical properties, bumetanide only poorly penetrates through the blood-brain barrier. Thus, concentrations needed to inhibit NKCC1 in hippocampal and neocortical neurons are not reached when using doses (0.1-0.5â¯mg/kg) in the range of those approved for use as a diuretic in humans. This prompted us to search for a bumetanide derivative that more easily penetrates into the brain. Here we show that bumepamine, a lipophilic benzylamine derivative of bumetanide, exhibits much higher brain penetration than bumetanide and is more potent than the parent drug to potentiate phenobarbital's anticonvulsant effect in two rodent models of chronic difficult-to-treat epilepsy, amygdala kindling in rats and the pilocarpine model in mice. However, bumepamine suppressed NKCC1-dependent giant depolarizing potentials (GDPs) in neonatal rat hippocampal slices much less effectively than bumetanide and did not inhibit GABA-induced Ca2+ transients in the slices, indicating that bumepamine does not inhibit NKCC1. This was substantiated by an oocyte assay, in which bumepamine did not block NKCC1a and NKCC1b after either extra- or intracellular application, whereas bumetanide potently blocked both variants of NKCC1. Experiments with equilibrium dialysis showed high unspecific tissue binding of bumetanide in the brain, which, in addition to its poor brain penetration, further reduces functionally relevant brain concentrations of this drug. These data show that CNS effects of bumetanide previously thought to be mediated by NKCC1 inhibition can also be achieved by a close derivative that does not share this mechanism. Bumepamine has several advantages over bumetanide for CNS targeting, including lower diuretic potency, much higher brain permeability, and higher efficacy to potentiate the anti-seizure effect of phenobarbital.