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1.
bioRxiv ; 2024 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-38979188

RESUMO

Recent malaria drug discovery approaches have been extensively focused on the development of oral, smallmolecule inhibitors for disease treatment whereas parenteral routes of administration have been avoided due to limitations in deploying a shelf-stable injectable even though it could be dosed less frequently. However, an updated target candidate profile from Medicines for Malaria Venture (MMV) and stakeholders have advocated for long-acting injectable chemopreventive agents as an important interventive tool to improve malaria prevention. Here, we present strategies for the development of a long-acting, intramuscular, injectable atovaquone prophylactic therapy. We have generated three prodrug approaches that are contrasted by their differential physiochemical properties and pharmacokinetic profiles: mCBK068, a docosahexaenoic acid ester of atovaquone formulated in sesame oil, mCKX352, a heptanoic acid ester of atovaquone formulated as a solution in sesame oil, and mCBE161, an acetic acid ester of atovaquone formulated as an aqueous suspension. As a result, from a single 20 mg/kg intramuscular injection, mCKX352 and mCBE161 maintain blood plasma exposure of atovaquone above the minimal efficacious concentration for >70 days and >30 days, respectively, in cynomolgus monkeys. The differences in plasma exposure are reflective of the prodrug strategy, which imparts altered chemical properties that ultimately influence aqueous solubility and depot release kinetics. On the strength of the pharmacokinetic and safety profiles, mCBE161 is being advanced as a first-in-class clinical candidate for first-in-human trials.

2.
Virology ; 540: 195-206, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31929001

RESUMO

Respiratory syncytial virus (RSV) infection can cause mucus overproduction and bronchiolitis in infants leading to severe disease and hospitalization. As a therapeutic strategy, immune modulatory agents may help prevent RSV-driven immune responses that cause severe airway disease. We developed a high throughput screen to identify compounds that reduced RSV-driven mucin 5AC (Muc5AC) expression and identified dexamethasone. Despite leading to a pronounced reduction in RSV-driven Muc5AC, dexamethasone increased RSV infection in vitro and delayed viral clearance in mice. This correlated with reduced expression of a subset of immune response genes and reduced lymphocyte infiltration in vivo. Interestingly, dexamethasone increased RSV infection levels without altering antiviral interferon signaling. In summary, the immunosuppressive activities of dexamethasone had favorable inhibitory effects on RSV-driven mucus production yet prevented immune defense activities that limit RSV infection in vitro and in vivo. These findings offer an explanation for the lack of efficacy of glucocorticoids in RSV-infected patients.


Assuntos
Dexametasona/farmacologia , Interferons/metabolismo , Muco/metabolismo , Infecções por Vírus Respiratório Sincicial/metabolismo , Infecções por Vírus Respiratório Sincicial/virologia , Vírus Sincicial Respiratório Humano/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Animais , Linhagem Celular , Citocinas/metabolismo , Redes Reguladoras de Genes , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Inata , Camundongos , Mucina-5AC/genética , Mucina-5AC/metabolismo , Mucosa Respiratória/metabolismo , Mucosa Respiratória/virologia , Infecções por Vírus Respiratório Sincicial/genética
3.
Sci Transl Med ; 11(491)2019 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-31068442

RESUMO

Parasitic filarial nematodes cause debilitating infections in people in resource-limited countries. A clinically validated approach to eliminating worms uses a 4- to 6-week course of doxycycline that targets Wolbachia, a bacterial endosymbiont required for worm viability and reproduction. However, the prolonged length of therapy and contraindication in children and pregnant women have slowed adoption of this treatment. Here, we describe discovery and optimization of quinazolines CBR417 and CBR490 that, with a single dose, achieve >99% elimination of Wolbachia in the in vivo Litomosoides sigmodontis filarial infection model. The efficacious quinazoline series was identified by pairing a primary cell-based high-content imaging screen with an orthogonal ex vivo validation assay to rapidly quantify Wolbachia elimination in Brugia pahangi filarial ovaries. We screened 300,368 small molecules in the primary assay and identified 288 potent and selective hits. Of 134 primary hits tested, only 23.9% were active in the worm-based validation assay, 8 of which contained a quinazoline heterocycle core. Medicinal chemistry optimization generated quinazolines with excellent pharmacokinetic profiles in mice. Potent antiwolbachial activity was confirmed in L. sigmodontis, Brugia malayi, and Onchocerca ochengi in vivo preclinical models of filarial disease and in vitro selectivity against Loa loa (a safety concern in endemic areas). The favorable efficacy and in vitro safety profiles of CBR490 and CBR417 further support these as clinical candidates for treatment of filarial infections.


Assuntos
Antibacterianos/uso terapêutico , Descoberta de Drogas , Filariose/tratamento farmacológico , Filariose/parasitologia , Filarioidea/fisiologia , Quinazolinas/uso terapêutico , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Modelos Animais de Doenças , Feminino , Filarioidea/efeitos dos fármacos , Filarioidea/microbiologia , Ensaios de Triagem em Larga Escala , Camundongos , Fenótipo , Quinazolinas/química , Quinazolinas/farmacologia , Bibliotecas de Moléculas Pequenas , Wolbachia/efeitos dos fármacos
4.
Proc Natl Acad Sci U S A ; 115(42): 10750-10755, 2018 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-30282735

RESUMO

The chemical diversity and known safety profiles of drugs previously tested in humans make them a valuable set of compounds to explore potential therapeutic utility in indications outside those originally targeted, especially neglected tropical diseases. This practice of "drug repurposing" has become commonplace in academic and other nonprofit drug-discovery efforts, with the appeal that significantly less time and resources are required to advance a candidate into the clinic. Here, we report a comprehensive open-access, drug repositioning screening set of 12,000 compounds (termed ReFRAME; Repurposing, Focused Rescue, and Accelerated Medchem) that was assembled by combining three widely used commercial drug competitive intelligence databases (Clarivate Integrity, GVK Excelra GoStar, and Citeline Pharmaprojects), together with extensive patent mining of small molecules that have been dosed in humans. To date, 12,000 compounds (∼80% of compounds identified from data mining) have been purchased or synthesized and subsequently plated for screening. To exemplify its utility, this collection was screened against Cryptosporidium spp., a major cause of childhood diarrhea in the developing world, and two active compounds previously tested in humans for other therapeutic indications were identified. Both compounds, VB-201 and a structurally related analog of ASP-7962, were subsequently shown to be efficacious in animal models of Cryptosporidium infection at clinically relevant doses, based on available human doses. In addition, an open-access data portal (https://reframedb.org) has been developed to share ReFRAME screen hits to encourage additional follow-up and maximize the impact of the ReFRAME screening collection.


Assuntos
Antiprotozoários/farmacologia , Criptosporidiose/tratamento farmacológico , Cryptosporidium/efeitos dos fármacos , Bases de Dados de Produtos Farmacêuticos , Descoberta de Drogas , Reposicionamento de Medicamentos/métodos , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Criptosporidiose/parasitologia , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Ensaios de Triagem em Larga Escala , Humanos , Camundongos , Camundongos Endogâmicos C57BL
5.
Cell Host Microbe ; 19(1): 114-26, 2016 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-26749441

RESUMO

Preventing transmission is an important element of malaria control. However, most of the current available methods to assay for malaria transmission blocking are relatively low throughput and cannot be applied to large chemical libraries. We have developed a high-throughput and cost-effective assay, the Saponin-lysis Sexual Stage Assay (SaLSSA), for identifying small molecules with transmission-blocking capacity. SaLSSA analysis of 13,983 unique compounds uncovered that >90% of well-characterized antimalarials, including endoperoxides and 4-aminoquinolines, as well as compounds active against asexual blood stages, lost most of their killing activity when parasites developed into metabolically quiescent stage V gametocytes. On the other hand, we identified compounds with consistent low nanomolar transmission-blocking activity, some of which showed cross-reactivity against asexual blood and liver stages. The data clearly emphasize substantial physiological differences between sexual and asexual parasites and provide a tool and starting points for the discovery and development of transmission-blocking drugs.


Assuntos
Antimaláricos/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Ensaios de Triagem em Larga Escala/métodos , Malária/parasitologia , Plasmodium falciparum/efeitos dos fármacos , Humanos , Malária/transmissão , Plasmodium falciparum/fisiologia
7.
Expert Rev Anti Infect Ther ; 13(8): 1031-45, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26081265

RESUMO

The development of artemisinin resistance in the Greater Mekong Subregion poses a significant threat to malaria elimination. Artemisinin-based combination therapies including artemether-lumefantrine (AL) are recommended by WHO as first-line treatment for uncomplicated Plasmodium falciparum malaria. This article provides a comprehensive review of the existing and latest data as a basis for interpretation of observed variability in parasite sensitivity to AL over the last 5 years. Clinical efficacy and preclinical data from a range of endemic countries are summarized, including potential molecular markers of resistance. Overall, AL remains effective in the treatment of uncomplicated P. falciparum malaria in most regions. Establishing validated molecular markers for resistance and strict efficacy monitoring will reinforce timely updates of treatment policies.


Assuntos
Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Resistência a Medicamentos , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum/efeitos dos fármacos , África Subsaariana , Artemeter , Artemisininas/farmacologia , Artemisininas/uso terapêutico , Ásia , Combinação de Medicamentos , Resistência a Medicamentos/genética , Etanolaminas/farmacologia , Etanolaminas/uso terapêutico , Fluorenos/farmacologia , Fluorenos/uso terapêutico , Humanos , Lumefantrina , Malária Falciparum/genética
8.
ACS Infect Dis ; 1(2): 98-109, 2015 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-25984567

RESUMO

An ultrahigh-throughput screen was performed to identify novel small molecule inhibitors of influenza virus replication. The screen employed a recombinant influenza A/WSN/33 virus expressing Renilla luciferase and yielded a hit rate of 0.5%, of which the vast majority showed little cytotoxicity at the inhibitory concentration. One of the top hits from this screen, designated S20, inhibits HA-mediated membrane fusion. S20 shows potent antiviral activity (IC50 = 80 nM) and low toxicity (CC50 = 40 µM), yielding a selectivity index of 500 and functionality against all of the group 1 influenza A viruses tested in this study, including the pandemic H1N1 and avian H5N1 viruses. Mechanism of action studies proved a direct S20-HA interaction and showed that S20 inhibits fusion by stabilizing the prefusion conformation of HA. In silico docking studies were performed, and the predicted binding site in HA2 corresponds with the area where resistance mutations occurred and correlates with the known role of this region in fusion. This high-throughput screen has yielded many promising new lead compounds, including S20, which will potentially shed light on the molecular mechanisms of viral infection and serve as research tools or be developed for clinical use as antivirals.

9.
Sci Transl Med ; 7(269): 269ra3, 2015 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-25568071

RESUMO

New chemotherapeutic agents are urgently required to combat the global spread of multidrug-resistant tuberculosis (MDR-TB). The mycobacterial enoyl reductase InhA is one of the few clinically validated targets in tuberculosis drug discovery. We report the identification of a new class of direct InhA inhibitors, the 4-hydroxy-2-pyridones, using phenotypic high-throughput whole-cell screening. This class of orally active compounds showed potent bactericidal activity against common isoniazid-resistant TB clinical isolates. Biophysical studies revealed that 4-hydroxy-2-pyridones bound specifically to InhA in an NADH (reduced form of nicotinamide adenine dinucleotide)-dependent manner and blocked the enoyl substrate-binding pocket. The lead compound NITD-916 directly blocked InhA in a dose-dependent manner and showed in vivo efficacy in acute and established mouse models of Mycobacterium tuberculosis infection. Collectively, our structural and biochemical data open up new avenues for rational structure-guided optimization of the 4-hydroxy-2-pyridone class of compounds for the treatment of MDR-TB.


Assuntos
Antituberculosos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/enzimologia , Oxirredutases/antagonistas & inibidores , Animais , Antituberculosos/química , Proteínas de Bactérias/metabolismo , Fenômenos Biofísicos/efeitos dos fármacos , Cristalografia por Raios X , Modelos Animais de Doenças , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Inibidores Enzimáticos/química , Camundongos Endogâmicos BALB C , Modelos Moleculares , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/isolamento & purificação , Oxirredutases/metabolismo , Piridinas/química , Piridinas/farmacologia , Reprodutibilidade dos Testes , Análise de Sequência de DNA , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia
10.
ACS Chem Biol ; 10(2): 413-20, 2015 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-25322084

RESUMO

Aminopyrazoles are a new class of antimalarial compounds identified in a cellular antiparasitic screen with potent activity against Plasmodium falciparum asexual and sexual stage parasites. To investigate their unknown mechanism of action and thus identify their target, we cultured parasites in the presence of a representative member of the aminopyrazole series, GNF-Pf4492, to select for resistance. Whole genome sequencing of three resistant lines showed that each had acquired independent mutations in a P-type cation-transporter ATPase, PfATP4 (PF3D7_1211900), a protein implicated as the novel Plasmodium spp. target of another, structurally unrelated, class of antimalarials called the spiroindolones and characterized as an important sodium transporter of the cell. Similarly to the spiroindolones, GNF-Pf4492 blocks parasite transmission to mosquitoes and disrupts intracellular sodium homeostasis. Our data demonstrate that PfATP4 plays a critical role in cellular processes, can be inhibited by two distinct antimalarial pharmacophores, and supports the recent observations that PfATP4 is a critical antimalarial target.


Assuntos
Adenosina Trifosfatases/metabolismo , Antimaláricos/farmacologia , Resistência a Medicamentos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Plasmodium falciparum/enzimologia , Plasmodium falciparum/metabolismo , Adenosina Trifosfatases/genética , Antimaláricos/química , Indóis/química , Indóis/farmacologia , Modelos Moleculares , Estrutura Molecular , Mutação , Plasmodium falciparum/genética , Conformação Proteica , Pirazóis/química , Pirazóis/farmacologia , Sódio/metabolismo
11.
ACS Med Chem Lett ; 5(8): 947-50, 2014 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-25147620

RESUMO

Imidazopyridine 1 was identified from a phenotypic screen against P. falciparum (Pf) blood stages and subsequently optimized for activity on liver-stage schizonts of the rodent parasite P. yoelii (Py) as well as hypnozoites of the simian parasite P. cynomolgi (Pc). We applied these various assays to the cell-based lead optimization of the imidazopyrazines, exemplified by 3 (KAI407), and show that optimized compounds within the series with improved pharmacokinetic properties achieve causal prophylactic activity in vivo and may have the potential to target the dormant stages of P. vivax malaria.

12.
Antimicrob Agents Chemother ; 58(9): 5060-7, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24913172

RESUMO

Renewed global efforts toward malaria eradication have highlighted the need for novel antimalarial agents with activity against multiple stages of the parasite life cycle. We have previously reported the discovery of a novel class of antimalarial compounds in the imidazolopiperazine series that have activity in the prevention and treatment of blood stage infection in a mouse model of malaria. Consistent with the previously reported activity profile of this series, the clinical candidate KAF156 shows blood schizonticidal activity with 50% inhibitory concentrations of 6 to 17.4 nM against P. falciparum drug-sensitive and drug-resistant strains, as well as potent therapeutic activity in a mouse models of malaria with 50, 90, and 99% effective doses of 0.6, 0.9, and 1.4 mg/kg, respectively. When administered prophylactically in a sporozoite challenge mouse model, KAF156 is completely protective as a single oral dose of 10 mg/kg. Finally, KAF156 displays potent Plasmodium transmission blocking activities both in vitro and in vivo. Collectively, our data suggest that KAF156, currently under evaluation in clinical trials, has the potential to treat, prevent, and block the transmission of malaria.


Assuntos
Antimaláricos/farmacologia , Imidazóis/farmacologia , Malária Falciparum/tratamento farmacológico , Malária Falciparum/transmissão , Piperazinas/farmacologia , Animais , Concentração Inibidora 50 , Camundongos , Camundongos Endogâmicos ICR , Plasmodium falciparum/efeitos dos fármacos , Esporozoítos/efeitos dos fármacos
13.
Antimicrob Agents Chemother ; 58(3): 1586-95, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24366744

RESUMO

Preventing relapses of Plasmodium vivax malaria through a radical cure depends on use of the 8-aminoquinoline primaquine, which is associated with safety and compliance issues. For future malaria eradication strategies, new, safer radical curative compounds that efficiently kill dormant liver stages (hypnozoites) will be essential. A new compound with potential radical cure activity was identified using a low-throughput assay of in vitro-cultured hypnozoite forms of Plasmodium cynomolgi (an excellent and accessible model for Plasmodium vivax). In this assay, primary rhesus hepatocytes are infected with P. cynomolgi sporozoites, and exoerythrocytic development is monitored in the presence of compounds. Liver stage cultures are fixed after 6 days and stained with anti-Hsp70 antibodies, and the relative proportions of small (hypnozoite) and large (schizont) forms relative to the untreated controls are determined. This assay was used to screen a series of 18 known antimalarials and 14 new non-8-aminoquinolines (preselected for blood and/or liver stage activity) in three-point 10-fold dilutions (0.1, 1, and 10 µM final concentrations). A novel compound, designated KAI407 showed an activity profile similar to that of primaquine (PQ), efficiently killing the earliest stages of the parasites that become either primary hepatic schizonts or hypnozoites (50% inhibitory concentration [IC50] for hypnozoites, KAI407, 0.69 µM, and PQ, 0.84 µM; for developing liver stages, KAI407, 0.64 µM, and PQ, 0.37 µM). When given as causal prophylaxis, a single oral dose of 100 mg/kg of body weight prevented blood stage parasitemia in mice. From these results, we conclude that KAI407 may represent a new compound class for P. vivax malaria prophylaxis and potentially a radical cure.


Assuntos
Antimaláricos/farmacologia , Imidazóis/farmacologia , Malária/tratamento farmacológico , Plasmodium cynomolgi/efeitos dos fármacos , Pirazinas/farmacologia , Animais , Antimaláricos/uso terapêutico , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Hepatócitos/parasitologia , Imidazóis/uso terapêutico , Técnicas In Vitro , Fígado/parasitologia , Macaca mulatta/parasitologia , Malária/parasitologia , Malária/prevenção & controle , Camundongos , Camundongos Endogâmicos ICR , Pirazinas/uso terapêutico , Esporozoítos/efeitos dos fármacos
14.
Sci Transl Med ; 5(214): 214ra168, 2013 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-24307692

RESUMO

New chemotherapeutic compounds against multidrug-resistant Mycobacterium tuberculosis (Mtb) are urgently needed to combat drug resistance in tuberculosis (TB). We have identified and characterized the indolcarboxamides as a new class of antitubercular bactericidal agent. Genetic and lipid profiling studies identified the likely molecular target of indolcarboxamides as MmpL3, a transporter of trehalose monomycolate that is essential for mycobacterial cell wall biosynthesis. Two lead candidates, NITD-304 and NITD-349, showed potent activity against both drug-sensitive and multidrug-resistant clinical isolates of Mtb. Promising pharmacokinetic profiles of both compounds after oral dosing in several species enabled further evaluation for efficacy and safety. NITD-304 and NITD-349 were efficacious in treating both acute and chronic Mtb infections in mouse efficacy models. Furthermore, dosing of NITD-304 and NITD-349 for 2 weeks in exploratory rat toxicology studies revealed a promising safety margin. Finally, neither compound inhibited the activity of major cytochrome P-450 enzymes or the hERG (human ether-a-go-go related gene) channel. These results suggest that NITD-304 and NITD-349 should undergo further development as a potential treatment for multidrug-resistant TB.


Assuntos
Antituberculosos/farmacologia , Indóis/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Administração Oral , Animais , Antituberculosos/administração & dosagem , Antituberculosos/farmacocinética , Antituberculosos/toxicidade , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/metabolismo , Disponibilidade Biológica , Modelos Animais de Doenças , Cães , Relação Dose-Resposta a Droga , Farmacorresistência Bacteriana Múltipla/genética , Humanos , Indóis/administração & dosagem , Indóis/farmacocinética , Indóis/toxicidade , Injeções Intravenosas , Proteínas de Membrana Transportadoras/efeitos dos fármacos , Proteínas de Membrana Transportadoras/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/crescimento & desenvolvimento , Mycobacterium tuberculosis/metabolismo , Ratos , Ratos Wistar , Tuberculose Resistente a Múltiplos Medicamentos/diagnóstico , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia
15.
Nature ; 504(7479): 248-253, 2013 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-24284631

RESUMO

Achieving the goal of malaria elimination will depend on targeting Plasmodium pathways essential across all life stages. Here we identify a lipid kinase, phosphatidylinositol-4-OH kinase (PI(4)K), as the target of imidazopyrazines, a new antimalarial compound class that inhibits the intracellular development of multiple Plasmodium species at each stage of infection in the vertebrate host. Imidazopyrazines demonstrate potent preventive, therapeutic, and transmission-blocking activity in rodent malaria models, are active against blood-stage field isolates of the major human pathogens P. falciparum and P. vivax, and inhibit liver-stage hypnozoites in the simian parasite P. cynomolgi. We show that imidazopyrazines exert their effect through inhibitory interaction with the ATP-binding pocket of PI(4)K, altering the intracellular distribution of phosphatidylinositol-4-phosphate. Collectively, our data define PI(4)K as a key Plasmodium vulnerability, opening up new avenues of target-based discovery to identify drugs with an ideal activity profile for the prevention, treatment and elimination of malaria.


Assuntos
1-Fosfatidilinositol 4-Quinase/antagonistas & inibidores , Malária/tratamento farmacológico , Malária/parasitologia , Plasmodium/efeitos dos fármacos , Plasmodium/enzimologia , 1-Fosfatidilinositol 4-Quinase/química , 1-Fosfatidilinositol 4-Quinase/genética , 1-Fosfatidilinositol 4-Quinase/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Sítios de Ligação , Citocinese/efeitos dos fármacos , Resistência a Medicamentos/efeitos dos fármacos , Resistência a Medicamentos/genética , Ácidos Graxos/metabolismo , Feminino , Hepatócitos/parasitologia , Humanos , Imidazóis/metabolismo , Imidazóis/farmacologia , Estágios do Ciclo de Vida/efeitos dos fármacos , Macaca mulatta , Masculino , Modelos Biológicos , Modelos Moleculares , Fosfatos de Fosfatidilinositol/metabolismo , Plasmodium/classificação , Plasmodium/crescimento & desenvolvimento , Pirazóis/metabolismo , Pirazóis/farmacologia , Quinoxalinas/metabolismo , Quinoxalinas/farmacologia , Reprodutibilidade dos Testes , Esquizontes/citologia , Esquizontes/efeitos dos fármacos , Proteínas rab de Ligação ao GTP/genética , Proteínas rab de Ligação ao GTP/metabolismo
16.
J Med Chem ; 56(21): 8849-59, 2013 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-24090347

RESUMO

Indole-2-carboxamides have been identified as a promising class of antituberculosis agents from phenotypic screening against mycobacteria. One of the hits, indole-2-carboxamide analog (1), had low micromolar potency against Mycobacterium tuberculosis (Mtb), high mouse liver microsomal clearance, and low aqueous solubility. Structure-activity relationship studies revealed that attaching alkyl groups to the cyclohexyl ring significantly improved Mtb activity but reduced solubility. Furthermore, chloro, fluoro, or cyano substitutions on the 4- and 6-positions of the indole ring as well as methyl substitution on the cyclohexyl ring significantly improved metabolic stability. 39 and 41, the lead candidates, displayed improved in vitro activity compared to most of the current standard TB drugs. The low aqueous solubility could not be mitigated because of the positive correlation of lipophilicity with Mtb potency. However, both compounds displayed favorable oral pharmacokinetic properties in rodents and demonstrated in vivo efficacy. Thus, indole-2-carboxamides represent a promising new class of antituberculosis agents.


Assuntos
Antituberculosos/farmacologia , Desenho de Fármacos , Indóis/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose/tratamento farmacológico , Animais , Antituberculosos/síntese química , Antituberculosos/química , Relação Dose-Resposta a Droga , Humanos , Indóis/síntese química , Indóis/química , Camundongos , Testes de Sensibilidade Microbiana , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Ratos , Solubilidade , Relação Estrutura-Atividade
17.
ACS Med Chem Lett ; 4(5): 451-5, 2013 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-24900693

RESUMO

Tetrahydropyrazolo[1,5-a]pyrimidine scaffold was identified as a hit series from a Mycobacterium tuberculosis (Mtb) whole cell high through-put screening (HTS) campaign. A series of derivatives of this class were synthesized to evaluate their structure-activity relationship (SAR) and structure-property relationship (SPR). Compound 9 had a promising in vivo DMPK profile in mouse and exhibited potent in vivo activity in a mouse efficacy model, achieving a reduction of 3.5 log CFU of Mtb after oral administration to infected mice once a day at 100 mg/kg for 28 days. Thus, compound 9 is a potential candidate for inclusion in combination therapies for both drug-sensitive and drug-resistant TB.

18.
ACS Chem Biol ; 7(7): 1190-7, 2012 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-22500615

RESUMO

Growing evidence suggests that the presence of a subpopulation of hypoxic non-replicating, phenotypically drug-tolerant mycobacteria is responsible for the prolonged duration of tuberculosis treatment. The discovery of new antitubercular agents active against this subpopulation may help in developing new strategies to shorten the time of tuberculosis therapy. Recently, the maintenance of a low level of bacterial respiration was shown to be a point of metabolic vulnerability in Mycobacterium tuberculosis. Here, we describe the development of a hypoxic model to identify compounds targeting mycobacterial respiratory functions and ATP homeostasis in whole mycobacteria. The model was adapted to 1,536-well plate format and successfully used to screen over 600,000 compounds. Approximately 800 compounds were confirmed to reduce intracellular ATP levels in a dose-dependent manner in Mycobacterium bovis BCG. One hundred and forty non-cytotoxic compounds with activity against hypoxic non-replicating M. tuberculosis were further validated. The resulting collection of compounds that disrupt ATP homeostasis in M. tuberculosis represents a valuable resource to decipher the biology of persistent mycobacteria.


Assuntos
Trifosfato de Adenosina/antagonistas & inibidores , Antituberculosos/farmacologia , Ensaios de Triagem em Larga Escala/métodos , Homeostase/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/crescimento & desenvolvimento , Trifosfato de Adenosina/fisiologia , Animais , Antituberculosos/química , Células CHO , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Cricetinae , Cricetulus , Células HeLa , Homeostase/fisiologia , Humanos , Mycobacterium bovis/efeitos dos fármacos , Mycobacterium bovis/crescimento & desenvolvimento
19.
J Med Chem ; 55(9): 4244-73, 2012 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-22524250

RESUMO

On the basis of the initial success of optimization of a novel series of imidazolopiperazines, a second generation of compounds involving changes in the core piperazine ring was synthesized to improve antimalarial properties. These changes were carried out to further improve the potency and metabolic stability of the compounds by leveraging the outcome of a set of in vitro metabolic identification studies. The optimized 8,8-dimethyl imidazolopiperazine analogues exhibited improved potency, in vitro metabolic stability profile and, as a result, enhanced oral exposure in vivo in mice. The optimized compounds were found to be more efficacious than the current antimalarials in a malaria mouse model. They exhibit moderate oral exposure in rat pharmacokinetic studies to achieve sufficient multiples of the oral exposure at the efficacious dose in toxicology studies.


Assuntos
Antimaláricos/farmacologia , Imidazóis/farmacologia , Malária Falciparum/tratamento farmacológico , Piperazinas/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Animais , Antimaláricos/síntese química , Antimaláricos/química , Antimaláricos/farmacocinética , Disponibilidade Biológica , Células CACO-2 , Humanos , Imidazóis/síntese química , Imidazóis/química , Imidazóis/farmacocinética , Malária Falciparum/parasitologia , Camundongos , Camundongos Endogâmicos BALB C , Piperazinas/síntese química , Piperazinas/química , Piperazinas/farmacocinética , Plasmodium falciparum/metabolismo , Ratos , Ratos Wistar , Relação Estrutura-Atividade
20.
Science ; 334(6061): 1372-7, 2011 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-22096101

RESUMO

Most malaria drug development focuses on parasite stages detected in red blood cells, even though, to achieve eradication, next-generation drugs active against both erythrocytic and exo-erythrocytic forms would be preferable. We applied a multifactorial approach to a set of >4000 commercially available compounds with previously demonstrated blood-stage activity (median inhibitory concentration < 1 micromolar) and identified chemical scaffolds with potent activity against both forms. From this screen, we identified an imidazolopiperazine scaffold series that was highly enriched among compounds active against Plasmodium liver stages. The orally bioavailable lead imidazolopiperazine confers complete causal prophylactic protection (15 milligrams/kilogram) in rodent models of malaria and shows potent in vivo blood-stage therapeutic activity. The open-source chemical tools resulting from our effort provide starting points for future drug discovery programs, as well as opportunities for researchers to investigate the biology of exo-erythrocytic forms.


Assuntos
Antimaláricos/farmacologia , Descoberta de Drogas , Imidazóis/farmacologia , Fígado/parasitologia , Malária/tratamento farmacológico , Piperazinas/farmacologia , Plasmodium/efeitos dos fármacos , Animais , Antimaláricos/química , Antimaláricos/farmacocinética , Antimaláricos/uso terapêutico , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Resistência a Medicamentos , Eritrócitos/parasitologia , Humanos , Imidazóis/química , Imidazóis/farmacocinética , Imidazóis/uso terapêutico , Malária/parasitologia , Malária/prevenção & controle , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Piperazinas/química , Piperazinas/farmacocinética , Piperazinas/uso terapêutico , Plasmodium/citologia , Plasmodium/crescimento & desenvolvimento , Plasmodium/fisiologia , Plasmodium berghei/citologia , Plasmodium berghei/efeitos dos fármacos , Plasmodium berghei/crescimento & desenvolvimento , Plasmodium berghei/fisiologia , Plasmodium falciparum/citologia , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/crescimento & desenvolvimento , Plasmodium falciparum/fisiologia , Plasmodium yoelii/citologia , Plasmodium yoelii/efeitos dos fármacos , Plasmodium yoelii/crescimento & desenvolvimento , Plasmodium yoelii/fisiologia , Polimorfismo de Nucleotídeo Único , Proteínas de Protozoários/química , Proteínas de Protozoários/genética , Proteínas de Protozoários/metabolismo , Distribuição Aleatória , Bibliotecas de Moléculas Pequenas , Esporozoítos/efeitos dos fármacos , Esporozoítos/crescimento & desenvolvimento
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