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1.
Molecules ; 26(16)2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34443484

RESUMO

The COVID-19 outbreak has rapidly spread on a global scale, affecting the economy and public health systems throughout the world. In recent years, peptide-based therapeutics have been widely studied and developed to treat infectious diseases, including viral infections. Herein, the antiviral effects of the lysine linked dimer des-Cys11, Lys12,Lys13-(pBthTX-I)2K ((pBthTX-I)2K)) and derivatives against SARS-CoV-2 are reported. The lead peptide (pBthTX-I)2K and derivatives showed attractive inhibitory activities against SARS-CoV-2 (EC50 = 28-65 µM) and mostly low cytotoxic effect (CC50 > 100 µM). To shed light on the mechanism of action underlying the peptides' antiviral activity, the Main Protease (Mpro) and Papain-Like protease (PLpro) inhibitory activities of the peptides were assessed. The synthetic peptides showed PLpro inhibition potencies (IC50s = 1.0-3.5 µM) and binding affinities (Kd = 0.9-7 µM) at the low micromolar range but poor inhibitory activity against Mpro (IC50 > 10 µM). The modeled binding mode of a representative peptide of the series indicated that the compound blocked the entry of the PLpro substrate toward the protease catalytic cleft. Our findings indicated that non-toxic dimeric peptides derived from the Bothropstoxin-I have attractive cellular and enzymatic inhibitory activities, thereby suggesting that they are promising prototypes for the discovery and development of new drugs against SARS-CoV-2 infection.


Assuntos
Venenos de Crotalídeos/química , Dimerização , Papaína/antagonistas & inibidores , Peptídeos/química , Peptídeos/farmacologia , SARS-CoV-2/enzimologia , Antivirais/química , Antivirais/metabolismo , Antivirais/farmacologia , Simulação de Acoplamento Molecular , Papaína/química , Papaína/metabolismo , Peptídeos/metabolismo , Inibidores de Proteases/química , Inibidores de Proteases/metabolismo , Inibidores de Proteases/farmacologia , Conformação Proteica , SARS-CoV-2/efeitos dos fármacos
2.
Int J Parasitol Drugs Drug Resist ; 13: 107-120, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32688218

RESUMO

Ergosterol biosynthesis inhibitors, such as posaconazole and ravuconazole, have been proposed as drug candidates for Chagas disease, a neglected infectious tropical disease caused by the protozoan parasite Trypanosoma cruzi. To understand better the mechanism of action and resistance to these inhibitors, a clone of the T. cruzi Y strain was cultured under intermittent and increasing concentrations of ravuconazole until phenotypic stability was achieved. The ravuconazole-selected clone exhibited loss in fitness in vitro when compared to the wild-type parental clone, as observed in reduced invasion capacity and slowed population growth in both mammalian and insect stages of the parasite. In drug activity assays, the resistant clone was above 300-fold more tolerant to ravuconazole than the sensitive parental clone, when the half-maximum effective concentration (EC50) was considered. The resistant clones also showed reduced virulence in vivo, when compared to parental sensitive clones. Cross-resistance to posaconazole and other CYP51 inhibitors, but not to other antichagasic drugs that act independently of CYP51, such as benznidazole and nifurtimox, was also observed. A novel amino acid residue change, T297M, was found in the TcCYP51 gene in the resistant but not in the sensitive clones. The structural effects of the T297M, and of the previously described P355S residue changes, were modelled to understand their impact on interaction with CYP51 inhibitors.


Assuntos
Inibidores de 14-alfa Desmetilase/farmacologia , Resistência a Múltiplos Medicamentos/genética , Esterol 14-Desmetilase/genética , Trypanosoma cruzi , Animais , Linhagem Celular , Doença de Chagas/tratamento farmacológico , Genes de Protozoários , Mutação , Nitroimidazóis/farmacologia , Tiazóis/farmacologia , Triazóis/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Trypanosoma cruzi/genética , Trypanosoma cruzi/crescimento & desenvolvimento
3.
Molecules ; 25(11)2020 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-32486239

RESUMO

High genetic and phenotypic variability between Leishmania species and strains within species make the development of broad-spectrum antileishmanial drugs challenging. Thus, screening panels consisting of several diverse Leishmania species can be useful in enabling compound prioritization based on their spectrum of activity. In this study, a robust and reproducible high content assay was developed, and 1280 small molecules were simultaneously screened against clinically relevant cutaneous and visceral species: L. amazonensis, L. braziliensis, and L. donovani. The assay is based on THP-1 macrophages infected with stationary phase promastigotes and posterior evaluation of both compound antileishmanial activity and host cell toxicity. The profile of compound activity was species-specific, and out of 51 active compounds, only 14 presented broad-spectrum activity against the three species, with activities ranging from 52% to 100%. Notably, the compounds CB1954, Clomipramine, Maprotiline, Protriptyline, and ML-9 presented pan-leishmanial activity, with efficacy greater than 70%. The results highlight the reduced number of compound classes with pan-leishmanial activity that might be available from diversity libraries, emphasizing the need to screen active compounds against a panel of species and strains. The assay reported here can be adapted to virtually any Leishmania species without the need for genetic modification of parasites, providing the basis for the discovery of broad spectrum anti-leishmanial agents.


Assuntos
Leishmaniose/tratamento farmacológico , Animais , Antiprotozoários/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Humanos , Leishmania/efeitos dos fármacos , Leishmania/patogenicidade , Leishmaniose Visceral/tratamento farmacológico , Maprotilina/química , Camundongos , Protriptilina/química , Especificidade da Espécie , Células THP-1
4.
Eur J Med Chem ; 183: 111676, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31542713

RESUMO

Leishmaniasis, a major health problem worldwide, has a limited arsenal of drugs for its control. The appearance of resistance to first- and second-line anti-leishmanial drugs confirms the need to develop new and less toxic drugs that overcome spontaneous resistance. In the present study, we report the design and synthesis of a novel library of 38 flavonol-like compounds and their evaluation in a panel of assays encompassing parasite killing, pharmacokinetics, genomics and ADME-Toxicity resulting in the progression of a compound in the drug discovery value chain. Compound 19, 2-(benzo[b]thiophen-3-yl)-3-hydroxy-6-methoxy-4H-chromen-4-one, exhibited a broad-spectrum activity against Leishmania spp. (EC50 1.9 µM for Leishmania infantum, 3.4 µM for L. donovani, 6.7 µM for L. major), Trypanosoma cruzi (EC50 7.5 µM) and T. brucei (EC50 0.8 µM). Focusing on anti-Leishmania activity, compound 19 challenge in vitro did not select for resistance markers in L. donovani, while a Cos-Seq screening for dominant resistance genes identified a gene locus on chromosome 36 that became ineffective at concentrations beyond EC50. Thus, compound 19 is a promising scaffold to tackle drug resistance in Leishmania infection. In vivo pharmacokinetic studies indicated that compound 19 has a long half-life (intravenous (IV): 63.2 h; per os (PO): 46.9 h) with an acceptable ADME-Toxicity profile. When tested in Leishmania infected hamsters, no toxicity and limited efficacy were observed. Low solubility and degradation were investigated spectroscopically as possible causes for the sub-optimal pharmacokinetic properties. Compound 19 resulted a specific compound based on the screening against a protein set, following the intrinsic fluorescence changes.


Assuntos
Antiprotozoários , Flavonóis , Leishmania/efeitos dos fármacos , Leishmaniose/tratamento farmacológico , Fosforilcolina/análogos & derivados , Tiofenos , Animais , Antiprotozoários/síntese química , Antiprotozoários/química , Antiprotozoários/farmacologia , Cricetinae , Avaliação Pré-Clínica de Medicamentos , Resistência a Medicamentos/efeitos dos fármacos , Flavonóis/síntese química , Flavonóis/química , Flavonóis/farmacologia , Genômica , Humanos , Fosforilcolina/química , Fosforilcolina/farmacologia , Tiofenos/síntese química , Tiofenos/química , Tiofenos/farmacologia
5.
SLAS Discov ; 24(7): 755-765, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31180789

RESUMO

The current methodologies used to identify promising new anthelmintic compounds rely on subjective microscopic examination of worm motility or involve genetic modified organisms. We describe a new methodology to detect worm viability that takes advantage of the differential incorporation of the fluorescent molecular marker propidium iodide and the 2,1,3-benzothiadiazole core, which has been widely applied in light technology. The new assay developed could be validated using the "Pathogen Box" library. By use of this bioassay, it was possible to identify three molecules with activity against Caenorhabditis elegans that were previously described as effective in in vitro assays against other pathogens, such as Schistosoma mansoni, Mycobacterium tuberculosis, and Plasmodium falciparum, accelerating the identification of molecules with anthelmintic potential. The current fluorescence-based bioassay may be used for assessing C. elegans viability. The described methodology replaces the subjectivity of previous assays and provides an enabling technology that is useful for rapid in vitro screens of both natural and synthetic compound libraries. It is expected that the results obtained from these robust in vitro screens would select the most effective compounds for follow-up in vivo experimentation with pathogenic helminths.


Assuntos
Anti-Helmínticos/farmacologia , Caenorhabditis elegans/efeitos dos fármacos , Descoberta de Drogas/métodos , Corantes Fluorescentes/química , Testes de Sensibilidade Parasitária/métodos , Tiadiazóis/química , Animais , Cinética , Estrutura Molecular , Imagem Óptica/métodos
6.
ACS Infect Dis ; 5(7): 1105-1114, 2019 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-31012301

RESUMO

Cycloguanil is a known dihydrofolate-reductase (DHFR) inhibitor, but there is no evidence of its activity on pteridine reductase (PTR), the main metabolic bypass to DHFR inhibition in trypanosomatid parasites. Here, we provide experimental evidence of cycloguanil as an inhibitor of Trypanosoma brucei PTR1 (TbPTR1). A small library of cycloguanil derivatives was developed, resulting in 1 and 2a having IC50 values of 692 and 186 nM, respectively, toward TbPTR1. Structural analysis revealed that the increased potency of 1 and 2a is due to the combined contributions of hydrophobic interactions, H-bonds, and halogen bonds. Moreover, in vitro cell-growth-inhibition tests indicated that 2a is also effective on T. brucei. The simultaneous inhibition of DHFR and PTR1 activity in T. brucei is a promising new strategy for the treatment of human African trypanosomiasis. For this purpose, 1,6-dihydrotriazines represent new molecular tools to develop potent dual PTR and DHFR inhibitors.


Assuntos
Oxirredutases/antagonistas & inibidores , Proguanil/química , Triazinas/síntese química , Tripanossomicidas/síntese química , Trypanosoma brucei brucei/enzimologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Interações Hidrofóbicas e Hidrofílicas , Modelos Moleculares , Estrutura Molecular , Oxirredutases/química , Proguanil/farmacologia , Proteínas de Protozoários/antagonistas & inibidores , Proteínas de Protozoários/química , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Estrutura-Atividade , Triazinas/química , Triazinas/farmacologia , Tripanossomicidas/química , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos
7.
J Med Chem ; 62(8): 3989-4012, 2019 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-30908048

RESUMO

2-Amino-benzo[ d]thiazole was identified as a new scaffold for the development of improved pteridine reductase-1 (PTR1) inhibitors and anti-trypanosomatidic agents. Molecular docking and crystallography guided the design and synthesis of 42 new benzothiazoles. The compounds were assessed for Trypanosoma brucei and Leishmania major PTR1 inhibition and in vitro activity against T. brucei and amastigote Leishmania infantum. We identified several 2-amino-benzo[ d]thiazoles with improved enzymatic activity ( TbPTR1 IC50 = 0.35 µM; LmPTR1 IC50 = 1.9 µM) and low µM antiparasitic activity against T. brucei. The ten most active compounds against TbPTR1 were able to potentiate the antiparasitic activity of methotrexate when evaluated in combination against T. brucei, with a potentiating index between 1.2 and 2.7. The compound library was profiled for early ADME toxicity, and 2-amino- N-benzylbenzo[ d]thiazole-6-carboxamide (4c) was finally identified as a novel potent, safe, and selective anti-trypanocydal agent (EC50 = 7.0 µM). Formulation of 4c with hydroxypropyl-ß-cyclodextrin yielded good oral bioavailability, encouraging progression to in vivo studies.


Assuntos
Antiprotozoários/química , Benzotiazóis/química , Inibidores Enzimáticos/química , Leishmania major/enzimologia , Oxirredutases/antagonistas & inibidores , Proteínas de Protozoários/antagonistas & inibidores , Trypanosoma brucei brucei/enzimologia , Animais , Antiprotozoários/metabolismo , Antiprotozoários/farmacologia , Antiprotozoários/uso terapêutico , Benzotiazóis/metabolismo , Benzotiazóis/farmacologia , Benzotiazóis/uso terapêutico , Sítios de Ligação , Domínio Catalítico , Cristalografia por Raios X , Desenho de Fármacos , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Meia-Vida , Leishmania major/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Oxirredutases/metabolismo , Proteínas de Protozoários/metabolismo , Relação Estrutura-Atividade , Trypanosoma brucei brucei/efeitos dos fármacos , Tripanossomíase/tratamento farmacológico , Tripanossomíase/patologia
8.
SLAS Discov ; 24(3): 346-361, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30784368

RESUMO

According to the World Health Organization, more than 1 billion people are at risk of or are affected by neglected tropical diseases. Examples of such diseases include trypanosomiasis, which causes sleeping sickness; leishmaniasis; and Chagas disease, all of which are prevalent in Africa, South America, and India. Our aim within the New Medicines for Trypanosomatidic Infections project was to use (1) synthetic and natural product libraries, (2) screening, and (3) a preclinical absorption, distribution, metabolism, and excretion-toxicity (ADME-Tox) profiling platform to identify compounds that can enter the trypanosomatidic drug discovery value chain. The synthetic compound libraries originated from multiple scaffolds with known antiparasitic activity and natural products from the Hypha Discovery MycoDiverse natural products library. Our focus was first to employ target-based screening to identify inhibitors of the protozoan Trypanosoma brucei pteridine reductase 1 ( TbPTR1) and second to use a Trypanosoma brucei phenotypic assay that made use of the T. brucei brucei parasite to identify compounds that inhibited cell growth and caused death. Some of the compounds underwent structure-activity relationship expansion and, when appropriate, were evaluated in a preclinical ADME-Tox assay panel. This preclinical platform has led to the identification of lead-like compounds as well as validated hits in the trypanosomatidic drug discovery value chain.


Assuntos
Descoberta de Drogas/métodos , Tripanossomicidas/análise , Tripanossomicidas/farmacologia , Tripanossomíase/tratamento farmacológico , Produtos Biológicos/química , Humanos , Relação Estrutura-Atividade , Tripanossomicidas/uso terapêutico
9.
Eur J Med Chem ; 163: 649-659, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30562700

RESUMO

Chagas disease is a neglected tropical disease (NTD) caused by the protozoan parasite Trypanosoma cruzi and is primarily transmitted to humans by the feces of infected Triatominae insects during their blood meal. The disease affects 6-8 million people, mostly in Latin America countries, and kills more people in the region each year than any other parasite-born disease, including malaria. Moreover, patient numbers are currently increasing in non-endemic, developed countries, such as Australia, Japan, Canada, and the United States. The treatment is limited to one drug, benznidazole, which is only effective in the acute phase of the disease and is very toxic. Thus, there is an urgent need to develop new, safer, and effective drugs against the chronic phase of Chagas disease. Using a QSAR-based virtual screening followed by in vitro experimental evaluation, we report herein the identification of novel potent and selective hits against T. cruzi intracellular stage. We developed and validated binary QSAR models for prediction of anti-trypanosomal activity and cytotoxicity against mammalian cells using the best practices for QSAR modeling. These models were then used for virtual screening of a commercial database, leading to the identification of 39 virtual hits. Further in vitro assays showed that seven compounds were potent against intracellular T. cruzi at submicromolar concentrations (EC50 < 1 µM) and were very selective (SI > 30). Furthermore, other six compounds were also inside the hit criteria for Chagas disease, which presented activity at low micromolar concentrations (EC50 < 10 µM) against intracellular T. cruzi and were also selective (SI > 15). Moreover, we performed a multi-parameter analysis for the comparison of tested compounds regarding their balance between potency, selectivity, and predicted ADMET properties. In the next studies, the most promising compounds will be submitted to additional in vitro and in vivo assays in acute model of Chagas disease, and can be further optimized for the development of new promising drug candidates against this important yet neglected disease.


Assuntos
Doença de Chagas/tratamento farmacológico , Descoberta de Drogas , Relação Quantitativa Estrutura-Atividade , Trypanosoma cruzi/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Tripanossomicidas/química
10.
Eur J Med Chem ; 146: 423-434, 2018 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-29407968

RESUMO

Basing on a library of thiadiazole derivatives showing anti-trypanosomatidic activity, we have considered the thiadiazoles opened forms and reaction intermediates, thiosemicarbazones, as compounds of interest for phenotypic screening against Trypanosoma brucei (Tb), intracellular amastigote form of Leishmania infantum (Li) and Trypanosoma cruzi (Tc). Similar compounds have already shown interesting activity against the same organisms. The compounds were particularly effective against T. brucei and T. cruzi. Among the 28 synthesized compounds, the best one was (E)-2-(4-((3.4-dichlorobenzyl)oxy)benzylidene) hydrazinecarbothioamide (A14) yielding a comparable anti-parasitic activity against the three parasitic species (TbEC50 = 2.31 µM, LiEC50 = 6.14 µM, TcEC50 = 1.31 µM) and a Selectivity Index higher than 10 with respect to human macrophages, therefore showing a pan-anti-trypanosomatidic activity. (E)-2-((3'.4'-dimethoxy-[1.1'-biphenyl]-3-yl)methyle ne) hydrazinecarbothioamide (A12) and (E)-2-(4-((3.4-dichlorobenzyl)oxy)benzylidene)hydrazine carbothioamide (A14) were able to potentiate the anti-parasitic activity of methotrexate (MTX) when evaluated in combination against T. brucei, yielding a 6-fold and 4-fold respectively Dose Reduction Index for MTX. The toxicity profile against four human cell lines and a panel of in vitro early-toxicity assays (comprising hERG, Aurora B, five cytochrome P450 isoforms and mitochondrial toxicity) demonstrated the low toxicity for the thosemicarbazones class in comparison with known drugs. The results confirmed thiosemicarbazones as a suitable chemical scaffold with potential for the development of properly decorated new anti-parasitic drugs.


Assuntos
Antiprotozoários/farmacologia , Doença de Chagas/tratamento farmacológico , Tiossemicarbazonas/farmacologia , Trypanosoma/efeitos dos fármacos , Antiprotozoários/síntese química , Antiprotozoários/química , Relação Dose-Resposta a Droga , Humanos , Macrófagos/efeitos dos fármacos , Estrutura Molecular , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade , Tiossemicarbazonas/síntese química , Tiossemicarbazonas/química
11.
ChemMedChem ; 13(7): 678-683, 2018 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-29451361

RESUMO

Protozoan infections caused by Plasmodium, Leishmania, and Trypanosoma spp. contribute significantly to the burden of infectious diseases worldwide, causing severe morbidity and mortality. The inadequacy of available treatments calls for cost- and time-effective drug discovery endeavors. To this end, we envisaged the triazole linkage of privileged structures as an effective drug design strategy to generate a focused library of high-quality compounds. The versatility of this approach was combined with the feasibility of a phenotypic assay, integrated with early ADME-tox profiling. Thus, an 18-membered library was efficiently assembled via Huisgen cycloaddition of phenothiazine, biphenyl, and phenylpiperazine scaffolds. The resulting 18 compounds were then tested against seven parasite strains, and counter-screened for selectivity against two mammalian cell lines. In parallel, hERG and cytochrome P450 (CYP) inhibition, and mitochondrial toxicity were assessed. Remarkably, 10-((1-(3-([1,1'-biphenyl]-3-yloxy)propyl)-1H-1,2,3-triazol-5-yl)methyl)-10H-phenothiazine (7) and 10-(3-(1-(3-([1,1'-biphenyl]-3-yloxy)propyl)-1H-1,2,3-triazol-4-yl)propyl)-10H-phenothiazine (12) showed respective IC50 values of 1.8 and 1.9 µg mL-1 against T. cruzi, together with optimal selectivity. In particular, compound 7 showed a promising ADME-tox profile. Thus, hit 7 might be progressed as an antichagasic lead.


Assuntos
Antiprotozoários/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Triazóis/farmacologia , Animais , Antiprotozoários/síntese química , Antiprotozoários/química , Antiprotozoários/toxicidade , Linhagem Celular Tumoral , Inibidores das Enzimas do Citocromo P-450/síntese química , Inibidores das Enzimas do Citocromo P-450/farmacologia , Inibidores das Enzimas do Citocromo P-450/toxicidade , Canal de Potássio ERG1/metabolismo , Humanos , Leishmania/efeitos dos fármacos , Estrutura Molecular , Testes de Sensibilidade Parasitária , Plasmodium falciparum/efeitos dos fármacos , Bloqueadores dos Canais de Potássio/síntese química , Bloqueadores dos Canais de Potássio/farmacologia , Bloqueadores dos Canais de Potássio/toxicidade , Ratos , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/toxicidade , Triazóis/síntese química , Triazóis/química , Triazóis/toxicidade , Trypanosoma/efeitos dos fármacos
12.
ACS Omega ; 2(9): 5666-5683, 2017 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-28983525

RESUMO

Pteridine reductase-1 (PTR1) is a promising drug target for the treatment of trypanosomiasis. We investigated the potential of a previously identified class of thiadiazole inhibitors of Leishmania major PTR1 for activity against Trypanosoma brucei (Tb). We solved crystal structures of several TbPTR1-inhibitor complexes to guide the structure-based design of new thiadiazole derivatives. Subsequent synthesis and enzyme- and cell-based assays confirm new, mid-micromolar inhibitors of TbPTR1 with low toxicity. In particular, compound 4m, a biphenyl-thiadiazole-2,5-diamine with IC50 = 16 µM, was able to potentiate the antitrypanosomal activity of the dihydrofolate reductase inhibitor methotrexate (MTX) with a 4.1-fold decrease of the EC50 value. In addition, the antiparasitic activity of the combination of 4m and MTX was reversed by addition of folic acid. By adopting an efficient hit discovery platform, we demonstrate, using the 2-amino-1,3,4-thiadiazole scaffold, how a promising tool for the development of anti-T. brucei agents can be obtained.

13.
Eur J Med Chem ; 141: 138-148, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-29031061

RESUMO

Crassiflorone is a natural product with anti-mycobacterial and anti-gonorrhoeal properties, isolated from the stem bark of the African ebony tree Diospyros crassiflora. We noticed that its pentacyclic core possesses structural resemblance to the quinone-coumarin hybrid 3, which we reported to exhibit a dual-targeted inhibitory profile towards Trypanosoma brucei glyceraldehyde-3-phosphate dehydrogenase (TbGAPDH) and Trypanosoma cruzi trypanothione reductase (TcTR). Following this basic idea, we synthesized a small library of crassiflorone derivatives 15-23 and investigated their potential as anti-trypanosomatid agents. 19 is the only compound of the series showing a balanced dual profile at 10 µM (% inhibitionTbGAPDH = 64% and % inhibitionTcTR = 65%). In phenotypic assay, the most active compounds were 18 and 21, which at 5 µM inhibited Tb bloodstream-form growth by 29% and 38%, respectively. Notably, all the newly synthesized compounds at 10 µM did not affect viability and the status of mitochondria in human A549 and 786-O cell lines, respectively. However, further optimization that addresses metabolic liabilities including solubility, as well as cytochromes P450 (CYP1A2, CYP2C9, CYP2C19, and CYP2D6) inhibition, is required before this class of natural product-derived compounds can be further progressed.


Assuntos
Gliceraldeído-3-Fosfato Desidrogenases/antagonistas & inibidores , NADH NADPH Oxirredutases/antagonistas & inibidores , Quinonas/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Trypanosoma cruzi/efeitos dos fármacos , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Gliceraldeído-3-Fosfato Desidrogenases/metabolismo , Humanos , Modelos Moleculares , Estrutura Molecular , NADH NADPH Oxirredutases/metabolismo , Testes de Sensibilidade Parasitária , Quinonas/síntese química , Quinonas/química , Relação Estrutura-Atividade , Tripanossomicidas/síntese química , Tripanossomicidas/química , Trypanosoma brucei brucei/enzimologia , Trypanosoma brucei brucei/crescimento & desenvolvimento , Trypanosoma cruzi/enzimologia , Trypanosoma cruzi/crescimento & desenvolvimento
14.
Bioorg Med Chem Lett ; 27(11): 2459-2464, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28434763

RESUMO

Leishmaniasis are infectious diseases caused by parasites of genus Leishmania that affect affects 12 million people in 98 countries mainly in Africa, Asia, and Latin America. Effective treatments for this disease are urgently needed. In this study, we present a computer-aided approach to investigate a set of 32 recently synthesized chalcone and chalcone-like compounds to act as antileishmanial agents. As a result, nine most promising compounds and three potentially inactive compounds were experimentally evaluated against Leishmania infantum amastigotes and mammalian cells. Four compounds exhibited EC50 in the range of 6.2-10.98µM. In addition, two compounds, LabMol-65 and LabMol-73, exhibited cytotoxicity in macrophages >50µM that resulted in better selectivity compared to standard drug amphotericin B. These two compounds also demonstrated low cytotoxicity and high selectivity towards Vero cells. The results of target fishing followed by homology modeling and docking studies suggest that these chalcone compounds could act in Leishmania because of their interaction with cysteine proteases, such as procathepsin L. Finally, we have provided structural recommendations for designing new antileishmanial chalcones.


Assuntos
Antiprotozoários/farmacologia , Chalconas/farmacologia , Inibidores de Cisteína Proteinase/farmacologia , Leishmania infantum/efeitos dos fármacos , Nitrofuranos/farmacologia , Piperazinas/farmacologia , Piperidinas/farmacologia , Anfotericina B/farmacologia , Animais , Antiprotozoários/síntese química , Antiprotozoários/química , Chalconas/síntese química , Chalconas/química , Chlorocebus aethiops , Simulação por Computador , Inibidores de Cisteína Proteinase/síntese química , Inibidores de Cisteína Proteinase/química , Bases de Dados Factuais , Descoberta de Drogas , Humanos , Simulação de Acoplamento Molecular , Nitrofuranos/síntese química , Nitrofuranos/química , Piperazinas/síntese química , Piperazinas/química , Piperidinas/síntese química , Piperidinas/química , Relação Estrutura-Atividade , Células Vero
15.
Molecules ; 22(3)2017 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-28282886

RESUMO

Flavonoids have previously been identified as antiparasitic agents and pteridine reductase 1 (PTR1) inhibitors. Herein, we focus our attention on the chroman-4-one scaffold. Three chroman-4-one analogues (1-3) of previously published chromen-4-one derivatives were synthesized and biologically evaluated against parasitic enzymes (Trypanosoma brucei PTR1-TbPTR1 and Leishmania major-LmPTR1) and parasites (Trypanosoma brucei and Leishmania infantum). A crystal structure of TbPTR1 in complex with compound 1 and the first crystal structures of LmPTR1-flavanone complexes (compounds 1 and 3) were solved. The inhibitory activity of the chroman-4-one and chromen-4-one derivatives was explained by comparison of observed and predicted binding modes of the compounds. Compound 1 showed activity both against the targeted enzymes and the parasites with a selectivity index greater than 7 and a low toxicity. Our results provide a basis for further scaffold optimization and structure-based drug design aimed at the identification of potent anti-trypanosomatidic compounds targeting multiple PTR1 variants.


Assuntos
Antiparasitários/química , Antiparasitários/farmacologia , Cromanos/química , Cromanos/farmacologia , Oxirredutases/antagonistas & inibidores , Antiparasitários/síntese química , Sítios de Ligação , Cromanos/síntese química , Ativação Enzimática/efeitos dos fármacos , Concentração Inibidora 50 , Leishmania major/efeitos dos fármacos , Leishmania major/enzimologia , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Oxirredutases/química , Ligação Proteica , Trypanosoma brucei brucei/efeitos dos fármacos , Trypanosoma brucei brucei/enzimologia
16.
Eur J Med Chem ; 128: 202-212, 2017 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-28189084

RESUMO

A library of 16 4-substituted 2-(1H-pyrrolo[3,2-c]pyridin-2-yl)propan-2-ols 17-32 has been synthesized for use in biological testing against Trypanosoma cruzi, the protozoan parasite that causes Chagas disease. The 4-substituted 2-(1H-pyrrolo[3,2-c]pyridin-2-yl)propan-2-ols 17-32 were subjected to biological testing to evaluate their efficacy against intracellular Trypanosoma cruzi (Y strain) amastigotes infecting U2OS human cells, with benznidazole as a reference compound. The assay was performed in duplicate (two independent experiments) and submitted to High Content Analysis (HCA) for determination of trypanocidal activity. Three of the tested compounds presented relatively high trypanocidal activity (19, 22 and 29), however severe host cell toxicity was observed concomitantly. Chemical optimization of the highly active compounds and the synthesis of more compounds for biological testing against Trypanosoma cruzi will be required to improve selectivity and so that a structure-activity relationship can be generated to provide a more insightful analysis of both chemical and biological aspects.


Assuntos
Doença de Chagas/tratamento farmacológico , Piridinas/química , Piridinas/síntese química , Piridinas/farmacologia , Pirróis/química , Pirróis/síntese química , Pirróis/farmacologia , Tripanossomicidas/síntese química , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Células Cultivadas , Doença de Chagas/parasitologia , Humanos , Modelos Moleculares , Estrutura Molecular , Nitroimidazóis/farmacologia , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade
17.
Eur J Med Chem ; 126: 1129-1135, 2017 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-28064141

RESUMO

Chalcones display a broad spectrum of pharmacological activities. Herein, a series of 2'-hydroxy methoxylated chalcones was synthesized and evaluated towards Trypanosoma brucei, Trypanosoma cruzi and Leishmania infantum. Among the synthesized library, compounds 1, 3, 4, 7 and 8 were the most potent and selective anti-T. brucei compounds (EC50 = 1.3-4.2 µM, selectivity index >10-fold). Compound 4 showed the best early-tox and antiparasitic profile. The pharmacokinetic studies of compound 4 in BALB/c mice using hydroxypropil-ß-cyclodextrins formulation showed a 7.5 times increase in oral bioavailability.


Assuntos
Antiparasitários/química , Antiparasitários/farmacologia , Chalconas/química , Chalconas/farmacologia , Animais , Antiparasitários/farmacocinética , Antiparasitários/toxicidade , Linhagem Celular Tumoral , Chalconas/farmacocinética , Chalconas/toxicidade , Ciclodextrinas/química , Portadores de Fármacos/química , Camundongos , Solubilidade , Trypanosomatina/efeitos dos fármacos
18.
Eur J Med Chem ; 121: 553-560, 2016 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-27318979

RESUMO

Chagas disease, caused by Trypanosoma cruzi, is a parasitosis that predominates in Latin America. It is estimated that 25 million people are under the risk of infection and, in 2008, more than 10 thousand deaths were registered. The only two drugs available in the therapeutics, nifurtimox and benznidazole, showed to be more effective in the acute phase of the disease. However, there is no standard treatment protocol effective for the chronic phase. Nitrofurazone (NF), an antimicrobial drug, has activity against T. cruzi, although being toxic. Considering the need for new antichagasic drugs, the existence of promising new therapeutic targets, as 14α-sterol demethylase and cruzain, and employing the bioisosterism and molecular hybridization approaches, four novel compounds were synthesized, characterized by melting point range, elemental analysis, IR and NMR spectroscopy. The compounds were tested against T. cruzi amastigotes in infected U2OS cells. All compounds showed selectivity towards T. cruzi and showed trypanomicidal activity in low micromolar range. The compound 3 showed potency similar to benznidazole, but lower efficacy. These results highlight the importance of the 1,2,4-triazole, thiosemicarbazonic and nitro group moieties for designing new efficient compounds, potentially for the chronic phase of Chagas disease.


Assuntos
Nitrofurazona/síntese química , Nitrofurazona/farmacologia , Triazóis/química , Tripanossomicidas/síntese química , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Linhagem Celular Tumoral , Técnicas de Química Sintética , Humanos , Hidrazonas/química , Modelos Moleculares , Conformação Molecular , Nitrofurazona/química , Tripanossomicidas/química
19.
Expert Opin Drug Discov ; 11(5): 447-55, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26967915

RESUMO

INTRODUCTION: Chagas disease is a chronic infection associated with long-term morbidity. Increased funding and advocacy for drug discovery for neglected diseases have prompted the introduction of several important technological advances, and Chagas disease is among the neglected conditions that has mostly benefited from technological developments. A number of screening campaigns, and the development of new and improved in vitro and in vivo assays, has led to advances in the field of drug discovery. AREAS COVERED: This review highlights the major advances in Chagas disease drug screening, and how these are being used not only to discover novel chemical entities and drug candidates, but also increase our knowledge about the disease and the parasite. Different methodologies used for compound screening and prioritization are discussed, as well as novel techniques for the investigation of these targets. The molecular mechanism of action is also discussed. EXPERT OPINION: Technological advances have been executed with scientific rigour for the development of new in vitro cell-based assays and in vivo animal models, to bring about novel and better drugs for Chagas disease, as well as to increase our understanding of what are the necessary properties for a compound to be successful in the clinic. The gained knowledge, combined with new exciting approaches toward target deconvolution, will help identifying new targets for Chagas disease chemotherapy in the future.


Assuntos
Doença de Chagas/tratamento farmacológico , Animais , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Humanos , Tripanossomicidas/farmacologia , Tripanossomicidas/uso terapêutico , Trypanosoma cruzi/efeitos dos fármacos
20.
Curr Med Chem ; 22(37): 4293-312, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26477622

RESUMO

Human American trypanosomiasis, commonly called Chagas disease, is one of the most neglected illnesses in the world and remains one of the most prevalent chronic infectious diseases of Latin America with thousands of new cases every year. The only treatments available have been introduced five decades ago. They have serious, undesirable side effects and disputed benefits in the chronic stage of the disease - a characteristic and debilitating cardiomyopathy and/or megavisceras. Several laboratories have therefore focused their efforts in finding better drugs. Although recent years have brought new clinical trials, these are few and lack diversity in terms of drug mechanism of action, thus resulting in a weak drug discovery pipeline. This fragility has been recently exposed by the failure of two candidates; posaconazole and E1224, to sterilely cure patients in phase 2 clinical trials. Such setbacks highlight the need for continuous, novel and high quality drug discovery and development efforts to discover better and safer treatments. In this article we will review past and current findings on drug discovery for Trypanosoma cruzi made by academic research groups, industry and other research organizations over the last half century. We also analyze the current research landscape that is now better placed than ever to deliver alternative treatments for Chagas disease in the near future.


Assuntos
Antiprotozoários/uso terapêutico , Doença de Chagas/tratamento farmacológico , Descoberta de Drogas/tendências , Humanos , Trypanosoma cruzi/fisiologia
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