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1.
J Chem Inf Model ; 61(8): 3804-3813, 2021 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-34286575

RESUMO

Yellow fever (YF) is an acute viral hemorrhagic disease transmitted by infected mosquitoes. Large epidemics of YF occur when the virus is introduced into heavily populated areas with high mosquito density and low vaccination coverage. The lack of a specific small molecule drug treatment against YF as well as for homologous infections, such as zika and dengue, highlights the importance of these flaviviruses as a public health concern. With the advancement in computer hardware and bioactivity data availability, new tools based on machine learning methods have been introduced into drug discovery, as a means to utilize the growing high throughput screening (HTS) data generated to reduce costs and increase the speed of drug development. The use of predictive machine learning models using previously published data from HTS campaigns or data available in public databases, can enable the selection of compounds with desirable bioactivity and absorption, distribution, metabolism, and excretion profiles. In this study, we have collated cell-based assay data for yellow fever virus from the literature and public databases. The data were used to build predictive models with several machine learning methods that could prioritize compounds for in vitro testing. Five molecules were prioritized and tested in vitro from which we have identified a new pyrazolesulfonamide derivative with EC50 3.2 µM and CC50 24 µM, which represents a new scaffold suitable for hit-to-lead optimization that can expand the available drug discovery candidates for YF.


Assuntos
Febre Amarela , Infecção por Zika virus , Zika virus , Animais , Antivirais/farmacologia , Descoberta de Drogas , Aprendizado de Máquina , Vírus da Febre Amarela
2.
ACS Med Chem Lett ; 12(5): 774-781, 2021 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-34055225

RESUMO

Opportunistic infections from pathogenic fungi present a major challenge to healthcare because of a very limited arsenal of antifungal drugs, an increasing population of immunosuppressed patients, and increased prevalence of resistant clinical strains due to overuse of the few available antifungals. Cryptococcal meningitis is a life-threatening opportunistic fungal infection caused by one of two species in the Cryptococcus genus, Cryptococcus neoformans and Cryptococcus gattii. Eighty percent of cryptococcosis diseases are caused by C. neoformans that is endemic in the environment. The standard of care is limited to old antifungals, and under a high standard of care, mortality remains between 10 and 30%. We have identified a series of 5-nitro-6-thiocyanatopyrimidine antifungal drug candidates using in vitro and computational machine learning approaches. These compounds can inhibit C. neoformans growth at submicromolar levels, are effective against fluconazole-resistant C. neoformans and a clinical strain of C. gattii, and are not antagonistic with currently approved antifungals.

3.
ACS Infect Dis ; 6(11): 3015-3025, 2020 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-32930569

RESUMO

Screening of a diversity-oriented compound library led to the identification of two 6,11-dioxobenzo[f]pyrido[1,2-a]indoles (DBPI) that displayed low micromolar bactericidal activity against the Erdman strain of Mycobacterium tuberculosis in vitro. The activity of these hit compounds was limited to tubercle bacilli, including the nonreplicating form, and to Mycobacterium marinum. On hit expansion and investigation of the structure activity relationship, selected modifications to the dioxo moiety of the DBPI scaffold were either neutral or led to reduction or abolition of antimycobacterial activity. To find the target, DBPI-resistant mutants of M. tuberculosis Erdman were raised and characterized first microbiologically and then by whole genome sequencing. Four different mutations, all affecting highly conserved residues, were uncovered in the essential gene rv0338c (ispQ) that encodes a membrane-bound protein, named IspQ, with 2Fe-2S and 4Fe-4S centers and putative iron-sulfur-binding reductase activity. With the help of a structural model, two of the mutations were localized close to the 2Fe-2S domain in IspQ and another in transmembrane segment 3. The mutant genes were recessive to the wild type in complementation experiments and further confirmation of the hit-target relationship was obtained using a conditional knockdown mutant of rv0338c in M. tuberculosis H37Rv. More mechanistic insight was obtained from transcriptome analysis, following exposure of M. tuberculosis to two different DBPI; this revealed strong upregulation of the redox-sensitive SigK regulon and genes induced by oxidative and thiol-stress. The findings of this investigation pharmacologically validate a novel target in tubercle bacilli and open a new vista for tuberculosis drug discovery.


Assuntos
Proteínas Ferro-Enxofre , Mycobacterium tuberculosis , Tuberculose , Humanos , Indóis , Proteínas Ferro-Enxofre/genética , Proteínas Ferro-Enxofre/metabolismo , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/metabolismo , Oxirredução
4.
Pathog Dis ; 78(7)2020 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-32860686

RESUMO

Influenza virus and coronaviruses continue to cause pandemics across the globe. We now have a greater understanding of their functions. Unfortunately, the number of drugs in our armory to defend us against them is inadequate. This may require us to think about what mechanisms to address. Here, we review the biological properties of these viruses, their genetic evolution and antiviral therapies that can be used or have been attempted. We will describe several classes of drugs such as serine protease inhibitors, heparin, heparan sulfate receptor inhibitors, chelating agents, immunomodulators and many others. We also briefly describe some of the drug repurposing efforts that have taken place in an effort to rapidly identify molecules to treat patients with COVID-19. While we put a heavy emphasis on the past and present efforts, we also provide some thoughts about what we need to do to prepare for respiratory viral threats in the future.


Assuntos
Antivirais/uso terapêutico , Infecções por Coronavirus/epidemiologia , Coronavirus/efeitos dos fármacos , Reposicionamento de Medicamentos , Influenza Humana/epidemiologia , Orthomyxoviridae/efeitos dos fármacos , Pandemias , Anticoagulantes/uso terapêutico , Antimaláricos/uso terapêutico , Antioxidantes/uso terapêutico , Quelantes/uso terapêutico , Coronavirus/genética , Coronavirus/crescimento & desenvolvimento , Coronavirus/patogenicidade , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Glicoconjugados/uso terapêutico , Humanos , Fatores Imunológicos/uso terapêutico , Influenza Humana/tratamento farmacológico , Influenza Humana/virologia , Orthomyxoviridae/genética , Orthomyxoviridae/crescimento & desenvolvimento , Orthomyxoviridae/patogenicidade , Inibidores de Serino Proteinase/uso terapêutico
5.
Front Microbiol ; 11: 562, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32318042

RESUMO

There is an urgent need for new antimicrobials to treat the opportunistic Gram-negative Burkholderia cenocepacia, which represents a problematic challenge for cystic fibrosis patients. Recently, a benzothiadiazole derivative, C109, was shown to be effective against the infections caused by B. cenocepacia and other Gram-negative and-positive bacteria. C109 has a promising cellular target, the cell division protein FtsZ, and a recently developed PEGylated formulation make it an attractive molecule to counteract Burkholderia infections. However, the ability of efflux pumps to extrude it out of the cell represents a limitation for its use. Here, more than 50 derivatives of C109 were synthesized and tested against Gram-negative species and the Gram-positive Staphylococcus aureus. In addition, their activity was evaluated on the purified FtsZ protein. The chemical, metabolic and cellular stability of C109 has been assayed using different biological systems, including quantitative single-cell imaging. However, no further improvement on C109 was achieved, and the role of efflux in resistance was further confirmed. Also, a novel nitroreductase that can inactivate the compound was characterized, but it does not appear to play a role in natural resistance. All these data allowed a deep characterization of the compound, which will contribute to a further improvement of its properties.

6.
Front Microbiol ; 11: 292, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32158439

RESUMO

Tuberculosis remains one of the leading causes of death from a single pathogen globally. It is estimated that 1/4 of the world's population harbors latent tuberculosis, but only a 5-10% of patients will develop active disease. During latent infection, Mycobacterium tuberculosis can persist unaffected by drugs for years in a non-replicating state with low metabolic activity. The rate of the successful tuberculosis treatment is curbed by the presence of these non-replicating bacilli that can resuscitate after decades and also by the spread of M. tuberculosis drug-resistant strains. International agencies, including the World Health Organization, urge the international community to combat this global health emergency. The thienopyrimidine TP053 is a promising new antitubercular lead compound highly active against both replicating and non-replicating M. tuberculosis cells, with an in vitro MIC of 0.125 µg/ml. TP053 is a prodrug activated by the reduced form of the mycothiol-dependent reductase Mrx2, encoded by Rv2466c gene. After its activation, TP053 releases nitric oxide and a highly reactive metabolite, explaining its activity also against M. tuberculosis non-replicating cells. In this work, a new mechanism of TP053 resistance was discovered. M. tuberculosis spontaneous mutants resistant to TP053 were isolated harboring the mutation L240V in Rv0579, a protein with unknown function, but without mutation in Rv2466c gene. Recombineering method demonstrated that this mutation is linked to TP053 resistance. To better characterize Rv0579, the protein was recombinantly produced in Escherichia coli and a direct interaction between the Mrx2 activated TP053 and Rv0579 was shown by an innovative target-fishing experiment based on click chemistry. Thanks to achieved results, a possible contribution of Rv0579 in M. tuberculosis RNA metabolism was hypothesized, linked to toxin anti-toxin system. Overall, these data confirm the role of Rv0579 in TP053 resistance and consequently in the metabolism of this prodrug.

7.
ACS Infect Dis ; 6(2): 313-323, 2020 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-31729215

RESUMO

The thienopyrimidine TP053 is an antitubercular prodrug active against both replicating and nonreplicating Mycobacterium tuberculosis (M. tuberculosis) cells, which requires activation by the mycothiol-dependent nitroreductase Mrx2. The investigation of the mechanism of action of TP053 revealed that Mrx2 releases nitric oxide from this drug both in the enzyme assays with purified Mrx2 and in mycobacterial cultures, which can explain its activity against nonreplicating bacilli, similar to pretomanid activated by the nitroreductase Ddn. In addition, we identified a highly reactive metabolite, 2-(4-mercapto-6-(methylamino)-2-phenylpyrimidin-5-yl)ethan-1-ol, which can contribute to the antimycobacterial effects on replicating cells as well as on nonreplicating cells. In summary, we explain the mechanism of action of TP053 on both replicating and nonreplicating M. tuberculosis and report a novel activity for Mrx2, which in addition to Ddn, represents another example of nitroreductase releasing nitric oxide from its substrate. These findings are particularly relevant in the context of drugs targeting nonreplicating M. tuberculosis, which is shown to be killed by increased levels of nitric oxide.


Assuntos
Antituberculosos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Pró-Fármacos/farmacologia , Pirimidinas/farmacologia
8.
Int J Mol Sci ; 20(23)2019 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-31766758

RESUMO

Nontuberculous mycobacteria (NTM) have recently emerged as important pathogens among cystic fibrosis (CF) patients worldwide. Mycobacterium abscessus is becoming the most worrisome NTM in this cohort of patients and recent findings clarified why this pathogen is so prone to this disease. M. abscessus drug therapy takes up to 2 years and its failure causes an accelerated lung function decline. The M. abscessus colonization of lung alveoli begins with smooth strains producing glycopeptidolipids and biofilm, whilst in the invasive infection, "rough" mutants are responsible for the production of trehalose dimycolate, and consequently, cording formation. Human-to-human M. abscessus transmission was demonstrated among geographically separated CF patients by whole-genome sequencing of clinical isolates worldwide. Using a M. abscessus infected CF zebrafish model, it was demonstrated that CFTR (cystic fibrosis transmembrane conductance regulator) dysfunction seems to have a specific role in the immune control of M. abscessus infections only. This pathogen is also intrinsically resistant to many drugs, thanks to its physiology and to the acquisition of new mechanisms of drug resistance. Few new compounds or drug formulations active against M. abscessus are present in preclinical and clinical development, but recently alternative strategies have been investigated, such as phage therapy and the use of ß-lactamase inhibitors.


Assuntos
Doenças Transmissíveis Emergentes , Fibrose Cística , Farmacorresistência Bacteriana Múltipla/imunologia , Infecções por Mycobacterium não Tuberculosas , Mycobacterium abscessus , Alvéolos Pulmonares , Animais , Doenças Transmissíveis Emergentes/epidemiologia , Doenças Transmissíveis Emergentes/imunologia , Doenças Transmissíveis Emergentes/patologia , Fibrose Cística/epidemiologia , Fibrose Cística/imunologia , Fibrose Cística/patologia , Regulador de Condutância Transmembrana em Fibrose Cística/imunologia , Modelos Animais de Doenças , Humanos , Infecções por Mycobacterium não Tuberculosas/epidemiologia , Infecções por Mycobacterium não Tuberculosas/imunologia , Infecções por Mycobacterium não Tuberculosas/patologia , Mycobacterium abscessus/imunologia , Mycobacterium abscessus/patogenicidade , Alvéolos Pulmonares/imunologia , Alvéolos Pulmonares/microbiologia , Peixe-Zebra
9.
Artigo em Inglês | MEDLINE | ID: mdl-30297366

RESUMO

To streamline the elucidation of antibacterial compounds' mechanism of action, comprehensive high-throughput assays interrogating multiple putative targets are necessary. However, current chemogenomic approaches for antibiotic target identification have not fully utilized the multiplexing potential of next-generation sequencing. Here, we used Illumina sequencing of transposon insertions to track the competitive fitness of a Burkholderia cenocepacia library containing essential gene knockdowns. Using this method, we characterized a novel benzothiadiazole derivative, 10126109 (C109), with antibacterial activity against B. cenocepacia, for which whole-genome sequencing of low-frequency spontaneous drug-resistant mutants had failed to identify the drug target. By combining the identification of hypersusceptible mutants and morphology screening, we show that C109 targets cell division. Furthermore, fluorescence microscopy of bacteria harboring green fluorescent protein (GFP) cell division protein fusions revealed that C109 prevents divisome formation by altering the localization of the essential cell division protein FtsZ. In agreement with this, C109 inhibited both the GTPase and polymerization activities of purified B. cenocepacia FtsZ. C109 displayed antibacterial activity against Gram-positive and Gram-negative cystic fibrosis pathogens, including Mycobacterium abscessus C109 effectively cleared B. cenocepacia infection in the Caenorhabditis elegans model and exhibited additive interactions with clinically relevant antibiotics. Hence, C109 is an enticing candidate for further drug development.


Assuntos
Antibacterianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Burkholderia cenocepacia/genética , Proteínas do Citoesqueleto/antagonistas & inibidores , Avaliação Pré-Clínica de Medicamentos/métodos , Animais , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Infecções por Burkholderia/tratamento farmacológico , Infecções por Burkholderia/microbiologia , Burkholderia cenocepacia/efeitos dos fármacos , Burkholderia cenocepacia/isolamento & purificação , Caenorhabditis elegans/microbiologia , Fibrose Cística/microbiologia , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/metabolismo , Técnicas de Silenciamento de Genes , Genes Essenciais , Proteínas de Fluorescência Verde/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Testes de Sensibilidade Microbiana , Mutação
10.
Artigo em Inglês | MEDLINE | ID: mdl-30012754

RESUMO

Macozinone (MCZ) is a tuberculosis (TB) drug candidate that specifically targets the essential flavoenzyme DprE1, thereby blocking synthesis of the cell wall precursor decaprenyl phosphoarabinose (DPA) and provoking lysis of Mycobacterium tuberculosis As part of the MCZ backup program, we exploited structure-guided drug design to produce a new series of sulfone-containing derivatives, 2-sulfonylpiperazin 8-nitro 6-trifluoromethyl 1,3-benzothiazin-4-one, or sPBTZ. These compounds are less active than MCZ but have a better solubility profile, and some derivatives display enhanced stability in microsomal assays. DprE1 was efficiently inhibited by sPBTZ, and covalent adducts with the active-site cysteine residue (C387) were formed. However, despite the H-bonding potential of the sulfone group, no additional bonds were seen in the crystal structure of the sPBTZ-DprE1 complex with compound 11326127 compared to MCZ. Compound 11626091, the most advanced sPBTZ, displayed good antitubercular activity in the murine model of chronic TB but was less effective than MCZ. Nonetheless, further testing of this MCZ backup compound is warranted as part of combination treatment with other TB drugs.


Assuntos
Antituberculosos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Piridazinas/farmacologia , Sulfonas/farmacologia , Proteínas de Bactérias , Desenho de Fármacos , Testes de Sensibilidade Microbiana , Relação Estrutura-Atividade , Tuberculose/microbiologia
11.
Metallomics ; 10(7): 992-1002, 2018 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-29946601

RESUMO

With the emerging primary resistance of Mycobacterium tuberculosis to current drugs and wide distribution of latent tuberculosis infection, the need for new compounds with a novel mode of action is growing. Copper-mediated innate immunity and its antibacterial toxicity pose novel strategies for tuberculosis drug discovery and development. Transcriptome response to 1-hydroxy-5-R-pyridine-2(1H)-thiones, which were found to be highly active in vitro against actively growing and dormant nonculturable M. tuberculosis, revealed signs of copper toxicity. 1-Hydroxy-5-R-pyridine-2(1H)-thiones were found to form stable charged lipophilic complexes with Cu2+ ions that could transport into mycobacterial cells. Copper accumulated inside treated bacilli as subsequent metabolic destruction of the complex led to chemical transformation of 1-hydroxy-5-R-pyridine-2(1H)-thiones and release of free Cu2+ into the cytoplasm. 1-Hydroxy-5-R-pyridine-2(1H)-thiones are a potent class of Cu-dependent inhibitors of M. tuberculosis, and may control infection by impairment of copper homeostasis.


Assuntos
Antituberculosos/química , Antituberculosos/farmacologia , Cobre/toxicidade , Mycobacterium tuberculosis/efeitos dos fármacos , Piridinas/química , Tionas/química , Tuberculose/tratamento farmacológico , Células Cultivadas , Humanos , Testes de Sensibilidade Microbiana , Oligoelementos/toxicidade , Tuberculose/microbiologia
12.
Ann Clin Microbiol Antimicrob ; 16(1): 69, 2017 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-29096645

RESUMO

BACKGROUND: Resuscitation promoting factors (Rpfs) are the proteins involved in the process of reactivation of the dormant cells of mycobacteria. Recently a new class of nitrophenylthiocyanates (NPTs), capable of inhibiting the biological and enzymatic activities of Rpfs has been discovered. In the current study the inhibitory properties of the compounds containing both nitro and thiocyanate groups alongside with the compounds with the modified number and different spatial location of the substituents are compared. METHODS: New benzoylphenyl thiocyanates alongside with nitrophenylthiocyanates were tested in the enzymatic assay of bacterial peptidoglycan hydrolysis as well as against strains of several actinobacteria (Mycobacterium smegmatis, Mycobacterium tuberculosis) on in-lab developed models of resuscitation of the dormant forms. RESULTS: Introduction of the additional nitro and thiocyanate groups to the benzophenone scaffold did not influence the inhibitory activity of the compounds. Removal of the nitro groups analogously did not impair the functional properties of the molecules. Among the tested compounds two molecules without nitro group: 3-benzoylphenyl thiocyanate and 4-benzoylphenyl thiocyanate demonstrated the maximum activity in both enzymatic assay (inhibition of the Rpf-mediated peptidoglycan hydrolysis) and in the resuscitation assay of the dormant M. tuberculosis cells. CONCLUSIONS: The current study demonstrates dispensability of the nitro group in the NPT's structure for inhibition of the enzymatic and biological activities of the Rpf protein molecules. These findings provide new prospects in anti-TB drug discovery especially in finding of molecular scaffolds effective for the latent infection treatment.


Assuntos
Proteínas de Bactérias/efeitos dos fármacos , Citocinas/efeitos dos fármacos , Mycobacterium smegmatis/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Tiocianatos/antagonistas & inibidores , Tuberculose/tratamento farmacológico , Proteínas de Bactérias/genética , Benzofenonas/antagonistas & inibidores , Domínio Catalítico , Cianatos/antagonistas & inibidores , Cianatos/química , Citocinas/genética , Desenho de Fármacos , Descoberta de Drogas , Testes de Sensibilidade Microbiana , Viabilidade Microbiana , Modelos Moleculares , Mycobacterium smegmatis/crescimento & desenvolvimento , Mycobacterium tuberculosis/crescimento & desenvolvimento , Peptidoglicano/metabolismo , Proteínas Recombinantes , Tiocianatos/química
13.
Sci Rep ; 6: 32487, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27580679

RESUMO

Burkholderia cenocepacia, an opportunistic respiratory pathogen particularly relevant for cystic fibrosis patients, is difficult to eradicate due to its high level of resistance to most clinically relevant antimicrobials. Consequently, the discovery of new antimicrobials as well as molecules capable of inhibiting its virulence is mandatory. In this regard quorum sensing (QS) represents a good target for anti-virulence therapies, as it has been linked to biofilm formation and is important for the production of several virulence factors, including proteases and siderophores. Here, we report the discovery of new diketopiperazine inhibitors of the B. cenocepacia acyl homoserine lactone synthase CepI, and report their anti-virulence properties. Out of ten different compounds assayed against recombinant CepI, four were effective inhibitors, with IC50 values in the micromolar range. The best compounds interfered with protease and siderophore production, as well as with biofilm formation, and showed good in vivo activity in a Caenorhabditis elegans infection model. These molecules were also tested in human cells and showed very low toxicity. Therefore, they could be considered for in vivo combined treatments with established or novel antimicrobials, to improve the current therapeutic strategies against B. cenocepacia.


Assuntos
Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Burkholderia cenocepacia/efeitos dos fármacos , Dicetopiperazinas/farmacologia , Inibidores Enzimáticos/farmacologia , Ligases/antagonistas & inibidores , Percepção de Quorum/efeitos dos fármacos , 4-Butirolactona/análogos & derivados , 4-Butirolactona/antagonistas & inibidores , 4-Butirolactona/biossíntese , 4-Butirolactona/genética , Animais , Antibacterianos/síntese química , Biofilmes/crescimento & desenvolvimento , Burkholderia cenocepacia/enzimologia , Burkholderia cenocepacia/genética , Burkholderia cenocepacia/patogenicidade , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/microbiologia , Sobrevivência Celular/efeitos dos fármacos , Clonagem Molecular , Dicetopiperazinas/síntese química , Inibidores Enzimáticos/síntese química , Escherichia coli/genética , Escherichia coli/metabolismo , Expressão Gênica , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Células HeLa , Humanos , Ligases/genética , Ligases/metabolismo , Percepção de Quorum/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade , Virulência
14.
Antiviral Res ; 123: 138-45, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26391975

RESUMO

Enteroviruses cause various acute and chronic diseases. The most promising therapeutics for these infections are capsid-binding molecules. These can act against a broad spectrum of enteroviruses, but emerging resistant virus variants threaten their efficacy. All known enterovirus variants with high-level resistance toward capsid-binding molecules have mutations of residues directly involved in the formation of the hydrophobic binding site. This is a first report of substitutions outside the binding pocket causing this type of drug resistance: I1207K and I1207R of the viral capsid protein 1 of coxsackievirus B3. Both substitutions completely abolish the antiviral activity of pleconaril (a capsid-binding molecule) but do not affect viral replication rates in vitro. Molecular dynamics simulations indicate that the resistance mechanism is mediated by a conformational rearrangement of R1095, which is a neighboring residue of 1207 located at the heel of the binding pocket. These insights provide a basis for the design of resistance-breaking inhibitors.


Assuntos
Antivirais/farmacologia , Proteínas do Capsídeo/genética , Farmacorresistência Viral , Enterovirus Humano B/efeitos dos fármacos , Mutação de Sentido Incorreto , Substituição de Aminoácidos , Sítios de Ligação , Proteínas do Capsídeo/metabolismo , Análise Mutacional de DNA , Enterovirus Humano B/genética , Enterovirus Humano B/fisiologia , Células HeLa , Humanos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Simulação de Dinâmica Molecular , Oxidiazóis/farmacologia , Oxazóis , Ligação Proteica , Conformação Proteica , Replicação Viral/efeitos dos fármacos
15.
ChemMedChem ; 10(10): 1629-34, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26260222

RESUMO

There are currently no drugs available for the treatment of enterovirus (EV)-induced acute and chronic diseases such as the common cold, meningitis, encephalitis, pneumonia, and myocarditis with or without consecutive dilated cardiomyopathy. Here, we report the discovery and characterization of pyrazolopyrimidines, a well-tolerated and potent class of novel EV inhibitors. The compounds inhibit the replication of a broad spectrum of EV in vitro with IC50 values between 0.04 and 0.64 µM for viruses resistant to pleconaril, a known capsid-binding inhibitor, without affecting cytochrome P450 enzyme activity. Using virological and genetics methods, the viral capsid was identified as the target of the most promising, orally bioavailable compound 3-(4-trifluoromethylphenyl)amino-6-phenylpyrazolo[3,4-d]pyrimidine-4-amine (OBR-5-340). Its prophylactic as well as therapeutic application was proved for coxsackievirus B3-induced chronic myocarditis in mice. The favorable pharmacokinetic, toxicological, and pharmacodynamics profile in mice renders OBR-5-340 a highly promising drug candidate, and the regulatory nonclinical program is ongoing.


Assuntos
Antivirais/farmacologia , Capsídeo/metabolismo , Infecções por Enterovirus/tratamento farmacológico , Enterovirus/efeitos dos fármacos , Pirazóis/farmacologia , Pirimidinas/farmacologia , Animais , Antivirais/síntese química , Antivirais/química , Relação Dose-Resposta a Droga , Células HeLa , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/química , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade
16.
Future Med Chem ; 3(1): 15-27, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21428823

RESUMO

BACKGROUND: Antiviral drugs are urgently needed for the treatment of acute and chronic diseases caused by enteroviruses such as coxsackievirus B3 (CVB3). The main goal of this study is quantitative structure-activity relationship (QSAR) analysis of anti-CVB3 activity (clinical CVB3 isolate 97927 [log IC50, µM]) and investigation of the selectivity of 25 ([biphenyloxy]propyl)isoxazoles, followed by computer-aided design and virtual screening of novel active compounds. DISCUSSION: The 2D QSAR obtained models are quite satisfactory (R(2) = 0.84-0.99, Q(2) = 0.76-0.92, R(2)(ext) = 0.62-0.79). Compounds with high antiviral activity and selectivity have to contain 5-trifluoromethyl-[1,2,4]oxadiazole or 2,4-difluorophenyl fragments. Insertion of 2,5-dimethylbenzene, napthyl and especially biphenyl substituents into investigated compounds substantially decreases both their antiviral activity and selectivity. Several compounds were proposed as a result of design and virtual screening. A high level of activity of 2-methoxy-1-phenyl-1H-imidazo[4,5-c]pyridine (sm428) was confirmed experimentally. CONCLUSION: Simplex representation of molecular structure allows successful QSAR analysis of anti-CVB3 activity of ([biphenyloxy]propyl)isoxazole derivatives. Two possible ways of battling CVB3 are considered as a future perspective.


Assuntos
Antivirais/química , Antivirais/farmacologia , Infecções por Coxsackievirus/tratamento farmacológico , Enterovirus Humano B/efeitos dos fármacos , Isoxazóis/química , Isoxazóis/farmacologia , Relação Quantitativa Estrutura-Atividade , Desenho de Fármacos , Células HeLa , Humanos , Modelos Moleculares
17.
Future Med Chem ; 2(7): 1205-26, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21426164

RESUMO

This review explores the application of the Simplex representation of molecular structure (SiRMS) QSAR approach in antiviral research. We provide an introduction to and description of SiRMS, its application in antiviral research and future directions of development of the Simplex approach and the whole QSAR field. In the Simplex approach every molecule is represented as a system of different simplexes (tetratomic fragments with fixed composition, structure, chirality and symmetry). The main advantages of SiRMS are consideration of the different physical-chemical properties of atoms, high adequacy and good interpretability of models obtained and clear procedures for molecular design. The reliability of developed QSAR models as predictive virtual screening tools and their ability to serve as the basis of directed drug design was validated by subsequent synthetic and biological experiments. The SiRMS approach is realized as the complex of the computer program 'HiT QSAR', which is available on request.


Assuntos
Antivirais/química , Antivirais/farmacologia , Desenho de Fármacos , Relação Quantitativa Estrutura-Atividade , Viroses/tratamento farmacológico , Animais , Humanos , Modelos Biológicos , Modelos Moleculares
18.
Antiviral Res ; 81(1): 56-63, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18840470

RESUMO

Amino acid 1092 (AA1092) in capsid protein 1 of coxsackievirus B3 (CVB3) is located in close vicinity to the central phenoxy group of capsid binders (i.e. pleconaril). Whereas isoleucine is associated with drug susceptibility, leucine and methionine confer resistance to pleconaril. In the present study, novel analogues with different substitutions in the central phenoxy group were synthesized to study their influence on anti-CVB3 activity with the aim to overcome pleconaril resistance. Two [(biphenyloxy)propyl]isoxazoles and pleconaril were synthesized without methyl groups in the central phenoxy ring using Suzuki coupling reaction and tested for antiviral activity against the pleconaril-resistant CVB3 Nancy. Furthermore, pleconaril with 3-methyl, 3-methoxy, 3-bromine, 2,3-dimethyl in the central ring as well as the external rings in meta position were synthesized for structure-activity relationship analysis with CVB3 variants containing leucine, methionine or isoleucine at position 1092, other coxsackieviruses B (CVB) as well as several rhinoviruses. The results demonstrate a high impact of substituents in the central ring of capsid inhibitors for anti-enteroviral activity. Pleconaril resistance of CVB3 based on Leu1092 or Met1092 was overcome by unsubstituted analogues or by monosubstitution with 3-methyl as well as 3-bromine in the central phenyl. The 3-bromine derivative inhibited a broad spectrum of CVB and rhinoviruses.


Assuntos
Antivirais/farmacologia , Farmacorresistência Viral , Enterovirus Humano B/efeitos dos fármacos , Infecções por Enterovirus/tratamento farmacológico , Isoxazóis/farmacologia , Oxidiazóis/farmacologia , Antivirais/síntese química , Antivirais/química , Desenho de Fármacos , Enterovirus Humano B/genética , Infecções por Enterovirus/virologia , Células HeLa , Humanos , Isoxazóis/síntese química , Isoxazóis/química , Mutação , Oxidiazóis/síntese química , Oxidiazóis/química , Oxazóis
19.
J Med Chem ; 50(17): 4205-13, 2007 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-17665898

RESUMO

The 50% cytotoxic concentration (CC50) in HeLa cells, the 50% inhibitory concentration (IC50) against human rhinovirus 2 (HRV-2), and the selectivity index (SI = CC50/IC50) of [(biphenyloxy)propyl]isoxazole derivatives were used to develop quantitative structure-activity relationships (QSAR) based on simplex representation of molecular structure. Statistic characteristics for partial least-squares models are quite satisfactory (R2 = 0.838 - 0.918; Q2 = 0.695 - 0.87) for prediction of CC50, IC50, and SI values and permit the virtual screening and molecular design of new compounds with strong anti-HRV-2 activity. The quality of prognosis for designed compounds was additionally estimated by analysis of domain applicability for each QSAR model. A hypothesis to the effect that terminal benzene substituents must have negative electrostatic potential and definite length (approximately 5.5-5.6 A) to possess strong antiviral activity has been suggested. The quality of developed analysis, i.e., high level of antiviral action of three new designed compounds, has been confirmed experimentally.


Assuntos
Antivirais/síntese química , Isoxazóis/síntese química , Modelos Moleculares , Relação Quantitativa Estrutura-Atividade , Rhinovirus/efeitos dos fármacos , Antivirais/farmacologia , Antivirais/toxicidade , Células HeLa , Humanos , Isoxazóis/farmacologia , Isoxazóis/toxicidade , Análise dos Mínimos Quadrados , Estrutura Molecular , Rhinovirus/fisiologia , Replicação Viral/efeitos dos fármacos
20.
J Antimicrob Chemother ; 57(6): 1134-8, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16595643

RESUMO

OBJECTIVES: To investigate the antileprosy potential of a set of original compounds with antimycobacterial activity. METHODS: We developed a facile synthesis of 2-chloro-3-cyano-5-nitropyridine and synthesized a series of 3-cyano-2-dialkyldithiocarbamoyl-5-nitropyridine derivatives. In vivo therapeutic efficacy against Mycobacterium leprae was assessed in the infected mouse footpad model. RESULTS: The compounds were active in vitro against Mycobacterium smegmatis, Mycobacterium aurum, Mycobacterium vaccae and Mycobacterium fortuitum, with MICs generally in the range of 0.4-6.25 mg/L. Reduction of the bacterial load in vivo in the mouse footpad and toxic side effects were dependent on the individual structure of the compounds and on the doses applied. Compounds 2a, 3a and 3b reduced the number of M. leprae by two orders of magnitude, comparable to the effect of dapsone. Co-administration of compounds 2a and 3a with dapsone synergistically enhanced the activity. In addition, these compounds were well tolerated over the treatment period of 7.5 months. CONCLUSIONS: Individual synthetic dithiocarbamate derivatives have promising antileprosy activity.


Assuntos
Hansenostáticos/farmacologia , Hanseníase/tratamento farmacológico , Mycobacterium leprae/efeitos dos fármacos , Mycobacterium/efeitos dos fármacos , Tiocarbamatos/síntese química , Tiocarbamatos/farmacologia , Animais , Contagem de Colônia Microbiana , Dapsona/farmacologia , Dapsona/uso terapêutico , Modelos Animais de Doenças , Quimioterapia Combinada , Humanos , Hansenostáticos/síntese química , Hansenostáticos/uso terapêutico , Hanseníase/microbiologia , Camundongos , Camundongos Endogâmicos CBA , Testes de Sensibilidade Microbiana , Estrutura Molecular , Tiocarbamatos/uso terapêutico
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