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1.
PLoS Pathog ; 17(4): e1009384, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33886696

RESUMO

It is estimated that more than 1 billion people across the world are affected by a neglected tropical disease (NTD) that requires medical intervention. These diseases tend to afflict people in areas with high rates of poverty and cost economies billions of dollars every year. Collaborative drug discovery efforts are required to reduce the burden of these diseases in endemic regions. The release of "Open Access Boxes" is an initiative launched by Medicines for Malaria Venture (MMV) in collaboration with its partners to catalyze new drug discovery in neglected diseases. These boxes are mainly requested by biology researchers across the globe who may not otherwise have access to compounds to screen nor knowledge of the workflow that needs to be followed after identification of actives from their screening campaigns. Here, we present guidelines on how to move such actives beyond the hit identification stage, to help in capacity strengthening and enable a greater impact of the initiative.


Assuntos
Descoberta de Drogas , Malária/tratamento farmacológico , Doenças Negligenciadas/tratamento farmacológico , Estudos de Validação como Assunto , Acesso à Informação , Humanos , Medicina Tropical/métodos
2.
Clin Microbiol Rev ; 30(3): 647-669, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28446445

RESUMO

In the last 2 decades, renewed attention to neglected tropical diseases (NTDs) has spurred the development of antiparasitic agents, especially in light of emerging drug resistance. The need for new drugs has required in vitro screening methods using parasite culture. Furthermore, clinical laboratories sought to correlate in vitro susceptibility methods with treatment outcomes, most notably with malaria. Parasites with their various life cycles present greater complexity than bacteria, for which standardized susceptibility methods exist. This review catalogs the state-of-the-art methodologies used to evaluate the effects of drugs on key human parasites from the point of view of drug discovery as well as the need for laboratory methods that correlate with clinical outcomes.


Assuntos
Antiparasitários/farmacologia , Parasitos/efeitos dos fármacos , Animais , Descoberta de Drogas , Humanos , Doenças Negligenciadas/parasitologia
3.
An Acad Bras Cienc ; 90(1 Suppl 2): 1215-1231, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29791525

RESUMO

Combination therapy drugs are considered a fundamental way to control malaria as it mimimizes the risk of emergence of resistance to the individual partner drugs. Consequently, this type of therapy constitutes a driving force for the discovery of new drugs with different modes of action, since this will provide options for combining different drugs to achieve the optimum antimalarial treatment. In this context, a 2,3,8-trisubstitued quinoline compound was found in a high throughput screen (HTS) to show an excellent inhibition of P. falciparum NF54 (IC50 = 22 nM) and low cytotoxicity. We performed a detailed evaluation of the substituents to improve the metabolic stability and solubility liabilities of the original hit and identified derivatives with enhanced physicochemical and/or PK properties and that maintained biological activity. However the high potency was not retained on testing against drug resistant plasmodium strains.


Assuntos
Antimaláricos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Quinolinas/farmacologia , Animais , Antimaláricos/síntese química , Antimaláricos/química , Desenho de Fármacos , Humanos , Testes de Sensibilidade Parasitária , Quinolinas/síntese química , Quinolinas/química , Ratos
4.
ACS Infect Dis ; 8(4): 713-720, 2022 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-35286809

RESUMO

The current Covid-19 pandemic has underlined the need for a more coordinated and forward-looking investment in the search for new medicines targeting emerging health care threats. Repositioning currently approved drugs is a popular approach to any new emerging disease, but it represents a first wave of response. Behind this would be a second wave of more specifically designed therapies based on activities against specific molecular targets or in phenotypic assays. Following the successful deployment and uptake of previous open access compound collections, we assembled the Pandemic Response Box, a collection of 400 compounds to facilitate drug discovery in emerging infectious disease. These are based on public domain information on chemotypes currently in discovery and early development which have been shown to have useful activities and were prioritized by medicinal chemistry experts. They are freely available to the community as a pharmacological test set with the understanding that data will be shared rapidly in the public domain.


Assuntos
Tratamento Farmacológico da COVID-19 , Pandemias , Surtos de Doenças , Descoberta de Drogas , Humanos
5.
ChemMedChem ; 14(14): 1329-1335, 2019 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-31188540

RESUMO

Herein we describe the optimization of a phenotypic hit against Plasmodium falciparum based on an aminoacetamide scaffold. This led to N-(3-chloro-4-fluorophenyl)-2-methyl-2-{[4-methyl-3-(morpholinosulfonyl)phenyl]amino}propanamide (compound 28) with low-nanomolar activity against the intraerythrocytic stages of the malaria parasite, and which was found to be inactive in a mammalian cell counter-screen up to 25 µm. Inhibition of gametes in the dual gamete activation assay suggests that this family of compounds may also have transmission blocking capabilities. Whilst we were unable to optimize the aqueous solubility and microsomal stability to a point at which the aminoacetamides would be suitable for in vivo pharmacokinetic and efficacy studies, compound 28 displayed excellent antimalarial potency and selectivity; it could therefore serve as a suitable chemical tool for drug target identification.


Assuntos
Acetamidas/farmacologia , Antimaláricos/farmacologia , Acetamidas/síntese química , Acetamidas/farmacocinética , Animais , Antimaláricos/síntese química , Antimaláricos/farmacocinética , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Testes de Sensibilidade Parasitária , Plasmodium berghei/efeitos dos fármacos , Plasmodium cynomolgi/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Relação Estrutura-Atividade
6.
J Med Chem ; 61(4): 1450-1473, 2018 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-29215279

RESUMO

Malaria deaths have been decreasing over the last 10-15 years, with global mortality rates having fallen by 47% since 2000. While the World Health Organization (WHO) recommends the use of artemisinin-based combination therapies (ACTs) to combat malaria, the emergence of artemisinin resistant strains underscores the need to develop new antimalarial drugs. Recent in vivo efficacy improvements of the historical antimalarial ICI 56,780 have been reported, however, with the poor solubility and rapid development of resistance, this compound requires further optimization. A series of piperazine-containing 4(1H)-quinolones with greatly enhanced solubility were developed utilizing structure-activity relationship (SAR) and structure-property relationship (SPR) studies. Furthermore, promising compounds were chosen for an in vivo scouting assay to narrow selection for testing in an in vivo Thompson test. Finally, two piperazine-containing 4(1H)-quinolones were curative in the conventional Thompson test and also displayed in vivo activity against the liver stages of the parasite.


Assuntos
Antimaláricos/síntese química , Piperazina/química , Quinolonas/química , Animais , Antimaláricos/farmacocinética , Desenho de Fármacos , Humanos , Camundongos , Plasmodium falciparum/efeitos dos fármacos , Quinolonas/uso terapêutico , Solubilidade , Relação Estrutura-Atividade
7.
Science ; 359(6372): 191-199, 2018 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-29326268

RESUMO

Chemogenetic characterization through in vitro evolution combined with whole-genome analysis can identify antimalarial drug targets and drug-resistance genes. We performed a genome analysis of 262 Plasmodium falciparum parasites resistant to 37 diverse compounds. We found 159 gene amplifications and 148 nonsynonymous changes in 83 genes associated with drug-resistance acquisition, where gene amplifications contributed to one-third of resistance acquisition events. Beyond confirming previously identified multidrug-resistance mechanisms, we discovered hitherto unrecognized drug target-inhibitor pairs, including thymidylate synthase and a benzoquinazolinone, farnesyltransferase and a pyrimidinedione, and a dipeptidylpeptidase and an arylurea. This exploration of the P. falciparum resistome and druggable genome will likely guide drug discovery and structural biology efforts, while also advancing our understanding of resistance mechanisms available to the malaria parasite.


Assuntos
Antimaláricos/farmacologia , Resistência a Medicamentos/genética , Genoma de Protozoário , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/genética , Ativação Metabólica , Alelos , Variações do Número de Cópias de DNA , Evolução Molecular Direcionada , Resistência a Múltiplos Medicamentos/genética , Genes de Protozoários , Metabolômica , Mutação , Plasmodium falciparum/crescimento & desenvolvimento , Seleção Genética , Fatores de Transcrição/química , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
8.
J Med Chem ; 59(14): 6943-60, 2016 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-27291102

RESUMO

Though malaria mortality rates are down 48% globally since 2000, reported occurrences of resistance against current therapeutics threaten to reverse that progress. Recently, antimalarials that were once considered unsuitable therapeutic agents have been revisited to improve physicochemical properties and efficacy required for selection as a drug candidate. One such compound is 4(1H)-quinolone ICI 56,780, which is known to be a causal prophylactic that also displays blood schizonticidal activity against P. berghei. Rapid induction of parasite resistance, however, stalled its further development. We have completed a full structure-activity relationship study on 4(1H)-quinolones, focusing on the reduction of cross-resistance with atovaquone for activity against the clinical isolates W2 and TM90-C2B, as well as the improvement of microsomal stability. These studies revealed several frontrunner compounds with superb in vivo antimalarial activity. The best compounds were found to be curative with all mice surviving a Plasmodium berghei infection after 30 days.


Assuntos
Antimaláricos/farmacologia , Plasmodium berghei/efeitos dos fármacos , Quinolonas/farmacologia , Animais , Antimaláricos/síntese química , Antimaláricos/química , Relação Dose-Resposta a Droga , Camundongos , Estrutura Molecular , Testes de Sensibilidade Parasitária , Quinolonas/síntese química , Quinolonas/química , Relação Estrutura-Atividade
9.
Nat Commun ; 7: 11901, 2016 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-27301419

RESUMO

Microbial resistance to chemotherapy has caused countless deaths where malaria is endemic. Chemotherapy may fail either due to pre-existing resistance or evolution of drug-resistant parasites. Here we use a diverse set of antimalarial compounds to investigate the acquisition of drug resistance and the degree of cross-resistance against common resistance alleles. We assess cross-resistance using a set of 15 parasite lines carrying resistance-conferring alleles in pfatp4, cytochrome bc1, pfcarl, pfdhod, pfcrt, pfmdr, pfdhfr, cytoplasmic prolyl t-RNA synthetase or hsp90. Subsequently, we assess whether resistant parasites can be obtained after several rounds of drug selection. Twenty-three of the 48 in vitro selections result in resistant parasites, with time to resistance onset ranging from 15 to 300 days. Our data indicate that pre-existing resistance may not be a major hurdle for novel-target antimalarial candidates, and focusing our attention on fast-killing compounds may result in a slower onset of clinical resistance.


Assuntos
Resistência a Medicamentos , Parasitos/fisiologia , Plasmodium falciparum/fisiologia , Animais , Antimaláricos/farmacologia , Células Clonais , Resistência a Medicamentos/efeitos dos fármacos , Mutação INDEL/genética , Mutação/genética , Parasitos/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Polimorfismo de Nucleotídeo Único/genética
10.
Expert Opin Ther Pat ; 22(6): 607-43, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22694759

RESUMO

INTRODUCTION: Malaria causes a huge humanitarian and economic burden. Parasite resistance to established and recently launched anti-malarials is a major issue which, when combined with a malaria eradication agenda, means there is a considerable need for new small molecule anti-malarials. Catalyzed by a recent surge in funding for malaria drug discovery and development, there is an increasing number of compounds in the malaria pipeline. AREAS COVERED: This review covers patents published in English between January 2010 and June 2011, which feature small molecules for the treatment of malaria. Approximately 50 series of compounds are described. Patents covering clinical applications, diagnosis kits or vaccines are not included, nor patents where the principle disease focus is not malaria. EXPERT OPINION: There is considerable activity in the field of small molecules for malaria which is likely to continue. The ultimate goal is to identify novel drugs to support the malaria eradication agenda. This requires safe and efficacious compounds, from novel chemotypes, which rapidly kill parasites and which are readily synthesized from cheap starting materials. In addition, compounds which have activity in the liver stages or in transmission blocking may be prioritized for development over analogs related to established anti-malarial series targeting the asexual blood stages of the parasite.


Assuntos
Antimaláricos/uso terapêutico , Desenho de Fármacos , Malária/tratamento farmacológico , Animais , Antimaláricos/química , Antimaláricos/farmacologia , Humanos , Malária/sangue , Malária/diagnóstico , Malária/parasitologia , Estrutura Molecular , Patentes como Assunto , Relação Estrutura-Atividade , Fatores de Tempo
11.
Bioorg Med Chem Lett ; 17(21): 6013-8, 2007 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-17827008

RESUMO

Starting from adenosine triphosphate (ATP), the identification of a novel series of P2Y(12) receptor antagonists and exploitation of their SAR is described. Modifications of the acidic side chain and the purine core and investigation of hydrophobic substituents led to a series of neutral molecules. The leading compound, 17 (AZD6140), is currently in a large phase III clinical trial for the treatment of acute coronary syndromes and prevention of thromboembolic clinical sequelae.


Assuntos
Trifosfato de Adenosina/uso terapêutico , Adenosina/análogos & derivados , Proteínas de Membrana/antagonistas & inibidores , Antagonistas do Receptor Purinérgico P2 , Trombose/prevenção & controle , Adenosina/uso terapêutico , Administração Oral , Animais , Humanos , Receptores Purinérgicos P2Y12 , Ticagrelor
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