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1.
Molecules ; 23(8)2018 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-30042315

RESUMO

A series of fourteen new asymmetrical 1,3-diketone derivatives have been synthesized and evaluated in the ABTS, FRAP and DPPH assays as a new chemotype with antioxidant and drug-like properties. All the compounds displayed low cytotoxicity in comparison to curcumin against the human neuroblastoma SH-SY5Y cell line. Among them, (3Z,5E)-6-(2,5-difluoro-4-hydroxy-phenyl)-1,1,1-trifluoro-4-hydroxyhexa-3,5-dien-2-one (6b) and (3Z,5E)-6-(2,3-difluoro-4-hydroxy-phenyl)-1,1,1-trifluoro-4-hydroxyhexa-3,5-dien-2-one (7b) with excellent solubility and chemical stability in biorelevant media, have also shown a similar Fe+2 chelation behavior to that of curcumin. Additionally, both derivatives 6b and 7b have afforded good neuroprotection activity against H2O2 induced oxidative stress in the same neuronal cell line, with a significant reduction of intracellular ROS levels, in parallel with a good recovery of the Mitochondrial Membrane Potential (ΔΨm). Compounds 6b and 7b with a promising antioxidant and drug-like profile, with low cytotoxic and good neuroprotectant activity, constitute a new interesting chemical class with high potential as new therapeutic agents against neurodegenerative diseases.


Assuntos
Antioxidantes/farmacologia , Quelantes de Ferro/farmacologia , Cetonas/farmacologia , Fármacos Neuroprotetores/farmacologia , Quinonas/farmacologia , Antioxidantes/síntese química , Apoptose/efeitos dos fármacos , Benzotiazóis/antagonistas & inibidores , Compostos de Bifenilo/antagonistas & inibidores , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Curcumina/farmacologia , Humanos , Peróxido de Hidrogênio/antagonistas & inibidores , Peróxido de Hidrogênio/farmacologia , Concentração Inibidora 50 , Quelantes de Ferro/síntese química , Cetonas/síntese química , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/síntese química , Estresse Oxidativo/efeitos dos fármacos , Picratos/antagonistas & inibidores , Quinonas/síntese química , Relação Estrutura-Atividade , Ácidos Sulfônicos/antagonistas & inibidores
2.
Nature ; 465(7296): 305-10, 2010 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-20485427

RESUMO

Malaria is a devastating infection caused by protozoa of the genus Plasmodium. Drug resistance is widespread, no new chemical class of antimalarials has been introduced into clinical practice since 1996 and there is a recent rise of parasite strains with reduced sensitivity to the newest drugs. We screened nearly 2 million compounds in GlaxoSmithKline's chemical library for inhibitors of P. falciparum, of which 13,533 were confirmed to inhibit parasite growth by at least 80% at 2 microM concentration. More than 8,000 also showed potent activity against the multidrug resistant strain Dd2. Most (82%) compounds originate from internal company projects and are new to the malaria community. Analyses using historic assay data suggest several novel mechanisms of antimalarial action, such as inhibition of protein kinases and host-pathogen interaction related targets. Chemical structures and associated data are hereby made public to encourage additional drug lead identification efforts and further research into this disease.


Assuntos
Antimaláricos/análise , Antimaláricos/farmacologia , Descoberta de Drogas , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/análise , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Antimaláricos/química , Antimaláricos/toxicidade , Linhagem Celular Tumoral , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Humanos , Malária Falciparum/parasitologia , Modelos Biológicos , Filogenia , Plasmodium falciparum/enzimologia , Plasmodium falciparum/genética , Plasmodium falciparum/crescimento & desenvolvimento , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/toxicidade
3.
Antimicrob Agents Chemother ; 59(4): 1868-75, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25583730

RESUMO

One way to speed up the TB drug discovery process is to search for antitubercular activity among compound series that already possess some of the key properties needed in anti-infective drug discovery, such as whole-cell activity and oral absorption. Here, we present MGIs, a new series of Mycobacterium tuberculosis gyrase inhibitors, which stem from the long-term efforts GSK has dedicated to the discovery and development of novel bacterial topoisomerase inhibitors (NBTIs). The compounds identified were found to be devoid of fluoroquinolone (FQ) cross-resistance and seem to operate through a mechanism similar to that of the previously described NBTI GSK antibacterial drug candidate. The remarkable in vitro and in vivo antitubercular profiles showed by the hits has prompted us to further advance the MGI project to full lead optimization.


Assuntos
Antituberculosos/farmacologia , Inibidores Enzimáticos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/enzimologia , Animais , Descoberta de Drogas , Feminino , Fluoroquinolonas/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Testes de Sensibilidade Microbiana , Modelos Moleculares , Mycobacterium bovis/efeitos dos fármacos , Inibidores da Topoisomerase I/farmacologia , Tuberculose/tratamento farmacológico , Tuberculose/microbiologia
4.
Biomed Microdevices ; 13(6): 1015-25, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21773725

RESUMO

The aim was to study the ability of bioadhesive cyclodextrin-poly(anhydride) nanoparticles as carriers for the oral delivery of atovaquone (ATO). In order to increase the loading capacity of ATO by poly(anhydride) nanoparticles, the following oligosaccharides were assayed: 2-hydroxypropyl-ß-cyclodextrin (HPCD), 2,6-di-O-methyl-ß-cyclodextrin (DCMD), randomly methylated-ß-cyclodextrin (RMCD) and sulfobuthyl ether-ß-cyclodextrin (SBECD). Nanoparticles were obtained by desolvation after the incubation between the poly(anhydride) with the ATO-cyclodextrin complexes. For the pharmacokinetic studies, ATO formulations were administered orally in rats. Overall, ATO displayed a higher affinity for methylated cyclodextrins than for the other derivatives. However, for in vivo studies, both ATO-DMCD-NP and ATO-HPCD-NP were chosen. These nanoparticle formulations showed more adequate physicochemical properties in terms of size (<260 nm), drug loading (17.8 and 16.9 µg/mg, respectively) and yield (>75%). In vivo, nanoparticle formulations induced higher and more prolonged plasmatic levels of atovaquone than control suspensions of the drug in methylcellulose. Relative bioavailability of ATO when loaded in nanoparticles ranged from 52% (for ATO-HPCD NP) to 71% (for ATO-DMCD NP), whereas for the suspension control formulation the bioavailability was only about 30%. The encapsulation of atovaquone in cyclodextrins-poly(anhydride) nanoparticles seems to be an interesting strategy to improve the oral bioavailability of this lipophilic drug.


Assuntos
Atovaquona/farmacologia , Portadores de Fármacos/administração & dosagem , Nanopartículas/administração & dosagem , Polianidridos/farmacocinética , beta-Ciclodextrinas/farmacocinética , 2-Hidroxipropil-beta-Ciclodextrina , Administração Oral , Animais , Disponibilidade Biológica , Fenômenos Químicos , Portadores de Fármacos/química , Desenho de Fármacos , Masculino , Nanopartículas/química , Ratos , Ratos Wistar , beta-Ciclodextrinas/administração & dosagem
5.
Antioxidants (Basel) ; 10(10)2021 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-34679721

RESUMO

A new series of twenty-three 1,5-benzodiazepin-2(3H)-ones were synthesized and evaluated in the 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS), ferric reducing antioxidant power (FRAP), and 2,2-diphenyl-1-picrylhydrazyl (DPPH) assays as a new chemotype with antioxidant and good drug-like properties. All of the derivatives showed low cytotoxicity in comparison to curcumin against the human neuroblastoma SH-SY5Y and the human hepatoma HepG2 cell lines. Experimental solubility in bio-relevant media showed a good relationship with melting points in this series. Five compounds with the best antioxidant properties showed neuroprotectant activity against H2O2-induced oxidative stress in the SH-SY5Y cell line. From them, derivatives 4-phenyl-1H-1,5-benzodiazepin-2(3H)-one (18) and 4-(3,4,5-trimethoxyphenyl)-1H-1,5-benzodiazepin-2(3H)-one (20) yielded good neuroprotection activity in the same neuronal cell line under 6-OHD and MPP+ insults as in vitro models of mitochondrial dysfunction and oxidative stress in Parkinson's disease (PD). Both compounds also demonstrated a significant reduction of intracellular Reactive Oxygen Species (ROS) and superoxide levels, in parallel with a good improvement of the Mitochondrial Membrane Potential (ΔΨm). Compared with curcumin, compound 18 better reduced lipid peroxidation levels, malondialdehyde (MDA), in SH-SY5Y cells under oxidative stress pressure and recovered intracellular glutathione synthetase (GSH) levels. Apoptosis and caspase-3 levels of SH-SY5Y under H2O2 pressure were also reduced after treatment with 18. Neuroprotection in neuron-like differentiated SH-SY5Y cells was also achieved with 18. In summary, this family of 1,5-benzodiazepin-2-ones with an interesting antioxidant and drug-like profile, with low cytotoxic and good neuroprotectant activity, constitutes a new promising chemical class with high potential for the development of new therapeutic agents against PD.

6.
Int J Parasitol Drugs Drug Resist ; 8(2): 295-303, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29775797

RESUMO

Phenotypic screening has produced most of the new chemical entities currently in clinical development for malaria, plus many lead compounds active against Plasmodium falciparum asexual stages. However, lack of knowledge about the mode of action of these compounds delays and may even hamper their future development. Identifying the mode of action of the inhibitors greatly helps to prioritise compounds for further development as novel antimalarials. Here we describe a whole-cell method to detect inhibitors of the mitochondrial electron transport chain, using oxygen consumption as high throughput readout in 384-well plate format. The usefulness of the method has been confirmed with the Tres Cantos Antimalarial Compound Set (TCAMS). The assay identified 124 respiratory inhibitors in TCAMS, seven of which were novel anti-plasmodial chemical structures never before described as mitochondrial inhibitors.


Assuntos
Antimaláricos/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Mitocôndrias/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Descoberta de Drogas/métodos , Avaliação Pré-Clínica de Medicamentos/instrumentação , Complexo de Proteínas da Cadeia de Transporte de Elétrons/antagonistas & inibidores , Humanos , Concentração Inibidora 50 , Malária/tratamento farmacológico , Malária/parasitologia , Malária Falciparum , Oxigênio/metabolismo , Plasmodium falciparum/citologia
7.
EBioMedicine ; 8: 291-301, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27428438

RESUMO

Despite being one of the first antitubercular agents identified, isoniazid (INH) is still the most prescribed drug for prophylaxis and tuberculosis (TB) treatment and, together with rifampicin, the pillars of current chemotherapy. A high percentage of isoniazid resistance is linked to mutations in the pro-drug activating enzyme KatG, so the discovery of direct inhibitors (DI) of the enoyl-ACP reductase (InhA) has been pursued by many groups leading to the identification of different enzyme inhibitors, active against Mycobacterium tuberculosis (Mtb), but with poor physicochemical properties to be considered as preclinical candidates. Here, we present a series of InhA DI active against multidrug (MDR) and extensively (XDR) drug-resistant clinical isolates as well as in TB murine models when orally dosed that can be a promising foundation for a future treatment.


Assuntos
Antituberculosos/farmacologia , Enoil-(Proteína de Transporte de Acila) Redutase (NADH)/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/enzimologia , Animais , Antituberculosos/química , Sítios de Ligação , Domínio Catalítico , Modelos Animais de Doenças , Enoil-(Proteína de Transporte de Acila) Redutase (NADH)/genética , Enoil-(Proteína de Transporte de Acila) Redutase (NADH)/metabolismo , Inibidores Enzimáticos/química , Feminino , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Microssomos , Modelos Moleculares , Mutação , Mycobacterium tuberculosis/genética , Ligação Proteica , Conformação Proteica , Tuberculose/tratamento farmacológico , Tuberculose/microbiologia , Tuberculose/mortalidade , Tuberculose Resistente a Múltiplos Medicamentos
8.
ChemMedChem ; 8(2): 313-21, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23307663

RESUMO

With the aim of fuelling open-source, translational, early-stage drug discovery activities, the results of the recently completed antimycobacterial phenotypic screening campaign against Mycobacterium bovis BCG with hit confirmation in M. tuberculosis H37Rv were made publicly accessible. A set of 177 potent non-cytotoxic H37Rv hits was identified and will be made available to maximize the potential impact of the compounds toward a chemical genetics/proteomics exercise, while at the same time providing a plethora of potential starting points for new synthetic lead-generation activities. Two additional drug-discovery-relevant datasets are included: a) a drug-like property analysis reflecting the latest lead-like guidelines and b) an early lead-generation package of the most promising hits within the clusters identified.


Assuntos
Antituberculosos/química , Antituberculosos/farmacologia , Descoberta de Drogas/métodos , Mycobacterium bovis/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Bases de Dados de Produtos Farmacêuticos , Células Hep G2 , Ensaios de Triagem em Larga Escala , Humanos , Testes de Sensibilidade Microbiana , Tuberculose/tratamento farmacológico
9.
Chem Biol ; 19(12): 1556-67, 2012 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-23261599

RESUMO

The glyoxylate shunt plays an important role in fatty acid metabolism and has been shown to be critical to survival of several pathogens involved in chronic infections. For Mycobacterium tuberculosis (Mtb), a strain with a defective glyoxylate shunt was previously shown to be unable to establish infection in a mouse model. We report the development of phenyl-diketo acid (PDKA) inhibitors of malate synthase (GlcB), one of two glyoxylate shunt enzymes, using structure-based methods. PDKA inhibitors were active against Mtb grown on acetate, and overexpression of GlcB ameliorated this inhibition. Crystal structures of complexes of GlcB with PDKA inhibitors guided optimization of potency. A selected PDKA compound demonstrated efficacy in a mouse model of tuberculosis. The discovery of these PDKA derivatives provides chemical validation of GlcB as an attractive target for tuberculosis therapeutics.


Assuntos
Antituberculosos/química , Antituberculosos/uso terapêutico , Inibidores Enzimáticos/química , Inibidores Enzimáticos/uso terapêutico , Malato Sintase/antagonistas & inibidores , Mycobacterium tuberculosis/enzimologia , Tuberculose/tratamento farmacológico , Animais , Antituberculosos/farmacocinética , Desenho de Fármacos , Inibidores Enzimáticos/farmacocinética , Feminino , Humanos , Malato Sintase/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Mycobacterium tuberculosis/efeitos dos fármacos
10.
ACS Med Chem Lett ; 2(10): 741-6, 2011 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-24900261

RESUMO

In 2010, GlaxoSmithKline published the structures of 13533 chemical starting points for antimalarial lead identification. By using an agglomerative structural clustering technique followed by computational filters such as antimalarial activity, physicochemical properties, and dissimilarity to known antimalarial structures, we have identified 47 starting points for lead optimization. Their structures are provided. We invite potential collaborators to work with us to discover new clinical candidates.

11.
Exp Parasitol ; 111(2): 105-14, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16098967

RESUMO

Plasmodium falciparum lactate dehydrogenase (PfLDH) is essential for ATP generation. Based on structural differences within the active site between P. falciparum and human LDH, we have identified a series of heterocyclic azole-based inhibitors that selectively bind within the PfLDH but not the human LDH (hLDH) active site and showed anti-malarial activity in vitro and in vivo. Here we expand on an azole, OXD1, from this series and found that the anti-P. falciparum activity was retained against a panel of strains independently of their anti-malarial drug sensitivity profile. Trophozoites had relatively higher PfLDH enzyme activity and PfLDH-RNA expression levels than rings and were the most susceptible stages to OXD1 exposure. This is probably linked to their increased energy requirements and consistent with glycolysis being an essential metabolic pathway for parasite survival within the erythrocyte. Further structural elaboration of these azoles could lead to the identification of compounds that target P. falciparum through such a novel mechanism and with more potent anti-malarial activity.


Assuntos
Antimaláricos/farmacologia , Ácidos Carboxílicos/farmacologia , L-Lactato Desidrogenase/antagonistas & inibidores , Oxidiazóis/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/enzimologia , Animais , Antimaláricos/química , Antimaláricos/toxicidade , Ácidos Carboxílicos/química , Ácidos Carboxílicos/toxicidade , Relação Dose-Resposta a Droga , Citometria de Fluxo , Corantes Fluorescentes/metabolismo , Regulação Enzimológica da Expressão Gênica , L-Lactato Desidrogenase/química , L-Lactato Desidrogenase/genética , Microscopia Confocal , Oxidiazóis/química , Oxidiazóis/toxicidade , Fenantridinas/metabolismo , Plasmodium falciparum/crescimento & desenvolvimento , RNA de Protozoário/biossíntese , Especificidade da Espécie
12.
J Biol Chem ; 279(30): 31429-39, 2004 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-15117937

RESUMO

Plasmodium falciparum, the causative agent of malaria, relies extensively on glycolysis coupled with homolactic fermentation during its blood-borne stages for energy production. Selective inhibitors of the parasite lactate dehydrogenase (LDH), central to NAD(+) regeneration, therefore potentially provide a route to new antimalarial drugs directed against a novel molecular target. A series of heterocyclic, azole-based compounds are described that preferentially inhibit P. falciparum LDH at sub-micromolar concentrations, typically at concentrations about 100-fold lower than required for human lactate dehydrogenase inhibition. Crystal structures show these competitive inhibitors form a network of interactions with amino acids within the active site of the enzyme, stacking alongside the nicotinamide ring of the NAD(+) cofactor. These compounds display modest activity against parasitized erythrocytes, including parasite strains with known resistance to existing anti-malarials and against Plasmodium berghei in BALB/c mice. Initial toxicity data suggest the azole derivatives have generally low cytotoxicity, and preliminary pharmoco-kinetic data show favorable bioavailability and circulation times. These encouraging results suggest that further enhancement of these structures may yield candidates suitable for consideration as new therapeutics for the treatment of malaria. In combination these studies also provide strong support for the validity of targeting the Plasmodium glycolytic pathway and, in particular, LDH in the search for novel anti-malarials.


Assuntos
Antimaláricos/química , Antimaláricos/farmacologia , Azóis/química , Azóis/farmacologia , L-Lactato Desidrogenase/antagonistas & inibidores , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/enzimologia , Animais , Domínio Catalítico , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Técnicas In Vitro , L-Lactato Desidrogenase/química , L-Lactato Desidrogenase/genética , Malária/tratamento farmacológico , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Mutagênese Sítio-Dirigida , Plasmodium berghei , Plasmodium falciparum/genética , Relação Estrutura-Atividade
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