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1.
ACS Chem Biol ; 18(3): 456-464, 2023 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-36762958

RESUMO

TRPM3 is an ion channel that is highly expressed in nociceptive neurons and plays a key role in pain perception. In the presence of the endogenous TRPM3 ligand, pregnenolone sulfate (PS), the antifungal compound clotrimazole (Clt) augments Ca2+ signaling and opens a non-canonical pore, permeable to Na+, which aggravates TRPM3-induced pain. To date, little is known about structural features that govern the Clt modulatory effect of TRPM3. Here, we synthesized and evaluated several Clt analogues in order to gain insights into their structure-activity relationship. Our results reveal a tight SAR with the three phenyl rings on the trityl moiety being essential for the activity, as well as the presence of fluorine or chlorine substituents on the trityl group. Imidazole as a heterocycle is also necessary for activity. Interestingly, we identified a pentafluoro-trityl analogue (29a) that is able to act as a TRPM3 agonist in the absence of PS. The compounds we report in this work will be useful tools for the further study of TRPM3 modulation and its effect on pain perception.


Assuntos
Clotrimazol , Canais de Cátion TRPM , Humanos , Clotrimazol/farmacologia , Canais de Cátion TRPM/metabolismo , Dor , Relação Estrutura-Atividade
2.
Chem Sci ; 14(7): 1666-1672, 2023 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-36819852

RESUMO

The COVID-19 pandemic has revealed the vulnerability of the modern, global society. With expected waves of future infections by SARS-CoV-2, treatment options for infected individuals will be crucial in order to decrease mortality and hospitalizations. The SARS-CoV-2 main protease is a validated drug target, for which the first inhibitor has been approved for use in patients. To facilitate future work on this drug target, we designed a solid-phase synthesis route towards azapeptide activity-based probes that are capped with a cysteine-reactive electrophile for covalent modification of the active site of Mpro. This design led to the most potent ABP for Mpro and one of the most potent inhibitors reported thus far. We demonstrate that this ABP can be used to visualize Mpro activity and target engagement by drugs in infected cells.

3.
J Med Chem ; 65(20): 13660-13680, 2022 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-36222708

RESUMO

The soluble epoxide hydrolase (sEH) has been suggested as a pharmacological target for the treatment of several diseases, including pain-related disorders. Herein, we report further medicinal chemistry around new benzohomoadamantane-based sEH inhibitors (sEHI) in order to improve the drug metabolism and pharmacokinetics properties of a previous hit. After an extensive in vitro screening cascade, molecular modeling, and in vivo pharmacokinetics studies, two candidates were evaluated in vivo in a murine model of capsaicin-induced allodynia. The two compounds showed an anti-allodynic effect in a dose-dependent manner. Moreover, the most potent compound presented robust analgesic efficacy in the cyclophosphamide-induced murine model of cystitis, a well-established model of visceral pain. Overall, these results suggest painful bladder syndrome as a new possible indication for sEHI, opening a new range of applications for them in the visceral pain field.


Assuntos
Epóxido Hidrolases , Dor Visceral , Camundongos , Humanos , Animais , Ureia/química , Modelos Animais de Doenças , Dor Visceral/induzido quimicamente , Dor Visceral/tratamento farmacológico , Capsaicina , Inibidores Enzimáticos/farmacologia , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Ciclofosfamida
4.
Commun Biol ; 4(1): 218, 2021 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-33594255

RESUMO

Membrane proteins are key in a large number of physiological and pathological processes. Their study often involves a prior detergent solubilization step, which strips away the membrane and can jeopardize membrane protein integrity. A recent alternative to detergents encompasses maleic acid based copolymers (xMAs), which disrupt the lipid bilayer and form lipid protein nanodiscs (xMALPs) soluble in aqueous buffer. Although xMALPs are often referred to as native nanodiscs, little is known about the resemblance of their lipid and protein content to the native bilayer. Here we have analyzed prokaryotic and eukaryotic xMALPs using lipidomics and in-gel analysis. Our results show that the xMALPs content varies with the chemical properties of the used xMA.


Assuntos
Membrana Celular/química , Lipidômica , Maleatos/química , Lipídeos de Membrana/química , Proteínas de Membrana/química , Nanopartículas , Polímeros/química , Proteínas de Bactérias/química , Escherichia coli/química , Humanos , Células Jurkat , Espectrometria de Massas , Poliestirenos/química , Compostos de Amônio Quaternário/química , Solubilidade
5.
Chembiochem ; 21(23): 3383-3388, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32717117

RESUMO

The global pandemic caused by SARS-CoV-2 calls for the fast development of antiviral drugs against this particular coronavirus. Chemical tools to facilitate inhibitor discovery as well as detection of target engagement by hit or lead compounds from high-throughput screens are therefore in urgent need. We here report novel, selective activity-based probes that enable detection of the SARS-CoV-2 main protease. The probes are based on acyloxymethyl ketone reactive electrophiles combined with a peptide sequence including unnatural amino acids that targets the nonprimed site of the main protease substrate binding cleft. They are the first activity-based probes for the main protease of coronaviruses and display target labeling within a human proteome without background. We expect that these reagents will be useful in the drug-development pipeline, not only for the current SARS-CoV-2, but also for other coronaviruses.


Assuntos
Proteínas M de Coronavírus/química , Cetonas/química , Sondas Moleculares/química , SARS-CoV-2/enzimologia , Sítios de Ligação , COVID-19/diagnóstico , COVID-19/virologia , Domínio Catalítico , Proteínas M de Coronavírus/metabolismo , Humanos , Cetonas/metabolismo , Cinética , Simulação de Acoplamento Molecular , Sondas Moleculares/metabolismo , Peptídeos/química , SARS-CoV-2/isolamento & purificação
6.
Biochim Biophys Acta Biomembr ; 1862(4): 183193, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31945321

RESUMO

Intramembrane proteases (IMPs) are proteolytic enzymes embedded in the lipid bilayer, where they cleave transmembrane substrates. The importance of IMPs relies on their role in a wide variety of cellular processes and diseases. In order to study the activity and function of IMPs, their purified form is often desired. The production of pure and active IMPs has proven to be a challenging task. This process unavoidably requires the use of solubilizing agents that will, to some extent, alter the native environment of these proteases. In this review we present the current solubilization and reconstitution techniques that have been applied to IMPs. In addition, we describe how these techniques had an influence on the activity and structural studies of IMPs, focusing on rhomboid proteases and γ-secretase.


Assuntos
Secretases da Proteína Precursora do Amiloide/isolamento & purificação , Proteínas de Membrana/isolamento & purificação , Peptídeo Hidrolases/isolamento & purificação , Secretases da Proteína Precursora do Amiloide/química , Secretases da Proteína Precursora do Amiloide/genética , Membrana Celular/química , Membrana Celular/enzimologia , Membrana Celular/genética , Microambiente Celular/genética , Proteínas de Membrana/química , Proteínas de Membrana/genética , Peptídeo Hidrolases/química , Peptídeo Hidrolases/genética
7.
ACS Chem Biol ; 14(11): 2372-2388, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31287658

RESUMO

Intramembrane proteases (IMPs) are localized within lipid bilayers of membranes-either the cell membrane or membranes of various organelles. Cleavage of substrates often results in release from the membrane, leading to a downstream biological effect. This mechanism allows different signaling events to happen through intramembrane proteolysis. Over the years, various mechanistically distinct families of IMPs have been discovered, but the research progress has generally been slower than for soluble proteases due to the challenges associated with membrane proteins. In this review we summarize how each mechanistic family of IMPs was discovered, which chemical tools are available for the study of IMPs, and which techniques have been developed for the discovery of IMP substrates. Finally, we discuss the various roles in cellular physiology of some of these IMPs.


Assuntos
Proteínas de Membrana/química , Proteínas de Membrana/metabolismo , Peptídeo Hidrolases/química , Peptídeo Hidrolases/metabolismo , Sequência de Aminoácidos , Secretases da Proteína Precursora do Amiloide/metabolismo , Membrana Celular/metabolismo , Cristalização , Humanos , Modelos Moleculares , Nanoestruturas/química , Ligação Proteica , Proteólise , Transdução de Sinais
8.
Eur J Med Chem ; 180: 613-626, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31351393

RESUMO

The development of multitarget compounds against multifactorial diseases, such as Alzheimer's disease, is an area of very intensive research, due to the expected superior therapeutic efficacy that should arise from the simultaneous modulation of several key targets of the complex pathological network. Here we describe the synthesis and multitarget biological profiling of a new class of compounds designed by molecular hybridization of an NMDA receptor antagonist fluorobenzohomoadamantanamine with the potent acetylcholinesterase (AChE) inhibitor 6-chlorotacrine, using two different linker lengths and linkage positions, to preserve or not the memantine-like polycyclic unsubstituted primary amine. The best hybrids exhibit greater potencies than parent compounds against AChE (IC50 0.33 nM in the best case, 44-fold increased potency over 6-chlorotacrine), butyrylcholinesterase (IC50 21 nM in the best case, 24-fold increased potency over 6-chlorotacrine), and NMDA receptors (IC50 0.89 µM in the best case, 2-fold increased potency over the parent benzohomoadamantanamine and memantine), which suggests an additive effect of both pharmacophoric moieties in the interaction with the primary targets. Moreover, most of these compounds have been predicted to be brain permeable. This set of biological properties makes them promising leads for further anti-Alzheimer drug development.


Assuntos
Adamantano/farmacologia , Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Fármacos Neuroprotetores/farmacologia , Tacrina/análogos & derivados , Acetilcolinesterase/metabolismo , Adamantano/análogos & derivados , Adamantano/química , Doença de Alzheimer/metabolismo , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Relação Estrutura-Atividade , Tacrina/química , Tacrina/farmacologia
9.
J Am Chem Soc ; 140(44): 14557-14561, 2018 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-30347979

RESUMO

Rhomboid proteases form a paradigm for intramembrane proteolysis and have been implicated in several human diseases. However, their study is hampered by difficulties in solubilization and purification. We here report on the use of polymers composed of maleic acid and either diisobutylene or styrene for solubilization of rhomboid proteases in lipid nanodiscs, which proceeds with up to 48% efficiency. We show that the activity of rhomboids in lipid nanodiscs is closer to that in the native membrane than rhomboids in detergent. Moreover, a rhomboid that was proteolytically unstable in detergent turned out to be stable in lipid nanodiscs, underlining the benefit of using these polymer-stabilized nanodiscs. The systems are also compatible with the use of activity-based probes and can be used for small molecule inhibitor screening, allowing several downstream applications.


Assuntos
Alcenos/metabolismo , Lipídeos/química , Maleatos/metabolismo , Nanopartículas/metabolismo , Polímeros/metabolismo , Serina Proteases/metabolismo , Alcenos/química , Humanos , Maleatos/química , Modelos Moleculares , Estrutura Molecular , Nanopartículas/química , Tamanho da Partícula , Polímeros/química , Serina Proteases/química , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia
10.
Chem Commun (Camb) ; 54(47): 5996-5999, 2018 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-29790509

RESUMO

The metal-catalyzed [2+2+2] cocycloaddition of arynes with pyramidalized alkenes is presented. The generation of a highly reactive pyramidalized alkene in the presence of a large excess of in situ-produced arynes led to the corresponding cocyclotrimerization (1 : 2)-adducts in good yields, establishing the first example of a palladium-based reaction of a pyramidalized alkene.

11.
Bioorg Med Chem Lett ; 28(8): 1423-1427, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29506958

RESUMO

Rhomboid proteases form one of the most widespread intramembrane protease families. They have been implicated in variety of human diseases. The currently reported rhomboid inhibitors display some selectivity, but their construction involves multistep synthesis protocols. Here, we report benzoxazin-4-ones as novel inhibitors of rhomboid proteases with a covalent, but slow reversible inhibition mechanism. Benzoxazin-4-ones can be synthesized from anthranilic acid derivatives in a one-step synthesis, making them easily accessible. We demonstrate that an alkoxy substituent at the 2-position is crucial for potency and results in low micromolar inhibitors of rhomboid proteases. Hence, we expect that these compounds will allow rapid synthesis and optimization of inhibitors of rhomboids from different organisms.


Assuntos
Benzoxazinas/farmacologia , Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas de Escherichia coli/antagonistas & inibidores , Proteínas de Membrana/antagonistas & inibidores , Inibidores de Serina Proteinase/farmacologia , Animais , Bacillus subtilis/enzimologia , Benzoxazinas/síntese química , Benzoxazinas/química , Bovinos , Quimotripsina/antagonistas & inibidores , Endopeptidases , Ensaios Enzimáticos , Escherichia coli/enzimologia , Estrutura Molecular , Inibidores de Serina Proteinase/síntese química , Inibidores de Serina Proteinase/química , Relação Estrutura-Atividade , Tripsina/química , Inibidores da Tripsina/síntese química , Inibidores da Tripsina/química , Inibidores da Tripsina/farmacologia , ortoaminobenzoatos/química
12.
Molecules ; 23(1)2018 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-29361735

RESUMO

Multi-target-directed ligands (MTDLs) offer new hope for the treatment of multifactorial complex diseases such as Alzheimer's Disease (AD). Herein, we present compounds aimed at targeting the NMDA and the P2X7 receptors, which embody a different approach to AD therapy. On one hand, we are seeking to delay neurodegeneration targeting the glutamatergic NMDA receptors; on the other hand, we also aim to reduce neuroinflammation, targeting P2X7 receptors. Although the NMDA receptor is a widely recognized therapeutic target in treating AD, the P2X7 receptor remains largely unexplored for this purpose; therefore, the dual inhibitor presented herein-which is open to further optimization-represents the first member of a new class of MTDLs.


Assuntos
Antagonistas do Receptor Purinérgico P2X/química , Antagonistas do Receptor Purinérgico P2X/farmacologia , Receptores Purinérgicos P2X/química , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Linhagem Celular Tumoral , Técnicas de Química Sintética , Relação Dose-Resposta a Droga , Desenho de Fármacos , Descoberta de Drogas , Humanos , Concentração Inibidora 50 , Ligantes , Estrutura Molecular , Antagonistas do Receptor Purinérgico P2X/síntese química , Receptores Purinérgicos P2X/metabolismo
13.
J Med Chem ; 61(1): 98-118, 2018 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-29220568

RESUMO

Two series of easily accessible anilines were identified as inhibitors of influenza A virus subtype H1N1, and extensive chemical synthesis and analysis of the structure-activity relationship were performed. The compounds were shown to interfere with low pH-induced membrane fusion mediated by the H1 and H5 (group 1) hemagglutinin (HA) subtypes. A combination of virus resistance, HA interaction, and molecular dynamics simulation studies elucidated the binding site of these aniline-based influenza fusion inhibitors, which significantly overlaps with the pocket occupied by some H3 HA-specific inhibitors, indicating the high relevance of this cavity for drug design.


Assuntos
Compostos de Anilina/química , Compostos de Anilina/farmacologia , Glicoproteínas de Hemaglutininação de Vírus da Influenza/metabolismo , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Vírus da Influenza A Subtipo H1N1/fisiologia , Internalização do Vírus/efeitos dos fármacos , Compostos de Anilina/metabolismo , Sítios de Ligação , Células HeLa , Glicoproteínas de Hemaglutininação de Vírus da Influenza/química , Humanos , Vírus da Influenza A Subtipo H1N1/metabolismo , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Mutação , Conformação Proteica
14.
Angew Chem Int Ed Engl ; 56(19): 5283-5287, 2017 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-28374543

RESUMO

Because of its importance in viral replication, the M2 proton channel of the influenza A virus has been the focus of many studies. Although we now know a great deal about the structural architecture underlying its proton conduction function, we know little about its conformational dynamics, especially those controlling the rate of this action. Herein, we employ a single-molecule fluorescence method to assess the dynamics of the inter-helical channel motion of both full-length M2 and the transmembrane domain of M2. The rate of this motion depends not only on the identity of the channel and membrane composition but also on the pH in a sigmoidal manner. For the full-length M2 channel, the rate is increased from approximately 190 µs-1 at high pH to approximately 80 µs-1 at low pH, with a transition midpoint at pH 6.1. Because the latter value is within the range reported for the conducting pKa value of the His37 tetrad, we believe that this inter-helical motion accompanies proton conduction.


Assuntos
Termodinâmica , Proteínas da Matriz Viral/metabolismo , Transporte de Elétrons , Corantes Fluorescentes/química , Concentração de Íons de Hidrogênio , Processos Fotoquímicos , Conformação Proteica , Espectrometria de Fluorescência , Proteínas da Matriz Viral/química
15.
J Med Chem ; 60(9): 3727-3738, 2017 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-28418242

RESUMO

New insights on the amantadine resistance mechanism of the V27A mutant were obtained through the study of novel, easily accessible 4-(1- and 2-adamantyl)piperidines, identified as dual binders of the wild-type and V27A mutant M2 channels of influenza A virus. Their antiviral activity and channel blocking ability were determined using cell-based assays and two-electrode voltage clamp (TEVC) technique on M2 channels, respectively. In addition, electrophysiology experiments revealed two interesting findings: (i) these inhibitors display a different behavior against the wild-type versus V27A mutant A/M2 channels, and (ii) the compounds display antiviral activity when they have kd equal or smaller than 10-6 while they do not exhibit antiviral activity when kd is 10-5 or higher although they may show blocking activity in the TEV assay. Thus, caution must be taken when predicting antiviral activity based on percent channel blockage in electrophysiological assays. These findings provide experimental evidence of the resistance mechanism of the V27A mutation to wild-type inhibitors, previously predicted in silico, offer an explanation for the lack of antiviral activity of compounds active in the TEV assay, and may help design new and more effective drugs.


Assuntos
Antivirais/farmacologia , Vírus da Influenza A/efeitos dos fármacos , Mutação , Animais , Cães , Farmacorresistência Viral , Vírus da Influenza A/genética , Vírus da Influenza A/metabolismo , Células Madin Darby de Rim Canino , Testes de Sensibilidade Microbiana , Técnicas de Patch-Clamp
16.
Chemistry ; 23(20): 4750-4755, 2017 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-28217842

RESUMO

An intramolecular acylal cyclisation (IAC) approach to the synthesis of a range of bicyclic heterocycles is reported. As an example of the utility of the IAC reaction, the methodology was applied in a protecting-group-free five-step total synthesis of (±)-γ-lycorane, incorporating a new intramolecular Heck addition reaction to generate the pentacyclic core structure of the natural product in good yield.


Assuntos
Alcaloides de Amaryllidaceae/síntese química , Alcaloides de Amaryllidaceae/química , Catálise , Complexos de Coordenação/química , Ciclização , Ácidos de Lewis/química , Paládio/química , Estereoisomerismo
17.
Bioorg Med Chem Lett ; 27(4): 759-763, 2017 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-28126517

RESUMO

The adamantane scaffold, despite being widely used in medicinal chemistry, is not devoid of problems. In recent years we have developed new polycyclic scaffolds as surrogates of the adamantane group with encouraging results in multiple targets. As an adamantane scaffold is a common structural feature in several P2X7 receptor antagonists, herein we report the synthesis and pharmacological evaluation of multiple replacement options of adamantane that maintain a good activity profile. Molecular modeling studies support the binding of the compounds to a site close to the central pore, rather than to the ATP-binding site and shed light on the structural requirements for novel P2X7 antagonists.


Assuntos
Adamantano/química , Antagonistas do Receptor Purinérgico P2X/química , Receptores Purinérgicos P2X7/metabolismo , Adamantano/síntese química , Adamantano/metabolismo , Trifosfato de Adenosina/química , Trifosfato de Adenosina/metabolismo , Sítios de Ligação , Células HEK293 , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Ligação Proteica , Estrutura Terciária de Proteína , Antagonistas do Receptor Purinérgico P2X/síntese química , Antagonistas do Receptor Purinérgico P2X/metabolismo , Receptores Purinérgicos P2X7/química , Relação Estrutura-Atividade
18.
Diabetes ; 65(10): 3185-99, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27486236

RESUMO

Fibroblast growth factor 21 (FGF21), a peptide hormone with pleiotropic effects on carbohydrate and lipid metabolism, is considered a target for the treatment of diabetes. We investigated the role of peroxisome proliferator-activated receptor (PPAR) ß/δ deficiency in hepatic FGF21 regulation. Increased Fgf21 expression was observed in the livers of PPARß/δ-null mice and in mouse primary hepatocytes when this receptor was knocked down by small interfering RNA (siRNA). Increased Fgf21 was associated with enhanced protein levels in the heme-regulated eukaryotic translation initiation factor 2α (eIF2α) kinase (HRI). This increase caused enhanced levels of phosphorylated eIF2α and activating transcription factor (ATF) 4, which is essential for Fgf21-induced expression. siRNA analysis demonstrated that HRI regulates Fgf21 expression in primary hepatocytes. Enhanced Fgf21 expression attenuated tunicamycin-induced endoplasmic reticulum stress, as demonstrated by using a neutralizing antibody against FGF21. Of note, increased Fgf21 expression in mice fed a high-fat diet or hepatocytes exposed to palmitate was accompanied by reduced PPARß/δ and activation of the HRI-eIF2α-ATF4 pathway. Moreover, pharmacological activation of HRI increased Fgf21 expression and reduced lipid-induced hepatic steatosis and glucose intolerance, but these effects were not observed in Fgf21-null mice. Overall, these findings suggest that HRI is a potential target for regulating hepatic FGF21 levels.


Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Fígado/metabolismo , PPAR delta/metabolismo , PPAR beta/metabolismo , eIF-2 Quinase/metabolismo , Fator 4 Ativador da Transcrição/genética , Fator 4 Ativador da Transcrição/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Estresse do Retículo Endoplasmático/genética , Estresse do Retículo Endoplasmático/fisiologia , Fatores de Crescimento de Fibroblastos/genética , Immunoblotting , Masculino , Camundongos , Camundongos Knockout , PPAR delta/deficiência , PPAR delta/genética , PPAR beta/deficiência , PPAR beta/genética , Fosforilação/genética , Fosforilação/fisiologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , eIF-2 Quinase/genética
19.
Bioorg Med Chem ; 23(2): 290-6, 2015 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-25515953

RESUMO

Staphylococcus aureus, especially strains resistant to multiple antibiotics, is a major pathogen for humans and animals. In this paper we have synthesized and evaluated the antibacterial activity of a new series of benzopolycyclic amines. Some of them exhibited µM MIC values against Staphylococcus aureus and other bacteria, including methicillin-resistant S. aureus MRSA. Compound 8 that displayed a good selectivity index, showed to be active in eliminating bacterial cells forming a preexisting biofilm.


Assuntos
Aminas/química , Antibacterianos/química , Aminas/síntese química , Aminas/farmacologia , Antibacterianos/síntese química , Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/fisiologia , Testes de Sensibilidade Microbiana , Pseudomonas aeruginosa/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-Atividade
20.
J Med Chem ; 57(13): 5738-47, 2014 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-24941437

RESUMO

Amantadine inhibits the M2 proton channel of influenza A virus, yet most of the currently circulating strains of the virus carry mutations in the M2 protein that render the virus amantadine-resistant. While most of the research on novel amantadine analogues has revolved around the synthesis of novel adamantane derivatives, we have recently found that other polycyclic scaffolds effectively block the M2 proton channel, including amantadine-resistant mutant channels. In this work, we have synthesized and characterized a series of pyrrolidine derivatives designed as analogues of amantadine. Inhibition of the wild-type M2 channel and the A/M2-S31N, A/M2-V27A, and A/M2-L26F mutant forms of the channel were measured in Xenopus oocytes using two-electrode voltage clamp assays. Most of the novel compounds inhibited the wild-type ion channel in the low micromolar range. Of note, two of the compounds inhibited the amantadine-resistant A/M2-V27A and A/M2-L26F mutant ion channels with submicromolar and low micromolar IC50, respectively. None of the compounds was found to inhibit the S31N mutant ion channel.


Assuntos
Amantadina/análogos & derivados , Aminas/síntese química , Vírus da Influenza A/efeitos dos fármacos , Pirrolidinas/síntese química , Proteínas da Matriz Viral/antagonistas & inibidores , Aminas/farmacologia , Animais , Cães , Farmacorresistência Viral , Canais Iônicos/efeitos dos fármacos , Células Madin Darby de Rim Canino , Modelos Moleculares , Mutação , Infecções por Orthomyxoviridae/tratamento farmacológico , Técnicas de Patch-Clamp , Pirrolidinas/farmacologia , Relação Estrutura-Atividade , Proteínas da Matriz Viral/genética , Xenopus
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