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1.
Molecules ; 26(14)2021 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-34299479

RESUMO

A library of seventeen novel ether phospholipid analogues, containing 5-membered heterocyclic rings (1,2,3-triazolyl, isoxazolyl, 1,3,4-oxadiazolyl and 1,2,4-oxadiazolyl) in the lipid portion were designed and synthesized aiming to identify optimised miltefosine analogues. The compounds were evaluated for their in vitro antiparasitic activity against Leishmania infantum and Leishmania donovani intracellular amastigotes, against Trypanosoma brucei brucei and against different developmental stages of Trypanosoma cruzi. The nature of the substituents of the heterocyclic ring (tail) and the oligomethylene spacer between the head group and the heterocyclic ring was found to affect the activity and toxicity of these compounds leading to a significantly improved understanding of their structure-activity relationships. The early ADMET profile of the new derivatives did not reveal major liabilities for the potent compounds. The 1,2,3-triazole derivative 27 substituted by a decyl tail, an undecyl spacer and a choline head group exhibited broad spectrum antiparasitic activity. It possessed low micromolar activity against the intracellular amastigotes of two L. infantum strains and T. cruzi Y strain epimastigotes, intracellular amastigotes and trypomastigotes, while its cytotoxicity concentration (CC50) against THP-1 macrophages ranged between 50 and 100 µM. Altogether, our work paves the way for the development of improved ether phospholipid derivatives to control neglected tropical diseases.


Assuntos
Antiparasitários/síntese química , Antiparasitários/farmacologia , Doença de Chagas/tratamento farmacológico , Desenho de Fármacos , Leishmaniose/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Fosfolipídeos/farmacologia , Doença de Chagas/parasitologia , Química Click , Humanos , Leishmania/efeitos dos fármacos , Leishmaniose/parasitologia , Relação Estrutura-Atividade , Trypanosoma cruzi/efeitos dos fármacos
2.
ChemMedChem ; 16(18): 2744-2759, 2021 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-34114360

RESUMO

Dysregulation of the mechanistic target of rapamycin (mTOR) pathway is implicated in cancer and neurological disorder, which identifies mTOR inhibition as promising strategy for the treatment of a variety of human disorders. First-generation mTOR inhibitors include rapamycin and its analogues (rapalogs) which act as allosteric inhibitors of TORC1. Structurally unrelated, ATP-competitive inhibitors that directly target the mTOR catalytic site inhibit both TORC1 and TORC2. Here, we review investigations of chemical scaffolds explored for the development of highly selective ATP-competitive mTOR kinase inhibitors (TORKi). Extensive medicinal chemistry campaigns allowed to overcome challenges related to structural similarity between mTOR and the phosphoinositide 3-kinase (PI3K) family. A broad region of chemical space is covered by TORKi. Here, the investigation of chemical substitutions and physicochemical properties has shed light on the compounds' ability to cross the blood brain barrier (BBB). This work provides insights supporting the optimization of TORKi for the treatment of cancer and central nervous system disorders.

3.
RSC Med Chem ; 12(4): 579-583, 2021 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-34041490

RESUMO

Highly selective mTOR inhibitors have been discovered through the exploration of the heteroaromatic ring engaging the binding affinity region in mTOR kinase. Compound 11 showed predicted BBB permeability in a MDCK-MDR1 permeability in vitro assay, being the first pyrimido-pyrrolo-oxazine with potential application in the treatment of neurological disorders.

4.
Elife ; 102021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33661099

RESUMO

Class I Phosphoinositide 3-kinases (PI3Ks) are master regulators of cellular functions, with the class IB PI3K catalytic subunit (p110γ) playing key roles in immune signalling. p110γ is a key factor in inflammatory diseases and has been identified as a therapeutic target for cancers due to its immunomodulatory role. Using a combined biochemical/biophysical approach, we have revealed insight into regulation of kinase activity, specifically defining how immunodeficiency and oncogenic mutations of R1021 in the C-terminus can inactivate or activate enzyme activity. Screening of inhibitors using HDX-MS revealed that activation loop-binding inhibitors induce allosteric conformational changes that mimic those in the R1021C mutant. Structural analysis of advanced PI3K inhibitors in clinical development revealed novel binding pockets that can be exploited for further therapeutic development. Overall, this work provides unique insights into regulatory mechanisms that control PI3Kγ kinase activity and shows a framework for the design of PI3K isoform and mutant selective inhibitors.

5.
J Med Chem ; 63(22): 13595-13617, 2020 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-33166139

RESUMO

The mechanistic target of rapamycin (mTOR) pathway is hyperactivated in cancer and neurological disorders. Rapalogs and mTOR kinase inhibitors (TORKi) have recently been applied to alleviate epileptic seizures in tuberous sclerosis complex (TSC). Herein, we describe a pharmacophore exploration to identify a highly potent, selective, brain penetrant TORKi. An extensive investigation of the morpholine ring engaging the mTOR solvent exposed region led to the discovery of PQR626 (8). 8 displayed excellent brain penetration and was well-tolerated in mice. In mice with a conditionally inactivated Tsc1 gene in glia, 8 significantly reduced the loss of Tsc1-induced mortality at 50 mg/kg p.o. twice a day. 8 overcomes the metabolic liabilities of PQR620 (52), the first-in-class brain penetrant TORKi showing efficacy in a TSC mouse model. The improved stability in human hepatocytes, excellent brain penetration, and efficacy in Tsc1GFAPCKO mice qualify 8 as a potential therapeutic candidate for the treatment of neurological disorders.


Assuntos
Encéfalo/metabolismo , Morfolinas/administração & dosagem , Morfolinas/metabolismo , Doenças do Sistema Nervoso/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Administração Oral , Animais , Encéfalo/efeitos dos fármacos , Cães , Feminino , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Células Madin Darby de Rim Canino , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Nus , Morfolinas/química , Doenças do Sistema Nervoso/tratamento farmacológico , Ratos , Ratos Sprague-Dawley
6.
ACS Med Chem Lett ; 11(5): 1028-1034, 2020 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-32435421

RESUMO

Sigma receptors (SRs) are recognized as valuable targets for the treatment of neurodegenerative disorders. A series of novel SRs ligands were designed by combining key pharmacophoric amines (i.e., benzylpiperidine or benzylpiperazine) with new 1,3-dithiolane-based heterocycles and their bioisosters. The new compounds exhibited a low nanomolar affinity for sigma-1 and sigma-2 receptors. Five selected compounds were evaluated for their neuroprotective capacity on SH-SY5Y neuroblastoma cell line. They were able to counteract the neurotoxicity induced by rotenone, oligomycin and NMDA. Competition studies with PB212, a S1R antagonist, confirmed the involvement of S1R in neuroprotection from the oxidative stress induced by rotenone. Electrophysiological experiments performed on cortical neurons in culture highlighted the compounds ability to reduce NMDA-evoked currents, suggesting a negative allosteric modulator activity toward the NMDA receptor. Altogether these results qualify our novel dithiolane derivatives as potential agents for fighting neurodegeneration.

7.
J Med Chem ; 63(5): 1908-1928, 2020 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-32023055

RESUMO

After the first seed concept introduced in the 18th century, different disciplines have attributed different names to dual-functional molecules depending on their application, including bioconjugates, bifunctional compounds, multitargeting molecules, chimeras, hybrids, engineered compounds. However, these engineered constructs share a general structure: a first component that targets a specific cell and a second component that exerts the pharmacological activity. A stable or cleavable linker connects the two modules of a chimera. Herein, we discuss the recent advances in the rapidly expanding field of chimeric molecules leveraging chemical biology concepts. This Perspective is focused on bifunctional compounds in which one component is a lead compound or a drug. In detail, we discuss chemical features of chimeric molecules and their use for targeted delivery and for target engagement studies.


Assuntos
Produtos Biológicos/química , Produtos Biológicos/metabolismo , Sistemas de Liberação de Medicamentos/tendências , Descoberta de Drogas/tendências , Animais , Produtos Biológicos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Descoberta de Drogas/métodos , Humanos , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/química , Preparações Farmacêuticas/metabolismo , Estrutura Secundária de Proteína
8.
Eur J Med Chem ; 189: 112047, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31982652

RESUMO

The LIBRA compound library is a collection of 522 non-commercial molecules contributed by various Italian academic laboratories. These compounds have been designed and synthesized during different medicinal chemistry programs and are hosted by the Italian Institute of Technology. We report the screening of the LIBRA compound library against Trypanosoma brucei and Leishmania major pteridine reductase 1, TbPTR1 and LmPTR1. Nine compounds were active against parasitic PTR1 and were selected for cell-based parasite screening, as single agents and in combination with methotrexate (MTX). The most interesting TbPTR1 inhibitor identified was 4-(benzyloxy)pyrimidine-2,6-diamine (LIB_66). Subsequently, six new LIB_66 derivatives were synthesized to explore its Structure-Activity-Relationship (SAR) and absorption, distribution, metabolism, excretion and toxicity (ADMET) properties. The results indicate that PTR1 has a preference to bind inhibitors, which resemble its biopterin/folic acid substrates, such as the 2,4-diaminopyrimidine derivatives.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Ensaios de Triagem em Larga Escala/métodos , Macrófagos/efeitos dos fármacos , Oxirredutases/antagonistas & inibidores , Pirimidinas/química , Trypanosoma brucei brucei/enzimologia , Células A549 , Antimetabólitos Antineoplásicos/farmacologia , Antineoplásicos/química , Proliferação de Células , Sinergismo Farmacológico , Inibidores Enzimáticos/química , Humanos , Metotrexato/farmacologia , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade
9.
ACS Med Chem Lett ; 10(10): 1473-1479, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31620236

RESUMO

The phosphoinositide 3-kinase (PI3K)/mechanistic target of rapamycin (mTOR) pathway is a critical regulator of cell growth and is frequently hyperactivated in cancer. Therefore, PI3K inhibitors represent a valuable asset in cancer therapy. Herein we have developed a novel anticancer agent, the potent pan-PI3K inhibitor PQR514 (4), which is a follow-up compound for the phase-II clinical compound PQR309 (1). Compound 4 has an improved potency both in vitro and in cellular assays with respect to its predecessor compounds. It shows superiority in the suppression of cancer cell proliferation and demonstrates significant antitumor activity in an OVCAR-3 xenograft model at concentrations approximately eight times lower than PQR309 (1). The favorable pharmacokinetic profile and a minimal brain penetration promote PQR514 (4) as an optimized candidate for the treatment of systemic tumors.

10.
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
11.
J Med Chem ; 62(18): 8609-8630, 2019 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-31465220

RESUMO

The mechanistic target of rapamycin (mTOR) plays a pivotal role in growth and tumor progression and is an attractive target for cancer treatment. ATP-competitive mTOR kinase inhibitors (TORKi) have the potential to overcome limitations of rapamycin derivatives in a wide range of malignancies. Herein, we exploit a conformational restriction approach to explore a novel chemical space for the generation of TORKi. Structure-activity relationship (SAR) studies led to the identification of compound 12b with a ∼450-fold selectivity for mTOR over class I PI3K isoforms. Pharmacokinetic studies in male Sprague Dawley rats highlighted a good exposure after oral dosing and a minimum brain penetration. CYP450 reactive phenotyping pointed out the high metabolic stability of 12b. These results identify the tricyclic pyrimido-pyrrolo-oxazine moiety as a novel scaffold for the development of highly selective mTOR inhibitors for cancer treatment.


Assuntos
Oxazinas/química , Inibidores de Proteínas Quinases/química , Pirimidinonas/química , Pirróis/química , Serina-Treonina Quinases TOR/antagonistas & inibidores , Trifosfato de Adenosina/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Cães , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Cinética , Masculino , Camundongos , Conformação Molecular , Neoplasias/tratamento farmacológico , Oxazinas/farmacocinética , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinonas/farmacocinética , Pirróis/farmacocinética , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Serina-Treonina Quinases TOR/química
12.
J Med Chem ; 62(13): 6241-6261, 2019 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-31244112

RESUMO

The phosphoinositide 3-kinase (PI3K)/mechanistic target of rapamycin (mTOR) pathway is frequently overactivated in cancer, and drives cell growth, proliferation, survival, and metastasis. Here, we report a structure-activity relationship study, which led to the discovery of a drug-like adenosine 5'-triphosphate-site PI3K/mTOR kinase inhibitor: (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine (PQR530, compound 6), which qualifies as a clinical candidate due to its potency and specificity for PI3K and mTOR kinases, and its pharmacokinetic properties, including brain penetration. Compound 6 showed excellent selectivity over a wide panel of kinases and an excellent selectivity against unrelated receptor enzymes and ion channels. Moreover, compound 6 prevented cell growth in a cancer cell line panel. The preclinical in vivo characterization of compound 6 in an OVCAR-3 xenograft model demonstrated good oral bioavailability, excellent brain penetration, and efficacy. Initial toxicity studies in rats and dogs qualify 6 for further development as a therapeutic agent in oncology.


Assuntos
Aminopiridinas/farmacologia , Antineoplásicos/farmacologia , Morfolinas/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Piridinas/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Triazinas/farmacologia , Aminopiridinas/síntese química , Aminopiridinas/metabolismo , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Encéfalo/metabolismo , Linhagem Celular Tumoral , Cães , Feminino , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Morfolinas/síntese química , Morfolinas/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/síntese química , Inibidores de Fosfoinositídeo-3 Quinase/metabolismo , Ligação Proteica , Piridinas/síntese química , Piridinas/metabolismo , Ratos Wistar , Relação Estrutura-Atividade , Serina-Treonina Quinases TOR/metabolismo , Triazinas/síntese química , Triazinas/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
13.
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
14.
ACS Med Chem Lett ; 10(4): 528-533, 2019 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-30996791

RESUMO

Chemical modulation of the flavonol 2-(benzo[d][1,3]dioxol-5-yl)-chromen-4-one (1), a promising anti-Trypanosomatid agent previously identified, was evaluated through a phenotypic screening approach. Herein, we have performed structure-activity relationship studies around hit compound 1. The pivaloyl derivative (13) showed significant anti-T. brucei activity (EC50 = 1.1 µM) together with a selectivity index higher than 92. The early in vitro ADME-tox properties (cytotoxicity, mitochondrial toxicity, cytochrome P450 and hERG inhibition) were determined for compound 1 and its derivatives, and these led to the identification of some liabilities. The 1,3-benzodioxole moiety in the presented compounds confers better in vivo pharmacokinetic properties than those of classical flavonols. Further studies using different delivery systems could lead to an increase of compound blood levels.

15.
Photochem Photobiol Sci ; 18(9): 2270-2280, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-30900698

RESUMO

A benzothiophene-substituted chromenone with promising activity against Leishmania and Trypanosoma species exhibits peculiar fluorescence properties useful for identifying its complexes with target proteins in the microorganism proteomes. The emission spectra, anisotropy and time profiles of this flavonoid strongly change when moving from the free to the protein-bound forms. The same two types of emission are observed in organic solvents and their mixtures with water, with the relative band intensities depending on the solvent ability to establish hydrogen bonds with the solute. The regular emission prevails in protic solvents, while in aprotic solvents the anomalously red-shifted emission occurs from a zwitterionic tautomeric form, produced in the excited state by proton transfer within the intramolecularly H-bonded form. This interpretation finds support from an experimental and theoretical investigation of the conformational preferences of this compound in the ground and lowest excited state, with a focus on the relative twisting about the chromenone-benzothiophene interconnecting bond. An analysis of the absorption and emission spectra and of the photophysical properties of the two emitting tautomers highlights the relevance of the local microenvironment, particularly of the intra- and intermolecular hydrogen bonds in which this bioactive compound is involved, in determining both its steady-state and time-resolved fluorescence behaviour.


Assuntos
Teoria da Densidade Funcional , Flavonoides/química , Flavonoides/farmacologia , Fluorescência , Proteoma/antagonistas & inibidores , Prótons , Proteínas de Protozoários/antagonistas & inibidores , Ligação de Hidrogênio , Leishmania/efeitos dos fármacos , Estrutura Molecular , Proteoma/química , Proteínas de Protozoários/química , Trypanosoma/efeitos dos fármacos
16.
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
17.
J Med Chem ; 61(22): 10084-10105, 2018 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-30359003

RESUMO

Mechanistic target of rapamycin (mTOR) promotes cell proliferation, growth, and survival and is overactivated in many tumors and central nervous system disorders. PQR620 (3) is a novel, potent, selective, and brain penetrable inhibitor of mTORC1/2 kinase. PQR620 (3) showed excellent selectivity for mTOR over PI3K and protein kinases and efficiently prevented cancer cell growth in a 66 cancer cell line panel. In C57BL/6J and Sprague-Dawley mice, maximum concentration ( Cmax) in plasma and brain was reached after 30 min, with a half-life ( t1/2) > 5 h. In an ovarian carcinoma mouse xenograft model (OVCAR-3), daily dosing of PQR620 (3) inhibited tumor growth significantly. Moreover, PQR620 (3) attenuated epileptic seizures in a tuberous sclerosis complex (TSC) mouse model. In conclusion, PQR620 (3) inhibits mTOR kinase potently and selectively, shows antitumor effects in vitro and in vivo, and promises advantages in CNS indications due to its brain/plasma distribution ratio.


Assuntos
Compostos Azabicíclicos/farmacologia , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Alvo Mecanístico do Complexo 2 de Rapamicina/antagonistas & inibidores , Piridinas/farmacologia , Convulsões/tratamento farmacológico , Triazinas/farmacologia , Animais , Compostos Azabicíclicos/metabolismo , Compostos Azabicíclicos/uso terapêutico , Barreira Hematoencefálica/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Camundongos , Modelos Moleculares , Fosfatidilinositol 3-Quinases/química , Fosfatidilinositol 3-Quinases/metabolismo , Conformação Proteica , Piridinas/metabolismo , Piridinas/uso terapêutico , Ratos , Triazinas/metabolismo , Triazinas/uso terapêutico
18.
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
19.
ChemMedChem ; 13(7): p. 678-683, 2018.
Artigo em Inglês | Sec. Est. Saúde SP, SESSP-IBPROD, Sec. Est. Saúde SP | ID: but-ib15264

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 1.9gmL(-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.

20.
ChemMedChem, v. 13, n. 7, p. 678-683, abr. 2018
Artigo em Inglês | Sec. Est. Saúde SP, SESSP-IBPROD, Sec. Est. Saúde SP | ID: bud-2507

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 1.9gmL(-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.

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