RESUMO
DNA gyrase enzyme has vital role in bacterial survival and can be considered as a potential drug target. Owing to the appearance of resistance to gyrase-targeted drugs, especially fluoroquinolone, screening new compounds which bind more efficiently to the mutant binding pocket is essential. Hence, in this work, using Smina Autodock and through structure-based virtual screening of StreptomeDB, several natural products were discovered based on the SimocyclinoneD8 (SD8) binding pocket of GyrA subunit of DNA gyrase. After evaluation of binding affinity, binding modes, critical interactions and physicochemical and pharmaceutical properties, three lead compounds were selected for further analysis. Afterward 60 ns molecular dynamics simulations were performed and binding free energies were calculated by the molecular mechanics/Poisson-Boltzmann surface area method. Also, interaction of the selected lead compounds with the mutated GyrA protein was evaluated. Results indicated that all of the selected compounds could bind to the both wild-type and mutated GyrA with the binding affinities remarkably higher than SimocyclinoneD8. Interestingly, we noticed that the selected compounds comprised angucycline moiety in their structure which could sufficiently interact with GyrA and block the DNA binding pocket of DNA gyrase, in silico. In conclusion, three DNA gyrase inhibitors were identified successfully which were highly capable of impeding DNA gyrase and can be considered as potential drug candidates for treatment of fluoroquinolone-resistant strains.Communicated by Ramaswamy H. Sarma.
Assuntos
DNA Girase/química , Avaliação Pré-Clínica de Medicamentos , Simulação de Dinâmica Molecular , Streptomyces/química , Inibidores da Topoisomerase II/química , Inibidores da Topoisomerase II/farmacologia , Sítios de Ligação , DNA Girase/genética , Escherichia coli/enzimologia , Ligação de Hidrogênio , Simulação de Acoplamento Molecular , Mutação/genética , Relação Estrutura-Atividade , Termodinâmica , Inibidores da Topoisomerase II/farmacocinéticaRESUMO
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/farmacocinéticaRESUMO
During the course of our research on the lead optimisation of the NBTI (Novel Bacterial Type II Topoisomerase Inhibitors) class of antibacterials, we discovered a series of tricyclic compounds that showed good Gram-positive and Gram-negative potency. Herein we will discuss the various subunits that were investigated in this series and report advanced studies on compound 1 (GSK945237) which demonstrates good PK and in vivo efficacy properties.
Assuntos
Antibacterianos/farmacologia , Compostos Heterocíclicos com 3 Anéis/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/química , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Inibidores da Topoisomerase II/química , Inibidores da Topoisomerase II/farmacologia , Animais , Antibacterianos/química , Antibacterianos/farmacocinética , Técnicas de Química Sintética , DNA Topoisomerases Tipo II/química , DNA Topoisomerases Tipo II/metabolismo , Cães , Avaliação Pré-Clínica de Medicamentos/métodos , Canal de Potássio ERG1/metabolismo , Bactérias Anaeróbias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/síntese química , Compostos Heterocíclicos com 3 Anéis/química , Infecções Pneumocócicas/tratamento farmacológico , Ratos , Infecções Respiratórias/tratamento farmacológico , Infecções Respiratórias/microbiologia , Inibidores da Topoisomerase II/farmacocinéticaRESUMO
PURPOSE: F14512 is a new topoisomerase II inhibitor containing a spermine moiety that facilitates selective uptake by tumor cells and increases topoisomerase II poisoning. F14512 is currently in a phase I/II clinical trial in patients with acute myeloid leukemia. The aim of this study was to investigate F14512 potential in a new clinical indication. Because of the many similarities between human and dog lymphomas, we sought to determine the tolerance, efficacy, pharmacokinetic/pharmacodynamic (PK/PD) relationship of F14512 in this indication, and potential biomarkers that could be translated into human trials. EXPERIMENTAL DESIGN: Twenty-three dogs with stage III-IV naturally occurring lymphomas were enrolled in the phase I dose-escalation trial, which consisted of three cycles of F14512 i.v. injections. Endpoints included safety and therapeutic efficacy. Serial blood samples and tumor biopsies were obtained for PK/PD and biomarker studies. RESULTS: Five dose levels were evaluated to determine the recommended dose. F14512 was well tolerated, with the expected dose-dependent hematologic toxicity. F14512 induced an early decrease of tumoral lymph node cells, and a high response rate of 91% (21/23) with 10 complete responses, 11 partial responses, 1 stable disease, and 1 progressive disease. Phosphorylation of histone H2AX was studied as a potential PD biomarker of F14512. CONCLUSIONS: This trial demonstrated that F14512 can be safely administered to dogs with lymphoma resulting in strong therapeutic efficacy. Additional evaluation of F14512 is needed to compare its efficacy with standards of care in dogs, and to translate biomarker and efficacy findings into clinical trials in humans.
Assuntos
Antineoplásicos/farmacologia , Doenças do Cão/tratamento farmacológico , Linfoma/veterinária , Podofilotoxina/análogos & derivados , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Biomarcadores , Linhagem Celular Tumoral , Doenças do Cão/metabolismo , Doenças do Cão/patologia , Cães , Avaliação Pré-Clínica de Medicamentos , Feminino , Histonas/metabolismo , Humanos , Masculino , Estadiamento de Neoplasias , Podofilotoxina/efeitos adversos , Podofilotoxina/farmacocinética , Podofilotoxina/farmacologia , Inibidores da Topoisomerase II/efeitos adversos , Inibidores da Topoisomerase II/farmacocinética , Inibidores da Topoisomerase II/farmacologia , Resultado do TratamentoRESUMO
PURPOSE: Proliferative vitreoretinopathy (PVR) is the most common cause of poor visual outcomes in association with retinal detachment surgeries and ocular trauma. Daunorubicin (DNR) has shown the strongest efficacy in proliferation inhibition in vitro. However, clinical studies have shown only mild effect owing to limitations of narrow therapeutic window and short vitreous half-life. METHODS: Three milligrams of DNR-loaded particles were intravitreally injected into 18 pigmented rabbits, and vitreous samples were collected up to 84 days for analysis. Thirty-seven rabbits were used for a dose-escalation (1, 3, 6 mg) safety and efficacy study in a rabbit PVR model using a pretreatment design. RESULTS: Loading efficiency of DNR was 108.55 ± 12 µg per 1 mg particles. Eighty-four days of follow-up did not reveal any adverse reaction. Pharmacokinetic analysis demonstrated a vitreous half-life of 29 days with a maximum DNR concentration of 178 ng/mL and a minimum concentration of 29 ng/mL at day 84. Daunorubicin-loaded porous silicon (pSi) particles were dosed 8 to 9 weeks before PVR induction, and PVR severity score was dose dependent (Spearman ρ = -0.25, P = 0.0005). Proliferative vitreoretinopathy with tractional retinal detachment was 88% in the control group, 63% in the low-dose group, 14% in the medium-dose group, and 0% in the high-dose group (Cochran-Armitage Trend Test, Z = 8.99, ρ = -0.67, P < 0.0001). CONCLUSIONS: Daunorubicin-loaded pSi particles can safely reside in the vitreous for at least 3 months. The pSi-based delivery expanded the therapeutic window of DNR by a factor of 862 and drove down the minimum effective concentration by a factor of 175.
Assuntos
Daunorrubicina/farmacocinética , Silício , Vitreorretinopatia Proliferativa/tratamento farmacológico , Corpo Vítreo/metabolismo , Animais , Daunorrubicina/administração & dosagem , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Sistemas de Liberação de Medicamentos , Porosidade , Coelhos , Inibidores da Topoisomerase II/administração & dosagem , Inibidores da Topoisomerase II/farmacocinética , Vitreorretinopatia Proliferativa/metabolismoRESUMO
Anacetrapib is a cholesteryl ester transfer protein inhibitor in Phase III development. This double-blind, double-dummy, randomized, placebo- and active-comparator-controlled, 4-period, balanced crossover study evaluated the effects of anacetrapib (100 mg and 800 mg) on QTcF interval in healthy subjects. QTcF measurements were made up to 24 h following administration of single doses of anacetrapib 100 or 800 mg, moxifloxacin 400 mg, or placebo in the fed state. The primary hypothesis was supported if the 90% CI for the least squares (LS) mean differences between anacetrapib 800 mg and placebo in QTcF interval change from baseline were entirely <10 msec at every post-dose time point (1, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 h). The upper bounds of the 90% CIs for LS mean differences from placebo in changes from baseline in QTcF intervals for anacetrapib 100 and 800 mg were <5 msec at every time point. In conclusion, single doses of anacetrapib 100 and 800 mg do not prolong the QTcF interval to a clinically meaningful degree relative to placebo and are generally well tolerated in healthy subjects.
Assuntos
Anticolesterolemiantes/administração & dosagem , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Drogas em Investigação/administração & dosagem , Coração/efeitos dos fármacos , Modelos Biológicos , Oxazolidinonas/administração & dosagem , Adolescente , Adulto , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Antibacterianos/sangue , Antibacterianos/farmacocinética , Anticolesterolemiantes/efeitos adversos , Anticolesterolemiantes/sangue , Anticolesterolemiantes/farmacocinética , Arritmias Cardíacas/induzido quimicamente , Estudos de Coortes , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Drogas em Investigação/efeitos adversos , Drogas em Investigação/farmacocinética , Eletrocardiografia/efeitos dos fármacos , Feminino , Fluoroquinolonas/administração & dosagem , Fluoroquinolonas/efeitos adversos , Fluoroquinolonas/sangue , Fluoroquinolonas/farmacocinética , Humanos , Masculino , Pessoa de Meia-Idade , Moxifloxacina , Oxazolidinonas/efeitos adversos , Oxazolidinonas/sangue , Oxazolidinonas/farmacocinética , Inibidores da Topoisomerase II/administração & dosagem , Inibidores da Topoisomerase II/efeitos adversos , Inibidores da Topoisomerase II/sangue , Inibidores da Topoisomerase II/farmacocinética , Adulto JovemRESUMO
OBJECTIVE: The aim of this study is to evaluate the antifilarial, antiwolbachial and DNA topoisomerase II inhibitory activity of nanocurcumin (nano-CUR). METHODS: Nano-CUR formulations (F1-F6) were prepared using free radical polymerization and were characterized by particle size, morphology, encapsulation efficiency and in vitro release kinetics. Antifilarial potential was evaluated in vivo against Brugian filariasis in an experimental rodent model, Mastomys coucha, by selecting the formulation that maximized parasite elimination characteristics. Wolbachial status was determined by PCR and a relaxation assay was used to estimate DNA topoisomerase II inhibitory activity. RESULTS: Nano-CUR (F3) having a 60 nm diameter and 89.78% entrapment efficiency showed the most favorable characteristics for the elimination of filarial parasites. In vivo pharmacokinetic and organ distribution studies demonstrate significantly greater C(max) (86.6 ± 2.56 ng ml(-1)), AUC0-∞ (796 ± 89.8 ng d ml(-1)), MRT (19.5 ± 7.82 days) and bioavailability of CUR (70.02%) in the organs from which the adult parasites were recovered. The optimized nano-CUR (F3) (5 × 5 mg/kg, orally) significantly augmented the microfilariciadal and adulticidal action of CUR over free CUR (5 × 50 mg/kg, orally) or Diethylcarbamizine (50 mg/kg, orally) against the Brugia malayi Mastomys coucha rodent model. The PCR results showed complete elimination of wolbachia from the recovered female parasites. Interestingly, nano-CUR was also found to be a novel inhibitor of filarial worm DNA topoisomerase II, Setaria Cervi in vitro. CONCLUSION: This study recognizes the beforehand antimicrofilarial, antimacrofilarial, anti-wolbachial activity of nano-CUR (F3) over free forms and additionally its strong inhibitory action against the major target filarial parasite enzyme DNA topoisomerase II in vitro.
Assuntos
Curcumina/uso terapêutico , Portadores de Fármacos/química , Filariose Linfática/tratamento farmacológico , Filaricidas/uso terapêutico , Nanopartículas/química , Inibidores da Topoisomerase II/uso terapêutico , Animais , Brugia/efeitos dos fármacos , Brugia/enzimologia , Brugia/fisiologia , Curcumina/administração & dosagem , Curcumina/farmacocinética , Modelos Animais de Doenças , Liberação Controlada de Fármacos , Filariose Linfática/parasitologia , Filaricidas/administração & dosagem , Interações Hospedeiro-Parasita/fisiologia , Masculino , Camundongos , Tamanho da Partícula , Ratos , Propriedades de Superfície , Distribuição Tecidual , Inibidores da Topoisomerase II/administração & dosagem , Inibidores da Topoisomerase II/farmacocinéticaRESUMO
Pixantrone, a novel aza-anthracenedione with cytotoxic activity, was tested against the PPTP in vitro panel (3.0 nM to 30.0 µM) and against a limited panel of PPTP Wilms tumors and sarcomas (7.5 mg/kg) administered intravenously using an every 4 day × 3 schedule. In vitro pixantrone showed a median relative IC50 value of 54 nM (range <3 nM to 1.03 µM). In vivo pixantrone induced significant differences in EFS distribution compared to controls in two of eight solid tumor xenografts at dose levels relevant to human drug exposure. A complete response was observed for one Wilms tumor xenograft.