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1.
J Med Chem ; 64(12): 8644-8665, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34080858

RESUMO

Due to the poor permeability across Gram-negative bacterial membranes and the troublesome bacterial efflux mechanism, only a few GyrB/ParE inhibitors with potent activity against Gram-negative pathogens have been reported. Among them, pyrimido[4,5-b]indole derivatives represented by GP-1 demonstrated excellent broad-spectrum antibacterial activity against both Gram-positive and Gram-negative bacteria but were limited by hERG inhibition and poor pharmacokinetics profile. To improve their drug-like properties, we designed a series of novel pyrimido[4,5-b]indole derivatives based on the tricyclic scaffold of GP-1 and the C-7 moiety of acorafloxacin. These efforts have culminated in the discovery of a promising compound 18r with reduced hERG liability and an improved PK profile. Compound 18r exhibited superior broad-spectrum in vitro antibacterial activity compared to GP-1, including a variety of clinical multidrug G- pathogens, especially Acinetobacter baumannii, and the in vivo efficacy was also demonstrated in a neutropenic mouse thigh model of infection with multidrug-resistant A. baumannii.


Assuntos
Infecções por Acinetobacter/tratamento farmacológico , Antibacterianos/uso terapêutico , Bactérias/efeitos dos fármacos , Indóis/uso terapêutico , Pirimidinas/uso terapêutico , Animais , Antibacterianos/síntese química , Antibacterianos/metabolismo , Antibacterianos/farmacocinética , DNA Girase/metabolismo , Desenho de Fármacos , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Estabilidade de Medicamentos , Células HEK293 , Humanos , Indóis/síntese química , Indóis/metabolismo , Indóis/farmacocinética , Testes de Sensibilidade Microbiana , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/metabolismo , Pirimidinas/farmacocinética , Ratos , Relação Estrutura-Atividade
2.
Bioorg Med Chem ; 31: 115953, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33388655

RESUMO

Prostate cancer (PC) is the most common malignancy in men worldwide. Here, two series of novel thiohydantoin derivatives of enzalutamide as potent androgen receptor (AR) antagonists were designed and synthesized. Among them, compound 31c was identified as an AR antagonist which is 2.3-fold more potent than enzalutamide. Molecular docking studies were performed to explain the improved potency of 31c at AR. In cell proliferation assays, 31c exhibited similar anti-proliferative activities with enzalutamide against hormone sensitive LNCaP cells and AR-overexpressing LNCaP/AR cells. These data indicate that 31c can be a good lead compound for further structure optimization for the treatment of prostate cancer.


Assuntos
Antagonistas de Receptores de Andrógenos/farmacologia , Desenho de Fármacos , Neoplasias da Próstata/tratamento farmacológico , Tioidantoínas/farmacologia , Antagonistas de Receptores de Andrógenos/síntese química , Antagonistas de Receptores de Andrógenos/química , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Masculino , Modelos Moleculares , Estrutura Molecular , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Relação Estrutura-Atividade , Tioidantoínas/síntese química , Tioidantoínas/química
3.
Bioorg Med Chem Lett ; 35: 127799, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33476772

RESUMO

Antimicrobial resistance is a global challenge and the effectiveness of old antibiotics is decreasing. Discovery and development of antibacterial agents have been accelerated to replenish the arsenal of antibiotics which is limited and shrinking. In recent years, significant advances have achieved in the antibacterial area, including new compounds of known classes and new compounds with new mechanisms. This review summarizes these advances and provides perspective on future directions of antibacterial agents.


Assuntos
Antibacterianos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Antibacterianos/química , Testes de Sensibilidade Microbiana , Conformação Molecular
4.
Arch Pharm (Weinheim) ; 352(11): e1900129, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31478565

RESUMO

To gain further knowledge of the structure-activity relationship and druggability of novel oxazolidinone-based UDP-3-O-acyl-N-acetylglucosamine deacetylase (LpxC) inhibitors as Gram-negative antibacterial agents, compounds containing the hydrophobic tails with different lengths and terminal substitutions were synthesized and their antibacterial activities against standard and clinically isolated Gram-negative strains were evaluated. We summarized their structure-activity relationships and found that oxazolidinone-based compounds exhibited a narrower antibacterial spectrum compared with threonine-based compounds. Furthermore, we parallelly compared the metabolic stabilities of the compounds with the classic threonine scaffold and the novel oxazolidinone scaffold in liver microsomes. The results indicated that the druggability of the oxazolidinone scaffold may be inferior to the classic threonine scaffold in the design of LpxC inhibitors.


Assuntos
Antibacterianos/farmacologia , Escherichia coli/efeitos dos fármacos , Oxazolidinonas/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Oxazolidinonas/síntese química , Oxazolidinonas/química , Relação Estrutura-Atividade
5.
J Med Chem ; 62(6): 3088-3106, 2019 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-30843696

RESUMO

P2Y12 antagonists are widely used as antiplatelet agents for the prevention and treatment of arterial thrombosis. Based on the scaffold of a known P2Y12 antagonist AZD1283, a series of novel bicyclic pyridine derivatives were designed and synthesized. The cyclization of the ester substituent on the pyridine ring to the ortho-methyl group led to lactone analogues of AZD1283 that showed significantly enhanced metabolic stability in subsequent structure-pharmacokinetic relationship studies. The metabolic stability was further enhanced by adding a 4-methyl substituent to the piperidinyl moiety. Compound 58l displayed potent inhibition of platelet aggregation in vitro as well as antithrombotic efficacy in a rat ferric chloride model. Moreover, 58l showed a safety profile that was superior to what was observed for clopidogrel in a rat tail-bleeding model. These results support the further evaluation of compound 58l as a promising drug candidate.


Assuntos
Descoberta de Drogas , Niacina/análogos & derivados , Inibidores da Agregação Plaquetária/farmacologia , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Receptores Purinérgicos P2Y12/efeitos dos fármacos , Sulfonamidas/farmacologia , Animais , Humanos , Masculino , Niacina/química , Niacina/farmacocinética , Niacina/farmacologia , Inibidores da Agregação Plaquetária/química , Inibidores da Agregação Plaquetária/farmacocinética , Antagonistas do Receptor Purinérgico P2Y/química , Antagonistas do Receptor Purinérgico P2Y/farmacocinética , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacocinética
6.
Bioorg Med Chem Lett ; 29(6): 848-852, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30685095

RESUMO

FFA1 (free fatty acid receptor 1) has emerged as an attractive antidiabetic target due to its role in mediating the enhancement of glucose-stimulated insulin secretion in pancreatic ß cells with a low risk of hypoglycemia. Many reported FFA1 agonists possessed somewhat pharmacokinetic and/or safety issues. Herein, we describe the identification of 2,3-dihydrobenzo[b][1,4]dioxine as a novel scaffold for FFA1 agonists. Comprehensive structure-activity relationship study based on this scaffold led to the discovery of (S)-3-(4-(((S)-7-(4-methoxyphenyl)-2,3-dihydrobenzo [b][1,4]dioxin-2-yl)methoxy) phenyl)hex-4-ynoic acid (26k), which displayed a potent FFA1 agonistic activity and good pharmacokinetic profiles. Subsequent in vivo studies demonstrated that compound 26k significantly improved the glucose tolerance in ICR mice. In summary, compound 26k is a promising drug candidate for further investigation.


Assuntos
Dioxanos/farmacologia , Hipoglicemiantes/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Animais , Glicemia/efeitos dos fármacos , Dioxanos/síntese química , Dioxanos/farmacocinética , Células HEK293 , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacocinética , Masculino , Camundongos Endogâmicos ICR , Estrutura Molecular , Ratos Sprague-Dawley , Relação Estrutura-Atividade
7.
J Med Chem ; 62(6): 2950-2973, 2019 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-30698430

RESUMO

Spiropyrimidinetriones are a novel class of antibacterial agents that target the bacterial type II topoisomerase via a new mode of action. Compound ETX0914 is thus far the only drug from this class that is being evaluated in clinical trials. To improve the antibacterial activity and pharmacokinetic properties of ETX0914, we carried out systematic structural modification of this compound, and a number of compounds with increased potency were obtained. The most promising compound 33e, with incorporation of a spirocyclopropane at the oxazolidinone 5 position reduced metabolism, exhibited excellent antibacterial activity against Gram-positive pathogens and a good pharmacokinetic profile combined with high aqueous solubility. In addition, compound 33e exhibited good selectivity for Staphylococcus aureus gyrase over human Topo IIα. In a murine model of systemic methicillin-resistant S. aureus infection, 33e exhibited superior in vivo efficacy (ED50 = 3.87 mg/kg) compared to ETX0914 (ED50 = 11.51 mg/kg).


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , DNA Girase/efeitos dos fármacos , Desenho de Fármacos , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Inibidores da Topoisomerase II/química , Inibidores da Topoisomerase II/farmacologia , Animais , Antibacterianos/farmacocinética , Cães , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Infecções por Bactérias Gram-Positivas/microbiologia , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Ratos , Compostos de Espiro/farmacocinética , Relação Estrutura-Atividade , Inibidores da Topoisomerase II/farmacocinética
8.
Bioorg Med Chem ; 26(22): 5780-5791, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30392954

RESUMO

GPR40 has become a new potential therapeutic target for the treatment of diabetes due to its role in mediating the enhancement of glucose-stimulated insulin secretion in pancreatic ß cells with a low risk of hypoglycemia. As an effort to extend the chemical space and identify structurally distinct GPR40 agonists with improved liver safety, a novel series of fused-ring phenyl propanoic acid analogues were designed. Comprehensive structure-activity relationship studies around novel scaffolds were conducted and led to several analogues exhibited potent GPR40 agonistic activities and high selectivity against other fatty acid receptors. Further evaluation of pharmacokinetic (PK) profiles and in vivo efficacy identified compound 40a with excellent PK properties and significant glucose-lowering efficacy during an oral glucose tolerance test. In addition, compound 40a displayed lower hepatobiliary transporter inhibition and favorable druggability. All results indicate that compound 40a is a promising candidate for further development.


Assuntos
Desenho de Fármacos , Hipoglicemiantes/farmacocinética , Propionatos/farmacocinética , Receptores Acoplados a Proteínas G/agonistas , Animais , Glicemia/efeitos dos fármacos , Relação Dose-Resposta a Droga , Teste de Tolerância a Glucose , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/química , Estrutura Molecular , Propionatos/administração & dosagem , Propionatos/química , Ratos , Ratos Sprague-Dawley , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Relação Estrutura-Atividade
9.
Eur J Med Chem ; 151: 98-109, 2018 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-29605810

RESUMO

A series of novel pyridone conjugated monobactams with various substituents at the (4) position were synthesized and evaluated for their antibacterial activities against a panel of multidrug-resistant (MDR) Gram-negative bacteria in vitro. Compounds 46d, 54 and 75e displayed good to moderate activities against P. aeruginosa, among which the activity of 75e against P. aeruginosa was comparable to that of BAL30072 under iron limitation condition. Compounds 35, 46d, 54, 56a, 56c and 56d exhibited good to excellent antibacterial activities against E. coli and K. pneumoniae, which were comparable or superior to that of BAL30072. In vitro liver microsomal stability was further evaluated and the results manifested that Compounds 35, 46d and 54 were metabolically stable in human liver microsomes.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Monobactamas/química , Monobactamas/farmacologia , Antibacterianos/síntese química , Desenho de Fármacos , Resistência a Múltiplos Medicamentos , Farmacorresistência Bacteriana Múltipla , Escherichia coli/efeitos dos fármacos , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Humanos , Klebsiella pneumoniae/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Monobactamas/síntese química , Pseudomonas aeruginosa/efeitos dos fármacos , Piridonas/síntese química , Piridonas/química , Piridonas/farmacologia
10.
Bioorg Med Chem Lett ; 28(3): 344-350, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29289430

RESUMO

In this letter, we report our efforts to design, synthesize and evaluate biological activities of a series of novel hybridized compounds containing 1-tetrazole and 4-pyridinyl-1,2,4-triazole-3-one. An analysis of structure-activity data indicates that the target compounds with bulky and hydrophobic side chains exhibited stronger activities against the Candida spp and Cryptococcus neoformans tested than those of fluconazole and racemic VT-1161. Furthermore, 13k and 13ad were active against Microsporum gypseum, which was resistant to racemic VT-1161. In addition, 13k, 13ac and 13ad, with good in vitro activities against all of pathogenic fungi tested except for Aspergillus fumigatus, had no inhibition of human CYP3A4, suggesting a low risk of drug-drug interactions.


Assuntos
Antifúngicos/farmacologia , Candida/efeitos dos fármacos , Cryptococcus neoformans/efeitos dos fármacos , Desenho de Fármacos , Microsporum/efeitos dos fármacos , Tetrazóis/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Citocromo P-450 CYP3A/metabolismo , Relação Dose-Resposta a Droga , Interações Medicamentosas , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade , Tetrazóis/síntese química , Tetrazóis/química
11.
Bioorg Med Chem Lett ; 28(2): 94-102, 2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-29233653

RESUMO

LpxC inhibitors are new-type antibacterial agents developed in the last twenty years, mainly against Gram-negative bacteria infections. To develop novel LpxC inhibitors with good antibacterial activities and biological metabolism, we summarized the basic skeleton of reported LpxC inhibitors, designed and synthesized several series of compounds and tested their antibacterial activities against Escherichial coli and Pseudomonas aeruginosa in vitro. Structure-activity relationships have been discussed in this article. The metabolism stability of YDL-2, YDL-5, YDL-8, YDL-14, YDL-20-YDL-23 have been evaluated in liver microsomes, which indicated that the 2-amino isopropyl group may be a preferred structure than the 2-hydroxy ethyl group in the design of LpxC inhibitors.


Assuntos
Amidoidrolases/antagonistas & inibidores , Antibacterianos/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Escherichia coli/efeitos dos fármacos , Pseudomonas aeruginosa/efeitos dos fármacos , Amidoidrolases/metabolismo , Antibacterianos/síntese química , Antibacterianos/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade
12.
J Med Chem ; 60(7): 2669-2684, 2017 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-28287720

RESUMO

Conjugating a siderophore to an antibiotic is a promising strategy to overcome the permeability-mediated resistance of Gram-negative pathogens. On the basis of the structure of BAL30072, novel pyridone-conjugated monosulfactams incorporating diverse substituents into the methylene linker between the 1,3-dihydroxypyridin-4(1H)-one and the aminothiazole oxime were designed and synthesized. Structure-activity relationship studies revealed that a variety of substituents were tolerated, with isopropyl (compound 12c) and methylthiomethyl (compound 16a) showing the best efficacy against multidrug-resistant (MDR) Gram-negative pathogens. In addition, compound 12c exhibits a good free fraction rate in an in vitro human plasma protein binding test, along with a low clearance and favorable plasma exposure in vivo. In a murine systemic infection model with MDR Klebsiella pneumoniae, compound 12c shows an ED50 of 10.20 mg/kg. Taken together, the results indicate that compound 12c is a promising drug candidate for the treatment of serious infections caused by MDR Gram-negative pathogens.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Farmacorresistência Bacteriana Múltipla , Bactérias Gram-Negativas/efeitos dos fármacos , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Monobactamas/química , Monobactamas/farmacologia , Tiazóis/química , Tiazóis/farmacologia , Animais , Antibacterianos/sangue , Antibacterianos/uso terapêutico , Descoberta de Drogas , Escherichia coli/efeitos dos fármacos , Infecções por Escherichia coli/tratamento farmacológico , Humanos , Infecções por Klebsiella/tratamento farmacológico , Klebsiella pneumoniae/efeitos dos fármacos , Masculino , Camundongos , Testes de Sensibilidade Microbiana , Monobactamas/sangue , Monobactamas/uso terapêutico , Piridonas/sangue , Piridonas/química , Piridonas/farmacologia , Piridonas/uso terapêutico , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Tiazóis/sangue , Tiazóis/uso terapêutico
13.
Eur J Med Chem ; 102: 471-6, 2015 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-26310892

RESUMO

In order to further enhance the anti-Aspergillus efficacy of our previously discovered antifungal lead compounds (I), two series of novel azoles featuring thieno[2,3-c]pyrrolidone and thieno[3,2-c]pyrrolidone nuclei were designed and evaluated for their in vitro activity on the basis of the binding mode of albaconazole using molecular docking, along with SARs of antifungal triazoles. Most of target compounds exhibited excellent activity against Candida and Cryptococcus spp., with MIC values in the range of 0.0625 µg/ml to 0.0156 µg/ml. The thieno[3,2-c]pyrrolidone unit was more suited for improving activity against Aspergillus spp. The most potent compound, 18a, was selected for further development due to its significant in vitro activity against Aspergillus spp. (MIC = 0.25 µg/ml), as well as its high metabolic stability in human liver microsomes.


Assuntos
Antifúngicos/farmacologia , Aspergillus fumigatus/efeitos dos fármacos , Azóis/farmacologia , Desenho de Fármacos , Pirróis/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Azóis/síntese química , Azóis/química , Candida/efeitos dos fármacos , Cryptococcus neoformans/efeitos dos fármacos , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pirróis/síntese química , Pirróis/química , Relação Estrutura-Atividade
14.
Bioorg Med Chem Lett ; 25(10): 2203-10, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25838143

RESUMO

In our previous Letter, we reported the discovery of a novel benzoxazinyl-oxazolidinone antibacterial candidate 2. In order to identify a potential backup compound, extensive modifications on the B/C ring and C3 side chain were undertaken. A series of novel [6,6,5] tricyclic analogues were synthesized and their in vitro antibacterial activities were tested against a panel of susceptible and resistant Gram-positive pathogens. Among of them, benzothiazinyl-oxazolidinones with acetamide or thioamide as C3 side chains exhibited moderate to good antibacterial activity, such as compounds 54, 58, 59 and 63. In vitro liver microsomal stability was further evaluated and the results manifested that compounds 54 and 58 were both metabolically stable in rat and human liver microsomes. Additionally, insights gained from this investigation should provide directions for the further research of new oxazolidinone antibiotics.


Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Bactérias Gram-Positivas/efeitos dos fármacos , Oxazolidinonas/síntese química , Oxazolidinonas/farmacologia , Animais , Antibacterianos/química , Ciclização , Humanos , Microssomos Hepáticos/efeitos dos fármacos , Estrutura Molecular , Oxazolidinonas/química , Ratos , Relação Estrutura-Atividade
15.
J Med Chem ; 57(18): 7770-91, 2014 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-25179681

RESUMO

The blood coagulation enzyme factor Xa (FXa) is a particularly promising target for anticoagulant therapy, and identification of oral small-molecule inhibitors of FXa remains a research focus. On the basis of the X-ray crystal structure of FXa and its inhibitor rivaroxaban, we designed and synthesized a series of conformationally restricted mimics containing a novel [6,6,5] tricyclic fused oxazolidinone scaffold. Intensive structure-activity relationship (SAR) and structure-pharmacokinetic relationship (SPR) studies on this new series led to the discovery of compound 11a: a highly potent, selective, direct, and orally bioavailable FXa inhibitor with excellent in vivo antithrombotic efficacy and preferable pharmacokinetic profiles. Druggability evaluation of compound 11a was undertaken and elicited positive outcomes. All results indicate that compound 11a is a promising drug candidate for the prevention and treatment of thromboembolic diseases in venous and arterial systems.


Assuntos
Desenho de Fármacos , Inibidores do Fator Xa/química , Inibidores do Fator Xa/farmacocinética , Fator Xa/metabolismo , Oxazolidinonas/química , Oxazolidinonas/farmacocinética , Administração Oral , Animais , Disponibilidade Biológica , Coagulação Sanguínea/efeitos dos fármacos , Técnicas de Química Sintética , Inibidores do Fator Xa/administração & dosagem , Inibidores do Fator Xa/farmacologia , Oxazolidinonas/administração & dosagem , Oxazolidinonas/farmacologia , Ratos , Relação Estrutura-Atividade , Trombose/tratamento farmacológico
16.
Eur J Med Chem ; 86: 133-52, 2014 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-25151577

RESUMO

Peptide deformylase (PDF) has been identified as a promising target for novel antibacterial agents. In this study, a series of novel formyl hydroxyamino derivatives were designed and synthesized as PDF inhibitors and their antibacterial activities were evaluated. Among the potent PDF inhibitors (1o, 1q, 1o', 1q', and 1x), in vivo studies showed that compound 1q possesses mild toxicity, a good pharmacokinetic profile and protective effects. The good in vivo efficacy and low toxicity suggest that this class of compounds has potential for development and use in future antibacterial drugs.


Assuntos
Amidoidrolases/antagonistas & inibidores , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Farmacorresistência Bacteriana/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Oligopeptídeos/farmacologia , Amidoidrolases/metabolismo , Antibacterianos/síntese química , Antibacterianos/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Oligopeptídeos/síntese química , Oligopeptídeos/química , Relação Estrutura-Atividade
17.
J Med Chem ; 57(11): 4772-95, 2014 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-24874438

RESUMO

A series of novel thioether pleuromutilin derivatives incorporating various heteroaromatic substituents into the C14 side chain have been reported. Structure-activity relationship (SAR) studies resulted in compounds 52 and 55 with the most potent in vitro antibacterial activity among the series (MIC = 0.031-0.063 µg/mL). Further optimization to overcome the poor water solubility of compound 55 resulted in compounds 87, 91, 109, and 110 possessing good in vitro antibacterial activity with increased hydrophilicity. Compound 114, the water-soluble phosphate prodrug of compound 52, was also prepared and evaluated. Among the derivatives, compound 110 showed moderate pharmacokinetic profiles and good in vivo efficacy in both MSSA and MRSA systemic infection models. Compound 110 was further evaluated in CYP450 inhibition assay and displayed intermediate in vitro inhibition of CYP3A4.


Assuntos
Aminopiridinas/síntese química , Antibacterianos/síntese química , Diterpenos/síntese química , Staphylococcus/efeitos dos fármacos , Streptococcus/efeitos dos fármacos , Sulfetos/síntese química , Aminopiridinas/farmacocinética , Aminopiridinas/farmacologia , Animais , Antibacterianos/farmacocinética , Antibacterianos/farmacologia , Citocromo P-450 CYP3A , Inibidores do Citocromo P-450 CYP3A , Diterpenos/farmacocinética , Diterpenos/farmacologia , Desenho de Fármacos , Farmacorresistência Bacteriana , Estabilidade de Medicamentos , Feminino , Humanos , Interações Hidrofóbicas e Hidrofílicas , Técnicas In Vitro , Masculino , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Camundongos , Testes de Sensibilidade Microbiana , Compostos Policíclicos , Ratos , Ratos Sprague-Dawley , Solubilidade , Infecções Estafilocócicas/tratamento farmacológico , Relação Estrutura-Atividade , Sulfetos/farmacocinética , Sulfetos/farmacologia
18.
J Med Chem ; 57(9): 3687-706, 2014 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-24564525

RESUMO

Triazoles with fused-heterocycle nuclei were designed and evaluated for their in vitro activity on the basis of the binding mode of albaconazole using molecular docking, along with SAR of antifungal triazoles. Tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine and tetrahydro-thiazolo[5,4-c]pyridine nuclei were preferable to the other four fused-heterocycle nuclei investigated. Potent in vitro activity, broad spectrum and better water solubility were attained when triazoles containing nitrogen aromatic heterocycles were attached to these two nuclei. The most potent compounds 27aa and 45x, with low hERG inhibition and hepatocyte toxicity, both exhibited excellent activity against Candida, Cryptococcus, and Aspergillus spp., as well as selected fluconazole-resistant strains. A high water-soluble compound 58 (the disulfate salt of 45x) displayed unsatisfactory in vivo activity because of its poor PK profiles. Mice infected with C.alb. SC5314 and C.alb. 103 (fluconazole-resistant strain) and administered with 27aa displayed significantly improved survival rates. 27aa also showed favorable pharmacokinetic (PK) profiles.


Assuntos
Antifúngicos/química , Desenho de Fármacos , Compostos Heterocíclicos/química , Triazóis/química , Animais , Antifúngicos/síntese química , Antifúngicos/farmacocinética , Antifúngicos/farmacologia , Área Sob a Curva , Candida/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Camundongos , Camundongos Endogâmicos ICR , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Ratos , Solubilidade , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/farmacocinética , Triazóis/farmacologia , Água/química
19.
Bioorg Med Chem Lett ; 23(13): 3697-9, 2013 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-23721807

RESUMO

A number of benzoxazinyl-oxazolidinones bearing 3-trizolylmethyl or 3-carboxamide side chain were designed and synthesized with the aim to develop antibacterial agents with improved properties. In vitro antibacterial activities of these novel compounds were evaluated against a panel of resistant and susceptible Gram-positive bacteria. Most analogues bearing 3-trizolylmethyl showed good to moderate antibacterial activities. Compound 12a exhibited a fourfold increase in activity compared with linezolid against all the tested strains, which was identified to be a promising antibacterial agent for further evaluation.


Assuntos
Antibacterianos/farmacologia , Benzoxazinas/farmacologia , Bactérias Gram-Positivas/efeitos dos fármacos , Oxazolidinonas/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Benzoxazinas/química , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Oxazolidinonas/química , Relação Estrutura-Atividade
20.
J Med Chem ; 56(6): 2642-50, 2013 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-23428155

RESUMO

The solubility-driven structural modification of (pyridin-3-yl) benzoxazinyl-oxazolidinones is described, which resulted in the development of a new series of benzoxazinyl-oxazolidinone analogues with high antibacterial activity against Gram-positive pathogens, including that against linezolid-resistant strains and low hERG inhibition. With regard to structure-activity relationship (SAR) trends among the various substituents on the pyridyl ring, relatively small and nonbasic substituents were preferable to sterically demanding or basic substituents. Oxazolidinone ring substitution on the pyridyl ring generated analogues with antibacterial activity superior to imidazolidinone ring. Solubility was enhanced by the incorporation of polar groups, especially when compounds were converted to their prodrugs. Among the prodrugs, compound 85 exhibited excellent solubility and a good pharmacokinetic profile. In a MRSA systemic infection model, compound 85 displayed an ED50 = 5.00 mg/kg, a potency that is 2-fold better than that of linezolid.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Desenho de Fármacos , Oxazolidinonas/química , Oxazolidinonas/farmacologia , Animais , Antibacterianos/farmacocinética , Bactérias/efeitos dos fármacos , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Feminino , Camundongos , Testes de Sensibilidade Microbiana , Oxazolidinonas/farmacocinética , Solubilidade
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