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1.
J Biomol Struct Dyn ; : 1-9, 2023 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-37837432

RESUMO

Tuberculosis (TB) is a major global cause of mortality, primarily stemming from latent tuberculosis infection (LTBI). Failure to fully treat LTBI can result in drug-resistant forms of TB. Therefore, it is essential to develop novel drugs with unique mechanisms of action to combat TB effectively. One crucial metabolic pathway in Mycobacterium tuberculosis (Mtb), which contributes to TB infection and persistence, is gluconeogenesis. Within this pathway, the enzyme fructose bisphosphatase (FBPase) plays a significant role and is considered a promising target for drug development. By targeting MtbFBPaseII, a specific class of FBPase, researchers have employed molecular dynamics simulations to identify regions capable of binding new drugs, thereby inhibiting the enzyme's activity and potentially paving the way for the development of effective treatments.Communicated by Ramaswamy H. Sarma.

2.
Bioorg Med Chem Lett ; 68: 128764, 2022 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-35504513

RESUMO

The discovery of potent and selective inhibitors for understudied kinases can provide relevant pharmacological tools to illuminate their biological functions. DYRK1A and DYRK1B are protein kinases linked to chronic human diseases. Current DYRK1A/DYRK1B inhibitors also antagonize the function of related protein kinases, such as CDC2-like kinases (CLK1, CLK2, CLK4) and DYRK2. Here, we reveal narrow spectrum dual inhibitors of DYRK1A and DYRK1B based on a benzothiophene scaffold. Compound optimization exploited structural differences in the ATP-binding sites of the DYRK1 kinases and resulted in the discovery of 3n, a potent and cell-permeable DYRK1A/DYRK1B inhibitor. This compound has a different scaffold and a narrower off-target profile compared to current DYRK1A/DYRK1B inhibitors. We expect the benzothiophene derivatives described here to aid establishing DYRK1A/DYRK1B cellular functions and their role in human pathologies.


Assuntos
Proteínas Serina-Treonina Quinases , Proteínas Tirosina Quinases , Humanos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases , Proteínas Tirosina Quinases/metabolismo , Tiofenos
3.
J Med Chem ; 64(4): 1904-1929, 2021 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-33626870

RESUMO

The modulation of melatonin signaling in peripheral tissues holds promise for treating metabolic diseases like obesity, diabetes, and nonalcoholic steatohepatitis. Here, several benzimidazole derivatives have been identified as novel agonists of the melatonin receptors MT1 and MT2. The lead compounds 10b, 15a, and 19a demonstrated subnanomolar potency at MT1/MT2 receptors, high oral bioavailability in rodents, peripherally preferred exposure, and excellent selectivity in a broad panel of targets. Two-month oral administration of 10b in high-fat diet rats led to a reduction in body weight gain similar to dapagliflozin with superior results on hepatic steatosis and triglyceride levels. An early toxicological assessment indicated that 10b (also codified as ACH-000143) was devoid of hERG binding, genotoxicity, and behavioral alterations at doses up to 100 mg/kg p.o., supporting further investigation of this compound as a drug candidate.


Assuntos
Acetamidas/uso terapêutico , Fármacos Antiobesidade/uso terapêutico , Benzimidazóis/uso terapêutico , Fígado Gorduroso/tratamento farmacológico , Receptor MT1 de Melatonina/agonistas , Receptor MT2 de Melatonina/agonistas , Acetamidas/síntese química , Acetamidas/farmacocinética , Animais , Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/farmacocinética , Compostos Benzidrílicos/farmacologia , Benzimidazóis/síntese química , Benzimidazóis/farmacocinética , Dieta Hiperlipídica , Desenho de Fármacos , Fígado Gorduroso/patologia , Glucosídeos/farmacologia , Fígado/patologia , Masculino , Camundongos , Estrutura Molecular , Obesidade/tratamento farmacológico , Ratos Sprague-Dawley , Ratos Wistar , Relação Estrutura-Atividade , Triglicerídeos/metabolismo
4.
Med Chem ; 17(5): 474-484, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-31763975

RESUMO

BACKGROUND: Antimicrobial resistance is a persistent problem regarding infection treatment and calls for developing new antimicrobial agents. Inhibition of bacterial ß-ketoacyl acyl carrier protein synthase III (FabH), which catalyzes the condensation reaction between a CoAattached acetyl group and an ACP-attached malonyl group in bacteria is an interesting strategy to find new antibacterial agents. OBJECTIVE: The aim of this work was to design and synthesize arylsulfonylhydrazones potentially FabH inhibitors and evaluate their antimicrobial activity. METHODS: MIC50 values of sulfonylhydrazones against E. coli and S. aureus were determined. Antioxidant activity was evaluated by DPPH (1-1'-diphenyl-2-picrylhydrazyl) assay and cytotoxicity against LL24 lung fibroblast cells was verified by MTT method. Principal component analysis (PCA) was performed in order to suggest a structure-activity relationship. Molecular docking allowed to propose sulfonylhydrazones interactions with FabH. RESULTS: The most active compound showed activity against S. aureus and E. coli, with MIC50 = 0.21 and 0.44 µM, respectively. PCA studies correlated better activity to lipophilicity and molecular docking indicated that sulfonylhydrazone moiety is important to hydrogen-bond with FabH while methylcatechol ring performs π-π stacking interaction. The DPPH assay revealed that some sulfonylhydrazones derived from the methylcatechol series had antioxidant activity. None of the evaluated compounds was cytotoxic to human lung fibroblast cells, suggesting that the compounds might be considered safe at the tested concentration. CONCLUSION: Arylsufonylhydrazones is a promising scaffold to be explored for the design of new antimicrobial agents.


Assuntos
3-Oxoacil-(Proteína de Transporte de Acila) Sintase/antagonistas & inibidores , Antibacterianos/farmacologia , Inibidores Enzimáticos/farmacologia , Hidrazonas/farmacologia , Sulfonamidas/farmacologia , 3-Oxoacil-(Proteína de Transporte de Acila) Sintase/química , 3-Oxoacil-(Proteína de Transporte de Acila) Sintase/metabolismo , Acetiltransferases/antagonistas & inibidores , Acetiltransferases/química , Acetiltransferases/metabolismo , Antibacterianos/síntese química , Antibacterianos/metabolismo , Domínio Catalítico , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Escherichia coli/efeitos dos fármacos , Proteínas de Escherichia coli/antagonistas & inibidores , Proteínas de Escherichia coli/química , Proteínas de Escherichia coli/metabolismo , Ácido Graxo Sintase Tipo II/antagonistas & inibidores , Ácido Graxo Sintase Tipo II/química , Ácido Graxo Sintase Tipo II/metabolismo , Hidrazonas/síntese química , Hidrazonas/metabolismo , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Análise de Componente Principal , Ligação Proteica , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/metabolismo
5.
Bioorg Med Chem Lett ; 26(16): 3988-93, 2016 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-27426865

RESUMO

The development of resistance to antibiotics by microorganisms is a major problem for the treatment of bacterial infections worldwide, and therefore, it is imperative to study new scaffolds that are potentially useful in the development of new antibiotics. In this regard, we propose the design, synthesis and biological evaluation of hybrid sulfonylhydrazone bioisosters/furoxans with potential antibacterial (Escherichia coli) activity. The most active compound of the series, (E)-3-methyl-4-((2-tosylhydrazono)methyl)-1,2,5-oxadiazole 2-oxide, with a MIC=0.36µM, was not cytotoxic when tested on Vero cells (IC50>100µM). To complement the in vitro screening, we also studied the interaction of the test compounds with ß-ketoacyl acyl carrier protein synthase (FabH), the target for the parent compounds, and we observed three important hydrogen-bonding interactions with two important active site residues in the catalytic site of the enzyme, providing complementary evidence to support the target of the new hybrid molecules.


Assuntos
Acetiltransferases/antagonistas & inibidores , Antibacterianos/química , Inibidores Enzimáticos/química , Proteínas de Escherichia coli/antagonistas & inibidores , Escherichia coli/enzimologia , 3-Oxoacil-(Proteína de Transporte de Acila) Sintase , Acetiltransferases/metabolismo , Animais , Antibacterianos/síntese química , Antibacterianos/toxicidade , Sítios de Ligação , Candida albicans/efeitos dos fármacos , Domínio Catalítico , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/toxicidade , Escherichia coli/efeitos dos fármacos , Proteínas de Escherichia coli/metabolismo , Ácido Graxo Sintase Tipo II/antagonistas & inibidores , Ácido Graxo Sintase Tipo II/metabolismo , Ligação de Hidrogênio , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Oxidiazóis/síntese química , Oxidiazóis/química , Oxidiazóis/toxicidade , Eletricidade Estática , Relação Estrutura-Atividade , Células Vero
6.
Tuberculosis (Edinb) ; 99: 11-16, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27449999

RESUMO

Tuberculosis (TB) is an important infectious disease caused by Mycobacterium tuberculosis (Mtb) and responsible for thousands of deaths every year. Although there are antimycobacterial drugs available in therapeutics, just few new chemical entities have reached clinical trials, and in fact, since introduction of rifampin only two important drugs had reached the market. Pyrazinoic acid (POA), the active agent of pyrazinamide, has been explored through prodrug approach to achieve novel molecules with anti-Mtb activity, however, there is no activity evaluation of these molecules against non-replicating Mtb until the present. Additionally, pharmacokinetic must be preliminary evaluated to avoid future problems during clinical trials. In this paper, we have presented six POA esters as prodrugs in order to evaluate their anti-Mtb activity in replicating and non-replicating Mtb, and these showed activity highly influenced by medium composition (especially by albumin). Lipophilicity seems to play the main role in the activity, possibly due to controlling membrane passage. Novel duplicated prodrugs of POA were also described, presenting interesting activity. Cytotoxicity of these prodrugs set was also evaluated, and these showed no important cytotoxic profile.


Assuntos
Antituberculosos/farmacologia , Ésteres/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Pró-Fármacos/farmacologia , Pirazinamida/análogos & derivados , Animais , Antituberculosos/síntese química , Antituberculosos/toxicidade , Proliferação de Células/efeitos dos fármacos , Chlorocebus aethiops , Relação Dose-Resposta a Droga , Ésteres/síntese química , Ésteres/toxicidade , Concentração Inibidora 50 , Testes de Sensibilidade Microbiana , Viabilidade Microbiana/efeitos dos fármacos , Estrutura Molecular , Mycobacterium tuberculosis/crescimento & desenvolvimento , Pró-Fármacos/síntese química , Pró-Fármacos/toxicidade , Pirazinamida/síntese química , Pirazinamida/farmacologia , Pirazinamida/toxicidade , Relação Estrutura-Atividade , Células Vero
7.
Curr Clin Pharmacol ; 10(2): 139-159, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-24433443

RESUMO

Tuberculosis (TB), a 19th century disease, is still present in the beginning of the Third Millennium. It has been considered pandemic, since around two billion people are infected with M. tuberculosis. Multi-drug resistant TB has been the biggest challenge for chemotherapy. In order to face this severe health problem, many institutions, private and public ones, have been investing in the search for new and better drug candidates. The pipeline of potential anti-TB drugs presents new molecules and formulations that have been submitted to pre-clinical and clinical assays. Medicinal Chemistry has an important role towards the objective of finding new leads through classic and modern processes. This paper reviews some aspects of this search, emphasizing the features of the main compounds under investigation and those that are in preliminary and final clinical trials and includes the contribution of our laboratory (LAPEN) in the area of designing new anti-TB drug candidates.

8.
Curr Pharm Des ; 20(27): 4474-85, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24245758

RESUMO

Worldwide, tuberculosis (TB) is the leading cause of death among curable infectious diseases. The emergence of multidrug resistant (MDR) and extensively drug resistant (XDR) TB is a growing global health concern and there is an urgent need for new anti-TB drugs. Enzymes involved in DNA and ATP biosynthesis are potential targets for tuberculostatic drug design, since these enzymes are essential for Mycobacterium tuberculosis growth. This review presents the current progress and applications of structure-activity relationship analysis for the discovery of innovative tuberculostatic agents as inhibitors of ribonucleotide reductase, DNA gyrase, ATP synthase, and thymidylate kinase enzymes, highlighting present challenges and new opportunities in TB drug design.


Assuntos
Antituberculosos/química , Desenho de Fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Ácidos Nucleicos/biossíntese , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Tuberculose Extensivamente Resistente a Medicamentos/microbiologia , Humanos , Estrutura Molecular , Mycobacterium tuberculosis/enzimologia , Mycobacterium tuberculosis/metabolismo , Relação Quantitativa Estrutura-Atividade , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia
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