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1.
Antimicrob Agents Chemother ; 66(6): e0013222, 2022 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-35607978

RESUMO

As a result of a high-throughput compound screening campaign using Mycobacterium tuberculosis-infected macrophages, a new drug candidate for the treatment of tuberculosis has been identified. GSK2556286 inhibits growth within human macrophages (50% inhibitory concentration [IC50] = 0.07 µM), is active against extracellular bacteria in cholesterol-containing culture medium, and exhibits no cross-resistance with known antitubercular drugs. In addition, it has shown efficacy in different mouse models of tuberculosis (TB) and has an adequate safety profile in two preclinical species. These features indicate a compound with a novel mode of action, although still not fully defined, that is effective against both multidrug-resistant (MDR) or extensively drug-resistant (XDR) and drug-sensitive (DS) M. tuberculosis with the potential to shorten the duration of treatment in novel combination drug regimens. (This study has been registered at ClinicalTrials.gov under identifier NCT04472897).


Assuntos
Mycobacterium tuberculosis , Tuberculose Resistente a Múltiplos Medicamentos , Tuberculose , Animais , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Macrófagos , Camundongos , Testes de Sensibilidade Microbiana , Tuberculose/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico
2.
Angew Chem Int Ed Engl ; 60(17): 9279-9283, 2021 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-33433953

RESUMO

Plasmodium falciparum proteasome (Pf20S) inhibitors are active against Plasmodium at multiple stages-erythrocytic, gametocyte, liver, and gamete activation stages-indicating that selective Pf20S inhibitors possess the potential to be therapeutic, prophylactic, and transmission-blocking antimalarials. Starting from a reported compound, we developed a noncovalent, macrocyclic peptide inhibitor of the malarial proteasome with high species selectivity and improved pharmacokinetic properties. The compound demonstrates specific, time-dependent inhibition of the ß5 subunit of the Pf20S, kills artemisinin-sensitive and artemisinin-resistant P. falciparum isolates in vitro and reduces parasitemia in humanized, P. falciparum-infected mice.


Assuntos
Antimaláricos/farmacologia , Desenvolvimento de Medicamentos , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/farmacologia , Animais , Antimaláricos/síntese química , Antimaláricos/química , Malária Falciparum/metabolismo , Camundongos , Modelos Moleculares , Conformação Molecular , Testes de Sensibilidade Parasitária , Plasmodium falciparum/enzimologia , Inibidores de Proteassoma/síntese química , Inibidores de Proteassoma/química
3.
Bioorg Med Chem Lett ; 28(17): 2899-2905, 2018 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-30031620

RESUMO

A convenient solid phase peptide synthetic (SPPS) route is reported for the preparation of antimycobacterial wollamides. The method is based on on-resin head-to-tail cyclization and is fast, efficient and amenable to automation. The in vitro antimycobacterial activities of the newly synthesized wollamides were evaluated against M. tuberculosis H37Rv (Mtb H37Rv). To assess their drug-likeness, in vitro pharmacokinetic (ADME) profiling was also performed. For wollamides with potent extracellular potency, intracellular activities and in vivo efficacy were determined. The results disclose the potent antimycobacterial (MICMtb H37Rv = 1.1 µM) and suitable drug-like properties of wollamide A (4b). Out of the synthesized wollamides, four compounds (4b-e) exhibited potent intracellular activities against Mtb H37Rv infected human macrophages (IC50 = 0.2-1.3 µM). Results of in vivo blood exposure and efficacy assays for 4d and 4e are discussed.


Assuntos
Antibacterianos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Peptídeos Cíclicos/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Relação Dose-Resposta a Droga , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/microbiologia , Testes de Sensibilidade Microbiana , Estrutura Molecular , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/química , Relação Estrutura-Atividade
4.
J Med Chem ; 67(16): 13985-14006, 2024 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-39136694

RESUMO

Human African trypanosomiasis is among the World Health Organization's designated neglected tropical diseases. Repurposing strategies are often employed in academic drug discovery programs due to financial limitations, and in this instance, we used human kinase inhibitor chemotypes to identify substituted 4-aminoazaindoles, exemplified by 1. Structure-activity and structure-property relationship analysis, informed by cheminformatics, identified 4s as a potent inhibitor of Trypanosoma brucei growth. While 4s appeared to be fast acting and cidal in the in vitro assays, it failed to cure a murine model of infection. Preliminary efforts to identify the potential mechanism of action of the series pointed to arginine kinase, though, as we demonstrate, this does not appear to be the sole target of our compounds. This comprehensive approach to drug discovery, encompassing cheminformatics, structure-potency and structure-property analysis, and pharmacophore identification, highlights our multipronged efforts to identify novel lead compounds for this deadly disease.


Assuntos
Indóis , Tripanossomicidas , Trypanosoma brucei brucei , Trypanosoma brucei brucei/efeitos dos fármacos , Relação Estrutura-Atividade , Animais , Tripanossomicidas/farmacologia , Tripanossomicidas/química , Tripanossomicidas/síntese química , Indóis/química , Indóis/farmacologia , Indóis/síntese química , Humanos , Camundongos , Tripanossomíase Africana/tratamento farmacológico , Compostos Aza/química , Compostos Aza/farmacologia , Compostos Aza/síntese química , Estrutura Molecular , Farmacóforo
5.
J Med Chem ; 66(2): 1522-1542, 2023 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-36626662

RESUMO

Herein, we describe the hit optimization of a novel diarylthioether chemical class found to be active against Trypanosoma cruzi; the parasite responsible for Chagas disease. The hit compound was discovered through a whole-cell phenotypic screen and as such, the mechanism of action for this chemical class is unknown. Our investigations led to clear structure-activity relationships and the discovery of several analogues with high in vitro potency. Furthermore, we observed excellent activity during acute in vivo efficacy studies in mice infected with transgenic T. cruzi. These diarylthioether compounds represent a promising new chemotype for Chagas disease drug discovery and merit further development to increase oral exposure without increasing toxicity.


Assuntos
Doença de Chagas , Tripanossomicidas , Trypanosoma cruzi , Camundongos , Animais , Tripanossomicidas/farmacologia , Tripanossomicidas/uso terapêutico , Tripanossomicidas/química , Doença de Chagas/tratamento farmacológico , Doença de Chagas/parasitologia , Relação Estrutura-Atividade , Descoberta de Drogas
6.
Elife ; 112022 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-35289746

RESUMO

Background: Diarrhoea remains one of the leading causes of childhood mortality globally. Recent epidemiological studies conducted in low-middle income countries (LMICs) identified Shigella spp. as the first and second most predominant agent of dysentery and moderate diarrhoea, respectively. Antimicrobial therapy is often necessary for Shigella infections; however, we are reaching a crisis point with efficacious antimicrobials. The rapid emergence of resistance against existing antimicrobials in Shigella spp. poses a serious global health problem. Methods: Aiming to identify alternative antimicrobial chemicals with activity against antimicrobial resistant Shigella, we initiated a collaborative academia-industry drug discovery project, applying high-throughput phenotypic screening across broad chemical diversity and followed a lead compound through in vitro and in vivo characterisation. Results: We identified several known antimicrobial compound classes with antibacterial activity against Shigella. These compounds included the oral carbapenem Tebipenem, which was found to be highly potent against broadly susceptible Shigella and contemporary MDR variants for which we perform detailed pre-clinical testing. Additional in vitro screening demonstrated that Tebipenem had activity against a wide range of other non-Shigella enteric bacteria. Cognisant of the risk for the development of resistance against monotherapy, we identified synergistic behaviour of two different drug combinations incorporating Tebipenem. We found the orally bioavailable prodrug (Tebipenem pivoxil) had ideal pharmacokinetic properties for treating enteric pathogens and was effective in clearing the gut of infecting organisms when administered to Shigella-infected mice and gnotobiotic piglets. Conclusions: Our data highlight the emerging antimicrobial resistance crisis and shows that Tebipenem pivoxil (licenced for paediatric respiratory tract infections in Japan) should be accelerated into human trials and could be repurposed as an effective treatment for severe diarrhoea caused by MDR Shigella and other enteric pathogens in LMICs. Funding: Tres Cantos Open Lab Foundation (projects TC239 and TC246), the Bill and Melinda Gates Foundation (grant OPP1172483) and Wellcome (215515/Z/19/Z).


Assuntos
Anti-Infecciosos , Doenças Transmissíveis , Shigella , Animais , Antibacterianos/farmacocinética , Antibacterianos/uso terapêutico , Carbapenêmicos/farmacologia , Carbapenêmicos/uso terapêutico , Criança , Diarreia , Reposicionamento de Medicamentos , Humanos , Camundongos , Suínos
7.
J Med Chem ; 64(13): 9404-9430, 2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34156862

RESUMO

Neglected tropical diseases such as human African trypanosomiasis (HAT) are prevalent primarily in tropical climates and among populations living in poverty. Historically, the lack of economic incentive to develop new treatments for these diseases has meant that existing therapeutics have serious shortcomings in terms of safety, efficacy, and administration, and better therapeutics are needed. We now report a series of 3,5-disubstituted-7-azaindoles identified as growth inhibitors of Trypanosoma brucei, the parasite that causes HAT, through a high-throughput screen. We describe the hit-to-lead optimization of this series and the development and preclinical investigation of 29d, a potent antitrypanosomal compound with promising pharmacokinetic (PK) parameters. This compound was ultimately not progressed beyond in vivo PK studies due to its inability to penetrate the blood-brain barrier (BBB), critical for stage 2 HAT treatments.


Assuntos
Indóis/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Tripanossomíase Africana/tratamento farmacológico , Relação Dose-Resposta a Droga , Humanos , Indóis/síntese química , Indóis/química , Estrutura Molecular , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade , Tripanossomicidas/síntese química , Tripanossomicidas/química
8.
ACS Omega ; 5(24): 14451-14460, 2020 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-32596583

RESUMO

Hirsutellide A is nature-derived cyclic hexadepsipeptide with reported antimycobacterial and antiplasmodial activities. To verify its structure, hirsutellide A was synthesized following a solution-phase peptide synthesis approach. A detailed analysis of the 1H and 13C NMR spectra of the synthesized compound revealed structural variation from what had been originally assigned for hirsutellide A, despite the use of identical building blocks. This variation occurred at the two allo-Ile moieties. To investigate the structure-activity relationship, the depsipeptide and peptide analogues of hirsutellide A were prepared and tested for antimycobacterial and antiplasmodial activities. The compounds displayed antiplasmodial potency against Plasmodium falciparum 3D7 while showing weak or no activity against Mycobacterium tuberculosis H37Rv. The drug-likeness of the series was assessed through in vitro absorption, distribution, metabolism, and excretion (ADME) profiling, revealing systematic differences between the pharmacokinetic properties of cyclic hexapeptides and hexadepsipeptides.

9.
J Med Chem ; 63(17): 9912-9927, 2020 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-32786222

RESUMO

Human African trypanosomiasis (HAT), or sleeping sickness, is caused by the protozoan parasite Trypanosoma brucei and transmitted through the bite of infected tsetse flies. The disease is considered fatal if left untreated. To identify new chemotypes against Trypanosoma brucei, previously we identified 797 potent kinase-targeting inhibitors grouped into 59 clusters plus 53 singleton compounds with at least 100-fold selectivity over HepG2 cells. From this set of hits, a cluster of diaminopurine-derived compounds was identified. Herein, we report our medicinal chemistry investigation involving the exploration of structure-activity and structure-property relationships around one of the high-throughput screening (HTS) hits, N2-(thiophen-3-yl)-N6-(2,2,2-trifluoroethyl)-9H-purine-2,6-diamine (1, NEU-1106). This work led to the identification of a potent lead compound (4aa, NEU-4854) with improved in vitro absorption, distribution, metabolism, and excretion (ADME) properties, which was progressed into proof-of-concept translation of in vitro antiparasitic activity to in vivo efficacy.


Assuntos
Purinas/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Animais , Células Hep G2 , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Testes de Sensibilidade Parasitária , Estudo de Prova de Conceito , Purinas/síntese química , Purinas/metabolismo , Purinas/farmacocinética , Ratos , Relação Estrutura-Atividade , Tripanossomicidas/síntese química , Tripanossomicidas/metabolismo , Tripanossomicidas/farmacocinética
10.
J Med Chem ; 63(5): 2527-2546, 2020 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-31670951

RESUMO

Human African trypanosomiasis (HAT) is a neglected tropical disease caused by infection with either of two subspecies of the parasite Trypanosoma brucei. Due to a lack of economic incentive to develop new drugs, current treatments have severe limitations in terms of safety, efficacy, and ease of administration. In an effort to develop new HAT therapeutics, we report the structure-activity relationships around T. brucei for a series of benzoxazepinoindazoles previously identified through a high-throughput screen of human kinase inhibitors, and the subsequent in vivo experiments for HAT. We identified compound 18, which showed an improved kinase selectivity profile and acceptable pharmacokinetic parameters, as a promising lead. Although treatment with 18 cured 60% of mice in a systemic model of HAT, the compound was unable to clear parasitemia in a CNS model of the disease. We also report the results of cross-screening these compounds against T. cruzi, L. donovani, and S. mansoni.


Assuntos
Indazóis/química , Indazóis/farmacologia , Tripanossomicidas/química , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Tripanossomíase Africana/tratamento farmacológico , Animais , Feminino , Humanos , Indazóis/farmacocinética , Camundongos , Oxazepinas/química , Oxazepinas/farmacocinética , Oxazepinas/farmacologia , Testes de Sensibilidade Parasitária , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacocinética , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Estrutura-Atividade , Tripanossomicidas/farmacocinética
11.
J Med Chem ; 63(2): 756-783, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31846577

RESUMO

From a high-throughput screen of 42 444 known human kinases inhibitors, a pyrazolo[1,5-b]pyridazine scaffold was identified to begin optimization for the treatment of human African trypanosomiasis. Previously reported data for analogous compounds against human kinases GSK-3ß, CDK-2, and CDK-4 were leveraged to try to improve the selectivity of the series, resulting in 23a which showed selectivity for T. b. brucei over these three human enzymes. In parallel, properties known to influence the absorption, distribution, metabolism, and excretion (ADME) profile of the series were optimized resulting in 20g being progressed into an efficacy study in mice. Though 20g showed toxicity in mice, it also demonstrated CNS penetration in a PK study and significant reduction of parasitemia in four out of the six mice.


Assuntos
Piridazinas/síntese química , Piridazinas/farmacologia , Tripanossomicidas/síntese química , Tripanossomicidas/farmacologia , Tripanossomíase Africana/tratamento farmacológico , Animais , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Quinase 2 Dependente de Ciclina/antagonistas & inibidores , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Reposicionamento de Medicamentos , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Ensaios de Triagem em Larga Escala , Humanos , Leishmania donovani/efeitos dos fármacos , Camundongos , Modelos Moleculares , Piridazinas/farmacocinética , Ratos , Relação Estrutura-Atividade , Especificidade por Substrato , Distribuição Tecidual , Tripanossomicidas/farmacocinética , Trypanosoma brucei brucei/efeitos dos fármacos , Tripanossomíase Africana/parasitologia
12.
ACS Infect Dis ; 6(5): 1098-1109, 2020 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-32196311

RESUMO

In the course of optimizing a novel indazole sulfonamide series that inhibits ß-ketoacyl-ACP synthase (KasA) of Mycobacterium tuberculosis, a mutagenic aniline metabolite was identified. Further lead optimization efforts were therefore dedicated to eliminating this critical liability by removing the embedded aniline moiety or modifying its steric or electronic environment. While the narrow SAR space against the target ultimately rendered this goal unsuccessful, key structural knowledge around the binding site of this underexplored target for TB was generated to inform future discovery efforts.


Assuntos
3-Oxoacil-(Proteína de Transporte de Acila) Sintase/antagonistas & inibidores , Compostos de Anilina/farmacologia , Mycobacterium tuberculosis , Antibacterianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Sítios de Ligação , Dano ao DNA , Mycobacterium tuberculosis/enzimologia
13.
RSC Med Chem ; 11(8): 950-959, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-33479690

RESUMO

Human African trypanosomiasis is a neglected tropical disease (NTD) that is fatal if left untreated. Although approximately 13 million people live in moderate- to high-risk areas for infection, current treatments are plagued by problems with safety, efficacy, and emerging resistance. In an effort to fill the drug development pipeline for HAT, we have expanded previous work exploring the chemotype represented by the compound NEU-1090, with a particular focus on improvement of absorption, distribution, metabolism and elimination (ADME) properties. These efforts resulted in several compounds with substantially improved aqueous solubility, although these modifications typically resulted in a loss of trypanosomal activity. We herein report the results of our investigation into the antiparasitic activity, toxicity, and ADME properties of this class of compounds in the interest of informing the NTD drug discovery community and avoiding duplication of effort.

14.
J Med Chem ; 63(9): 4929-4956, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32248693

RESUMO

Malaria puts at risk nearly half the world's population and causes high mortality in sub-Saharan Africa, while drug resistance threatens current therapies. The pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) is a validated target for malaria treatment based on our finding that triazolopyrimidine DSM265 (1) showed efficacy in clinical studies. Herein, we describe optimization of a pyrrole-based series identified using a target-based DHODH screen. Compounds with nanomolar potency versus Plasmodium DHODH and Plasmodium parasites were identified with good pharmacological properties. X-ray studies showed that the pyrroles bind an alternative enzyme conformation from 1 leading to improved species selectivity versus mammalian enzymes and equivalent activity on Plasmodium falciparum and Plasmodium vivax DHODH. The best lead DSM502 (37) showed in vivo efficacy at similar levels of blood exposure to 1, although metabolic stability was reduced. Overall, the pyrrole-based DHODH inhibitors provide an attractive alternative scaffold for the development of new antimalarial compounds.


Assuntos
Antimaláricos/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Malária Falciparum/tratamento farmacológico , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/antagonistas & inibidores , Pirróis/uso terapêutico , Animais , Antimaláricos/síntese química , Antimaláricos/metabolismo , Antimaláricos/farmacocinética , Linhagem Celular Tumoral , Cristalografia por Raios X , Di-Hidro-Orotato Desidrogenase , Cães , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacocinética , Feminino , Humanos , Masculino , Camundongos SCID , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/metabolismo , Testes de Sensibilidade Parasitária , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/enzimologia , Plasmodium vivax/efeitos dos fármacos , Plasmodium vivax/enzimologia , Ligação Proteica , Pirróis/síntese química , Pirróis/metabolismo , Pirróis/farmacocinética , Ratos , Relação Estrutura-Atividade
15.
ACS Infect Dis ; 4(10): 1439-1447, 2018 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-30141902

RESUMO

ß-Lactams represent perhaps the most important class of antibiotics yet discovered. However, despite many years of active research, none of the currently approved drugs in this class combine oral activity with long duration of action. Recent developments suggest that new ß-lactam antibiotics with such a profile would have utility in the treatment of tuberculosis. Consequently, the historical ß-lactam pharmacokinetic data have been compiled and analyzed to identify possible directions and drug discovery strategies aimed toward new ß-lactam antibiotics with this profile.


Assuntos
Antibacterianos/farmacocinética , Antibacterianos/uso terapêutico , Descoberta de Drogas/métodos , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose/tratamento farmacológico , beta-Lactamas/farmacocinética , beta-Lactamas/uso terapêutico , Administração Oral , Animais , Antibacterianos/administração & dosagem , Antibacterianos/classificação , Disponibilidade Biológica , Permeabilidade da Membrana Celular/efeitos dos fármacos , Meia-Vida , Haplorrinos , Humanos , Ligação Proteica , Estudos Retrospectivos , Solubilidade , Resultado do Tratamento , beta-Lactamas/administração & dosagem , beta-Lactamas/classificação
16.
PLoS One ; 12(4): e0176088, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28423019

RESUMO

Wollamide B is a cationic antimycobacterial cyclohexapeptide that exhibits activity against Mycobacterium bovis (M. bovis) (IC50 of 3.1 µM). Aiming to define its structural activity relationship (SAR), optimizing potency and pharmacokinetic properties, libraries of analogues were synthesized following a standard Fmoc-based solid phase peptide synthesis approach. The antimycobacterial activities of wollamide B and all the synthesized analogues were tested against Mycobacterium tuberculosis (Mtb) H37Rv. Parallely, in vitro drug metabolism and pharmacokinetic (ADME) profiling was done for the synthesized compounds to evaluate their drug likeness. Among the 25 synthesized wollamides five of them showed potent activities with MICs ≤ 3.1 µM and found to be nontoxic against human HepG2 cells up to 100 µM. The results of the in vitro ADME profiling revealed the remarkable plasma stability and very good aqueous solubility of the class in general while the metabolic stability was found to be moderate to low. Of particular note, compounds 7c (MIC = 1.1 µM) and 13c (0.6 µM) that exhibited good balance of antimycobacterial activity vs. optimal pharmacokinetic properties could be used as a new lead for further development.


Assuntos
Antituberculosos/síntese química , Mycobacterium tuberculosis/efeitos dos fármacos , Peptídeos Cíclicos/síntese química , Animais , Antituberculosos/sangue , Antituberculosos/farmacocinética , Antituberculosos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Desenho de Fármacos , Meia-Vida , Células Hep G2 , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/crescimento & desenvolvimento , Peptídeos Cíclicos/sangue , Peptídeos Cíclicos/farmacocinética , Peptídeos Cíclicos/farmacologia , Especificidade da Espécie , Relação Estrutura-Atividade
18.
Nat Commun ; 8: 15159, 2017 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-28537265

RESUMO

K13 gene mutations are a primary marker of artemisinin resistance in Plasmodium falciparum malaria that threatens the long-term clinical utility of artemisinin-based combination therapies, the cornerstone of modern day malaria treatment. Here we describe a multinational drug discovery programme that has delivered a synthetic tetraoxane-based molecule, E209, which meets key requirements of the Medicines for Malaria Venture drug candidate profiles. E209 has potent nanomolar inhibitory activity against multiple strains of P. falciparum and P. vivax in vitro, is efficacious against P. falciparum in in vivo rodent models, produces parasite reduction ratios equivalent to dihydroartemisinin and has pharmacokinetic and pharmacodynamic characteristics compatible with a single-dose cure. In vitro studies with transgenic parasites expressing variant forms of K13 show no cross-resistance with the C580Y mutation, the primary variant observed in Southeast Asia. E209 is a superior next generation endoperoxide with combined pharmacokinetic and pharmacodynamic features that overcome the liabilities of artemisinin derivatives.


Assuntos
Antimaláricos/farmacologia , Artemisininas/farmacologia , Resistência a Medicamentos/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Plasmodium vivax/efeitos dos fármacos , Proteínas de Protozoários/metabolismo , Tetraoxanos/química , Tetraoxanos/farmacologia , Animais , Antimaláricos/química , Cães , Relação Dose-Resposta a Droga , Resistência a Medicamentos/genética , Eritrócitos/parasitologia , Feminino , Meia-Vida , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Mutação , Plasmodium falciparum/genética , Plasmodium vivax/genética , Ratos , Ratos Sprague-Dawley , Tetraoxanos/farmacocinética , Transgenes
19.
J Med Chem ; 59(11): 5416-31, 2016 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-27127993

RESUMO

Malaria persists as one of the most devastating global infectious diseases. The pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) has been identified as a new malaria drug target, and a triazolopyrimidine-based DHODH inhibitor 1 (DSM265) is in clinical development. We sought to identify compounds with higher potency against Plasmodium DHODH while showing greater selectivity toward animal DHODHs. Herein we describe a series of novel triazolopyrimidines wherein the p-SF5-aniline was replaced with substituted 1,2,3,4-tetrahydro-2-naphthyl or 2-indanyl amines. These compounds showed strong species selectivity, and several highly potent tetrahydro-2-naphthyl derivatives were identified. Compounds with halogen substitutions displayed sustained plasma levels after oral dosing in rodents leading to efficacy in the P. falciparum SCID mouse malaria model. These data suggest that tetrahydro-2-naphthyl derivatives have the potential to be efficacious for the treatment of malaria, but due to higher metabolic clearance than 1, they most likely would need to be part of a multidose regimen.


Assuntos
Antimaláricos/farmacologia , Inibidores Enzimáticos/farmacologia , Malária Falciparum/tratamento farmacológico , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/antagonistas & inibidores , Plasmodium falciparum/efeitos dos fármacos , Pirimidinas/farmacologia , Triazóis/farmacologia , Animais , Antimaláricos/síntese química , Antimaláricos/química , Di-Hidro-Orotato Desidrogenase , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Camundongos , Camundongos SCID , Estrutura Molecular , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/metabolismo , Testes de Sensibilidade Parasitária , Plasmodium falciparum/enzimologia , Pirimidinas/síntese química , Pirimidinas/química , Ratos , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química
20.
Nat Commun ; 7: 12581, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27581223

RESUMO

Phenotypic screens for bactericidal compounds are starting to yield promising hits against tuberculosis. In this regard, whole-genome sequencing of spontaneous resistant mutants generated against an indazole sulfonamide (GSK3011724A) identifies several specific single-nucleotide polymorphisms in the essential Mycobacterium tuberculosis ß-ketoacyl synthase (kas) A gene. Here, this genomic-based target assignment is confirmed by biochemical assays, chemical proteomics and structural resolution of a KasA-GSK3011724A complex by X-ray crystallography. Finally, M. tuberculosis GSK3011724A-resistant mutants increase the in vitro minimum inhibitory concentration and the in vivo 99% effective dose in mice, establishing in vitro and in vivo target engagement. Surprisingly, the lack of target engagement of the related ß-ketoacyl synthases (FabH and KasB) suggests a different mode of inhibition when compared with other Kas inhibitors of fatty acid biosynthesis in bacteria. These results clearly identify KasA as the biological target of GSK3011724A and validate this enzyme for further drug discovery efforts against tuberculosis.


Assuntos
3-Oxoacil-(Proteína de Transporte de Acila) Sintase/antagonistas & inibidores , 3-Oxoacil-(Proteína de Transporte de Acila) Sintase/genética , Antituberculosos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/genética , Indazóis/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Sulfonamidas/farmacologia , Tuberculose Pulmonar/tratamento farmacológico , Animais , Farmacorresistência Bacteriana/genética , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/genética , Polimorfismo de Nucleotídeo Único/genética , Tuberculose Pulmonar/microbiologia , Tuberculose Pulmonar/prevenção & controle
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