RESUMO
Cyclic peptides are increasingly important structures in drugs but their development can be impeded by difficulties associated with their synthesis. Here, we introduce the 3-aminoazetidine (3-AAz) subunit as a new turn-inducing element for the efficient synthesis of small head-to-tail cyclic peptides. Greatly improved cyclizations of tetra-, penta- and hexapeptides (28 examples) under standard reaction conditions are achieved by introduction of this element within the linear peptide precursor. Post-cyclization deprotection of the amino acid side chains with strong acid is realized without degradation of the strained four-membered azetidine. A special feature of this chemistry is that further late-stage modification of the resultant macrocyclic peptides can be achieved via the 3-AAz unit. This is done by: (i) chemoselective deprotection and substitution at the azetidine nitrogen, or by (ii) a click-based approach employing a 2-propynyl carbamate on the azetidine nitrogen. In this way, a range of dye and biotin tagged macrocycles are readily produced. Structural insights gained by XRD analysis of a cyclic tetrapeptide indicate that the azetidine ring encourages access to the less stable, all-trans conformation. Moreover, introduction of a 3-AAz into a representative cyclohexapeptide improves stability towards proteases compared to the homodetic macrocycle.
Assuntos
Azetidinas , Peptídeos Cíclicos , Azetidinas/química , Azetidinas/síntese química , Ciclização , Peptídeos Cíclicos/química , Peptídeos Cíclicos/síntese química , Compostos Macrocíclicos/química , Compostos Macrocíclicos/síntese química , Química ClickRESUMO
Monoacylglycerol lipase (MAGL) is a 33 kDa serine protease primarily responsible for hydrolyzing 2-arachidonoylglycerol into the proinflammatory eicosanoid precursor arachidonic acid in the central nervous system. Inhibition of MAGL constitutes an attractive therapeutic concept for treating psychiatric disorders and neurodegenerative diseases. Herein, we present the design and synthesis of multiple reversible MAGL inhibitor candidates based on a piperazinyl azetidine scaffold. Compounds 10 and 15 were identified as the best-performing reversible MAGL inhibitors by pharmacological evaluations, thus channeling their radiolabeling with fluorine-18 in high radiochemical yields and favorable molar activity. Furthermore, evaluation of [18F]10 and [18F]15 ([18F]MAGL-2102) by autoradiography and positron emission tomography (PET) imaging in rodents and nonhuman primates demonstrated favorable brain uptakes, heterogeneous radioactivity distribution, good specific binding, and adequate brain kinetics, and [18F]15 demonstrated a better performance. In conclusion, [18F]15 was found to be a suitable PET radioligand for the visualization of MAGL, harboring potential for the successful translation into humans.
Assuntos
Azetidinas/farmacologia , Monoacilglicerol Lipases/antagonistas & inibidores , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/farmacologia , Animais , Azetidinas/síntese química , Azetidinas/química , Sítios de Ligação/efeitos dos fármacos , Relação Dose-Resposta a Droga , Haplorrinos , Ligantes , Modelos Moleculares , Estrutura Molecular , Monoacilglicerol Lipases/metabolismo , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/química , Ratos , Relação Estrutura-AtividadeRESUMO
A novel class of diaryl substituted azetidin-2-one derivatives were designed, asymmetrically synthesized, and evaluated for antiproliferative activities. The in vitro antitumor assay revealed that among the 4-aryl-substituted 1-(3,4,5-trimethoxyphenyl)azetidin-2-ones (B series), most possessed moderate to strong activities, with compound B7c that bears a 2-naphthyl substituent being the most potent one (IC50 0.16-0.40 µM) against a panel of human cancer cell lines. In contrast, none of the 3-(arylmethylene)-substituted 1-(3,4,5-trimethoxyphenyl)azetidin-2-ones (L series) showed significant activities in the assay. Further studies indicated that B7c inhibited tubulin polymerization, disrupted in vitro vascularization, blocked cell cycle progression at G2/M phase, induced cell apoptosis, decreased mitochondrial membrane potential, and increased the intracellular reactive oxygen species level in a dose-dependent way. Compound B7c also inhibited significantly tumor growth in a xenograft mice model with no obvious drop in the mice body weights. Collectively, these results suggested that B7c and its analogues should merit further investigation as new promising antitumor agents.
Assuntos
Antineoplásicos/farmacologia , Azetidinas/farmacologia , Desenho de Fármacos , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Azetidinas/síntese química , Azetidinas/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Polimerização/efeitos dos fármacos , Relação Estrutura-Atividade , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/químicaRESUMO
Twenty-two novel, variously substituted nitroazetidines were designed as both sulfonamide and urethane vinylogs possibly endowed with antimicrobial activity. The compounds under study were obtained following a general procedure recently developed, starting from 4-nitropentadienoates deriving from a common ß-nitrothiophenic precursor. While being devoid of any activity against fungi and Gram-negative bacteria, most of the title compounds performed as potent antibacterial agents on Gram-positive bacteria (E. faecalis and three strains of S. aureus), with the most potent congener being the 1-(4-chlorobenzyl)-3-nitro-4-(p-tolyl)azetidine 22, which displayed potency close to that of norfloxacin, the reference antibiotic (minimum inhibitory concentration values 4 and 1-2 µg/mL, respectively). Since 22 combines a relatively efficient activity against Gram-positive bacteria and a cytotoxicity on eucharyotic cells only at 4-times higher concentrations (inhibiting concentration on 50% of the cultured eukaryotic cells: 36 ± 10 µM, MIC: 8.6 µM), it may be considered as a promising hit compound for the development of a new series of antibacterials selectively active on Gram-positive pathogens. The relatively concise synthetic route described herein, based on widely available starting materials, could feed further structure-activity relationship studies, thus allowing for the fine investigation and optimization of the toxico-pharmacological profile.
Assuntos
Antibacterianos , Azetidinas , Enterococcus faecalis/crescimento & desenvolvimento , Staphylococcus aureus/crescimento & desenvolvimento , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Azetidinas/síntese química , Azetidinas/química , Azetidinas/farmacologia , Relação Dose-Resposta a Droga , Avaliação de Medicamentos , Células Hep G2 , Humanos , Relação Estrutura-AtividadeRESUMO
The current pandemic of COVID-19 caused by SARS-Cov-2 has posed a severe threat to the whole world with its highly infectious, progressive nature with up to 10% mortality rates. The severity of the situation faced by the whole world and the lack of efficient therapeutics to treat this viral disease have led the WHO to depend on the drug-repurposing approach to tackle this major global health problem. This review aims at highlighting the various synthetic approaches employed for the synthesis of these FDA approved drugs that have been presently used for COVID-19 treatment. Additionally, a brief overview of several therapeutic strategies is also presented. This review will encourage the scientific community across the globe to come up with better and efficient synthetic protocols and also novel chemical entities along with this core with more potent activity.
Assuntos
Antivirais/farmacologia , Tratamento Farmacológico da COVID-19 , Reposicionamento de Medicamentos/métodos , SARS-CoV-2/efeitos dos fármacos , Antivirais/síntese química , Antivirais/química , Antivirais/uso terapêutico , Azetidinas/síntese química , Azetidinas/química , Azetidinas/farmacologia , Azetidinas/uso terapêutico , Técnicas de Química Sintética/métodos , Humanos , Nitrilas , Purinas/síntese química , Purinas/química , Purinas/farmacologia , Purinas/uso terapêutico , Pirazóis/síntese química , Pirazóis/química , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Pirimidinas , SARS-CoV-2/fisiologia , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Internalização do Vírus/efeitos dos fármacosRESUMO
In the present study, we intend to synthesize a series of novel substituted phenyl azetidine-2-one sulphonyl derivatives. The entire set of derivatives 5 (a-t) were screened for in-vitro antibacterial, and antifungal activity, and among them eleven compounds were further screened for the antiviral activity to predict their efficacy against pathogenic viruses. Interestingly, compound 5d, 5e, 5f, 5h, 5i, and 5j showed similar or better antibacterial activity as compared to ampicillin (standard). Moreover, compounds 5h, 5i, 5j, and 5q showed good inhibitory activity against fungal strains whereas other derivatives had mild or diminished activity in comparison with standard drug clotrimazole. The antimicrobial study indicated that compounds having electron-withdrawing groups showed the highest activity. Interestingly, these tested compounds showed weak antiviral activity against Vaccinia virus, Human Coronavirus (229E), Reovirus-1, Herpes simplex virus, Sindbis virus, Coxsackievirus B4, Yellow Fever virus, and Influenza B virus in HEL cell, Vero cell, and MDCK cell cultures. The findings of the present study might open new avenues to target human disease-causing deadly microbes and viruses.
Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Antivirais/farmacologia , Azetidinas/farmacologia , Sulfonamidas/farmacologia , Animais , Antibacterianos/síntese química , Antifúngicos/síntese química , Antivirais/síntese química , Aspergillus fumigatus/efeitos dos fármacos , Aspergillus niger/efeitos dos fármacos , Azetidinas/síntese química , Candida albicans/efeitos dos fármacos , Linhagem Celular Tumoral , Chlorocebus aethiops , Cães , Escherichia coli/efeitos dos fármacos , Humanos , Células Madin Darby de Rim Canino , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pseudomonas aeruginosa/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Células Vero , Vírus/efeitos dos fármacosRESUMO
Pharmacological reactivation of the γ-globin gene for the production of fetal hemoglobin (HbF) is a promising approach for the management of ß-thalassemia and sickle cell disease (SCD). We conducted a phenotypic screen in human erythroid progenitor cells to identify molecules that could induce HbF, which resulted in identification of the hit compound 1. Exploration of structure-activity relationships and optimization of ADME properties led to 2-azaspiro[3.3]heptane derivative 18, which is more rigid and has a unique structure. In vivo using cynomolgus monkeys, compound 18 induced a significant dose-dependent increase in globin switching, with developable properties. Moreover, compound 18 showed no genotoxic effects and was much safer than hydroxyurea. These findings could facilitate the development of effective new therapies for the treatment of ß-hemoglobinopathies, including SCD.
Assuntos
Azetidinas/farmacologia , Células Precursoras Eritroides/efeitos dos fármacos , Hemoglobina Fetal/metabolismo , Compostos de Espiro/farmacologia , Animais , Azetidinas/síntese química , Azetidinas/farmacocinética , Desenho de Fármacos , Estabilidade de Medicamentos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Isoxazóis/síntese química , Isoxazóis/farmacocinética , Isoxazóis/farmacologia , Macaca fascicularis , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Compostos de Espiro/síntese química , Compostos de Espiro/farmacocinética , Relação Estrutura-AtividadeRESUMO
A strategy to conformationally restrain a series of GlyT1 inhibitors identified potent analogs that exhibited slowly interconverting rotational isomers. Further studies to address this concern led to a series of azetidine-based inhibitors. Compound 26 was able to elevate CSF glycine levels in vivo and demonstrated potency comparable to Bitopertin in an in vivo rat receptor occupancy study. Compound 26 was subsequently shown to enhance memory in a Novel Object Recognition (NOR) behavioral study after a single dose of 0.03 mg/kg, and in a contextual fear conditioning (cFC) study after four QD doses of 0.01-0.03 mg/kg.
Assuntos
Azetidinas/farmacologia , Proteínas da Membrana Plasmática de Transporte de Glicina/antagonistas & inibidores , Memória/efeitos dos fármacos , Azetidinas/síntese química , Azetidinas/química , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Targeting the menin-MLL protein-protein interaction is a new therapeutic strategy for the treatment of acute leukemia carrying MLL fusion (MLL leukemia). We describe herein the structure-based optimization of a class of covalent menin inhibitors, which led to the discovery of M-808 (16) as a highly potent and efficacious covalent menin inhibitor. M-808 effectively inhibits leukemia cell growth at low nanomolar concentrations and is capable of achieving partial tumor regression in an MV4;11 xenograft tumor model in mice at a well-tolerated dose schedule. Determination of the co-crystal structure of M-808 in complex with menin provides a structural basis for their high-affinity, covalent interactions. M-808 represents a promising, covalent menin inhibitor for further optimization and evaluation toward developing a new therapy for the treatment of MLL leukemia.
Assuntos
Antineoplásicos/uso terapêutico , Azetidinas/uso terapêutico , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Leucemia Mieloide Aguda/tratamento farmacológico , Proteína de Leucina Linfoide-Mieloide/antagonistas & inibidores , Ligação Proteica/efeitos dos fármacos , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Azetidinas/síntese química , Azetidinas/farmacologia , Linhagem Celular Tumoral , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Camundongos SCID , Estrutura Molecular , Proteína de Leucina Linfoide-Mieloide/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Inhibition of tubulin polymerisation with small molecules has been clinically validated as a promising therapy for multiple solid tumours. Herein, a series of chiral azetidin-2-ones were asymmetrically synthesised and biologically evaluated for antitumour activities. Among them, a chiral fluorinated azetidin-2-one, 18, was found to exhibit the most potent activities against five cancer cell lines, including a drug-resistant cell line, with IC50 values ranging from 1.0 to 3.6 nM. Further mechanistic studies revealed that the compound 18 worked by disrupting tubulin polymerisation, blocking the cell cycle in the G2/M phase, inducing cellular apoptosis, and suppressing angiogenesis. Additionally, 18 exhibited higher human-microsomal metabolic stability and aqueous solubility compared to those of combretastatin A-4. Finally, 18 was also found to effectively inhibit tumour growth in a xenograft mice model with low toxicity and thus might be a promising lead for further clinical development.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Azetidinas/uso terapêutico , Neoplasias/tratamento farmacológico , Moduladores de Tubulina/uso terapêutico , Tubulina (Proteína)/metabolismo , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/metabolismo , Inibidores da Angiogênese/toxicidade , Animais , Apoptose/efeitos dos fármacos , Azetidinas/síntese química , Azetidinas/metabolismo , Azetidinas/toxicidade , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Estabilidade de Medicamentos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Tubulina (Proteína)/química , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/metabolismo , Moduladores de Tubulina/toxicidade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Fostemsavir/temsavir is an investigational HIV-1 entry inhibitor currently in late-stage clinical trials. Although it holds promise to be a first-in-class Env-targeted entry inhibitor for the clinic, issues with bioavailability relegate its use to salvage therapies only. As such, the development of a small molecule HIV-1 entry inhibitor that can be used in standard combination antiretroviral therapy (cART) remains a longstanding goal for the field. We previously demonstrated the ability of extending the chemotypes available to this class of inhibitor as the first step towards this overarching goal. In addition to poor solubility, metabolic stability is a crucial determinant of bioavailability. Therefore, in this short communication, we assess the metabolic stabilities of five of our novel chemotype entry inhibitors. We found that changing the piperazine core region of temsavir alters the stability of the compound in human liver microsome assays. Moreover, we identified an entry inhibitor with more than twice the metabolic stability of temsavir and demonstrated that the orientation of the core replacement is critical for this increase. This work further demonstrates the feasibility of our long-term goal-to design an entry inhibitor with improved drug-like qualities-and warrants expanded studies to achieve this.
Assuntos
Fármacos Anti-HIV/farmacologia , Inibidores da Fusão de HIV/farmacologia , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Organofosfatos/química , Piperazinas/química , Triazóis/metabolismo , Compostos Azabicíclicos/síntese química , Compostos Azabicíclicos/química , Compostos Azabicíclicos/farmacologia , Azetidinas/síntese química , Azetidinas/química , Azetidinas/farmacologia , Cromatografia Líquida , Células HEK293 , Proteína do Núcleo p24 do HIV/química , Proteína do Núcleo p24 do HIV/metabolismo , Inibidores da Fusão de HIV/metabolismo , Infecções por HIV/virologia , Humanos , Microssomos Hepáticos/virologia , Organofosfatos/farmacologia , Piperazinas/farmacologia , Ligação Proteica , Pirrolidinas/síntese química , Pirrolidinas/química , Pirrolidinas/farmacologia , Espectrometria de Massas em Tandem , Triazóis/síntese química , Triazóis/farmacologia , Triazóis/toxicidadeRESUMO
A new series of 1,4-diarylazetidin-2-one derivatives (ß-lactams) were designed and synthesized to evaluate their biological activities as selective cyclooxygenase-2 (COX-2) inhibitors. In vitro COX-1 and COX-2 inhibition studies showed that all compounds were selective inhibitors of the COX-2 isozyme with IC50 values in the 0.05-0.11 µM range, and COX-2 selectivity indexes in the range of 170-703.7. Among the synthesized ß-lactams, 3-methoxy-4-(4-(methylsulfonyl)phenyl)-1-(3,4,5-trimethoxyphenyl)azetidin-2-one (4j) possessing trimethoxy groups at the N-1 phenyl ring exhibited the highest COX-2 inhibitory selectivity and potency, even more potent than the reference drug celecoxib. The analgesic activity of the synthesized compounds was also determined using the formalin test. Compound 4f displayed the best analgesic activity among the synthesized molecules. Molecular modeling studies indicated that the methylsulfonyl pharmacophore group can be inserted into the secondary pocket of the COX-2 active site for interactions with Arg513 . The structure-activity data acquired indicate that the ß-lactam ring moiety constitutes a suitable scaffold to design new 1,4-diarylazetidin-2-ones with selective COX-2 inhibitory activity.
Assuntos
Analgésicos/farmacologia , Azetidinas/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/metabolismo , Dor/tratamento farmacológico , beta-Lactamas/farmacologia , Analgésicos/síntese química , Analgésicos/química , Animais , Azetidinas/síntese química , Azetidinas/química , Gatos , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Modelos Moleculares , Estrutura Molecular , Ratos , Relação Estrutura-Atividade , beta-Lactamas/síntese química , beta-Lactamas/químicaRESUMO
The TiIV -mediated synthesis of spirocyclic NH-azetidines from oxime ethers using either an alkyl Grignard reagent or terminal olefin ligand exchange coupling partner is described. Through a proposed Kulinkovich-type mechanism, a titanacyclopropane intermediate forms and serves as a 1,2-aliphatic dianion equivalent, inserting into the 1,2-dielectrophilc oxime ether to ultimately give rise to the desired N-heterocyclic four-membered ring. This transformation proceeds in moderate yield to furnish previously unreported and structurally diverse NH-azetidines in a single step.
Assuntos
Azetidinas/síntese química , Éteres/química , Oximas/química , Compostos de Espiro/síntese química , Titânio/química , Azetidinas/química , Estrutura Molecular , Compostos de Espiro/químicaRESUMO
We have designed (S)-(5-(azetidin-2-ylmethoxy)pyridine-3-yl)methyl cyclopentadienyltricarbonyl technetium carboxylate ([99mTc]CPTT-A-E) with high affinity for nicotinic acetylcholine receptors (nAChRs) using (2(S)-azetidinylmethoxy)-pyridine (A-85380) as the lead compound to develop a Tc-99m-cyclopentadienyltricarbonyl-technetium (99mTc)-labeled nAChR imaging probe. Because technetium does not contain a stable isotope, cyclopentadienyltricarbonyl rhenium (CPTR) was synthesized by coordinating rhenium, which is a homologous element having the same coordination structure as technetium. Further, the binding affinity to nAChR was evaluated. CPTR-A-E exhibited a high binding affinity to nAChR (Kiâ¯=â¯0.55â¯nM). Through the radiosynthesis of [99mTc]CPTT-A-E, an objective compound could be obtained with a radiochemical yield of 33% and a radiochemical purity of greater than 97%. In vitro autoradiographic study of the brain exhibited that the local nAChR density strongly correlated with the amount of [99mTc]CPTT-A-E that was accumulated in each region of interest. Further, the in vivo evaluation of biodistribution revealed a higher accumulation of [99mTc]CPTT-A-E in the thalamus (characterized by the high nAChR density) when compared with that in the cerebellum (characterized by the low nAChR density). Although additional studies will be necessary to improve the uptake of [99mTc]CPTT-A-E to the brain, [99mTc]CPTT-A-E met the basic requirements for nAChR imaging.
Assuntos
Azetidinas/farmacologia , Encéfalo/metabolismo , Compostos de Organotecnécio/farmacologia , Compostos Radiofarmacêuticos/farmacologia , Receptores Nicotínicos/metabolismo , Animais , Azetidinas/síntese química , Azetidinas/farmacocinética , Masculino , Camundongos , Compostos de Organotecnécio/síntese química , Compostos de Organotecnécio/farmacocinética , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinética , Ratos Sprague-Dawley , Tomografia Computadorizada de Emissão de Fóton Único/métodosRESUMO
Highly diastereoselective addition of ethyl cyclobutanecarboxylate anions to Davis-Ellman's imines is reported. This methodology afforded the preparation of enantiomerically and diastereomerically pure 1-substituted 2-azaspiro[3.3]heptanes. This three-step procedure proceeded efficiently (yield up to 90%) and diastereoselectively (dr values up to 98 : 2). This methodology is applicable to the synthesis of 1-substituted 2-azaspiro[3.4]octane and 1-substituted 2-azaspiro[3.5]nonane.
Assuntos
Azetidinas/síntese química , Descoberta de Drogas , Compostos de Espiro/síntese química , Ácidos Carboxílicos/química , Ciclização , Ciclobutanos/química , Iminas/química , Estereoisomerismo , Sulfonamidas/químicaRESUMO
Monoacylglycerol lipase (MAGL) is a serine hydrolase that degrades 2-arachidonoylglycerol (2-AG) in the endocannabinoid system (eCB). Selective inhibition of MAGL has emerged as a potential therapeutic approach for the treatment of diverse pathological conditions, including chronic pain, inflammation, cancer, and neurodegeneration. Herein, we disclose a novel array of reversible and irreversible MAGL inhibitors by means of "tail switching" on a piperazinyl azetidine scaffold. We developed a lead irreversible-binding MAGL inhibitor 8 and reversible-binding compounds 17 and 37, which are amenable for radiolabeling with 11C or 18F. [11C]8 ([11C]MAGL-2-11) exhibited high brain uptake and excellent binding specificity in the brain toward MAGL. Reversible radioligands [11C]17 ([11C]PAD) and [18F]37 ([18F]MAGL-4-11) also demonstrated excellent in vivo binding specificity toward MAGL in peripheral organs. This work may pave the way for the development of MAGL-targeted positron emission tomography tracers with tunability in reversible and irreversible binding mechanisms.
Assuntos
Azetidinas/química , Desenho de Fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Monoacilglicerol Lipases/antagonistas & inibidores , Piperazinas/química , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/farmacologia , Animais , Azetidinas/síntese química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Camundongos , Camundongos Knockout , Simulação de Acoplamento Molecular , Estudo de Prova de Conceito , Ensaio Radioligante , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacocinética , Ratos , Ratos Sprague-Dawley , Distribuição TecidualRESUMO
We report the discovery of a novel azetidine scaffold for colony stimulating factor-1 receptor (CSF-1R) Type II inhibitors by using a structure-based drug design (SBDD) based on a docking model. The work leads to the representative compound 4a with high CSF-1R inhibitory activity (IC50â¯=â¯9.1â¯nM). The obtained crystal structure of an azetidine compound with CSF-1R, which matched our predicted docking model, demonstrates that the azetidine compounds bind to the DFG-out conformation of the protein as a Type II inhibitor.
Assuntos
Azetidinas/farmacologia , Descoberta de Drogas , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Azetidinas/síntese química , Azetidinas/química , Relação Dose-Resposta a Droga , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Relação Estrutura-AtividadeRESUMO
Excess lipid accumulation can initiate the development and progression of atherosclerotic lesions, thus eventually leading to cardiovascular disease. Lipid-lowering medication therapy is one of the cornerstones of cardiovascular disease therapy. On the basis of the cholesterol absorption inhibitor ezetimibe, we successfully synthesized seven 2-azetidinone derivatives and eighteen 1H-pyrrole-2,5-dione derivatives. Most of the new compounds significantly inhibited cholesterol uptake inâ vitro. In addition, one of the most active inhibitors, 3-(4-fluorophenyl)-1-[(3S)-3-hydroxy-3-(4-hydroxyphenyl)propyl]-4-(4-hydroxyphenyl)-1H-pyrrole-2,5-dione (14q), showed no cytotoxicity in L02 and HEK293T cell lines. Further evaluation indicated that 14q inhibited considerably the amount of TNF-α, ROS, MDA, and LDH inâ vitro. Therefore, 14q might be a novel cholesterol absorption inhibitor.
Assuntos
Anticolesterolemiantes/síntese química , Azetidinas/farmacologia , Inflamação/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Pirróis/farmacologia , Anticolesterolemiantes/farmacologia , Azetidinas/síntese química , Transporte Biológico/efeitos dos fármacos , Colesterol/metabolismo , Células HEK293 , Humanos , Pirróis/síntese química , Relação Estrutura-AtividadeRESUMO
Target- and phenotype-agnostic assessments of biological activity have emerged as viable strategies for prioritizing scaffolds, structural features, and synthetic pathways in screening sets, with the goal of increasing performance diversity. Here, we describe the synthesis of a small library of functionalized stereoisomeric azetidines and its biological annotation by "cell painting," a multiplexed, high-content imaging assay capable of measuring many hundreds of compound-induced changes in cell morphology in a quantitative and unbiased fashion. Using this approach, we systematically compare the degrees to which a core scaffold's biological activity, inferred from its effects on cell morphology, is affected by variations in stereochemistry and appendages. We show that stereoisomerism and appendage diversification can produce effects of similar magnitude, and that the concurrent use of these strategies results in a broader sampling of biological activity.
Assuntos
Azetidinas/química , Bibliotecas de Moléculas Pequenas/química , Azetidinas/síntese química , Linhagem Celular Tumoral , Humanos , Conformação Molecular , Imagem Óptica , Bibliotecas de Moléculas Pequenas/síntese química , EstereoisomerismoRESUMO
A series of ten novel derivatives of 4-(benzyloxy)-N-(3-chloro-2-(substituted phenyl)-4-oxoazetidin-1-yl) benzamide 6aâ»j were synthesized in good yield from the key compound 4-(benzyloxy)-N'-(substituted benzylidene) benzo hydrazide, called Schiff 's bases 5aâ»j, by Staudinger reaction ([2 + 2] ketene-imine cycloaddition reaction) with chloro acetyl chloride in the presence of catalyst tri ethylamine and solvent dimethyl formamide (DMF), by using ultra-sonication as one of the green chemistry tools. All the synthesised compounds were evaluated for in vitro anti-tubercular activity against Mycobacterium tuberculosis (MTB) and most of them showed promising activity with an IC50 value of less than 1 µg/mL. To establish the safety, all the synthesized compounds were further tested for cytotoxicity against the human cancer cell line HeLa and all 6aâ»j compounds were found to be non-cytotoxic in nature. The molecular docking study was carried out with essential enzyme InhA (FabI/ENR) of Mycobacterium responsible for cell wall synthesis which suggests that 6a and 6e are the most active derivatives of the series. The theoretical evaluation of cell permeability based on Lipinski's rule of five has helped to rationalize the biological results and hence the synthesized azetidinone derivatives 6aâ»j were also analyzed for physicochemical evaluation that is, absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties and the results showed that all the derivatives could comply with essential features required for a potential lead in the anti-tubercular drug discovery process.