RESUMO
Nature-derived products, like juices and peel extracts of fruits and vegetables, have emerged in recent years as interesting and sustainable alternatives to traditional solvents in several synthetic applications. Herein, we present a green and fast method for the N-acetylation of amino acids, using several bio-based solvents (vinegar, tomato/kiwi/apple peel extracts, lemon juice, etc.). The high reactivity of the amino group is often a limitation in synthetic processes, making its protection a necessary step to achieve pure products and limit side reactions. Therefore, versatile, time-efficient procedures, minimal purification efforts, and good yields are desirable features for these transformations. Our new method meets all these criteria, offering a valuable and eco-friendly alternative to traditional approaches. In detail, we managed to obtain comparable yields to established setups, while improving safety and reducing the environmental impact of the overall process. Most notably, the milder conditions made it possible to avoid the use of running water (saving about 250â L/reaction) and electric-powered cooling devices.
Assuntos
Aminoácidos , Frutas , Solventes , Acetilação , AminasRESUMO
This study presents an exploration of the chemical space around derivatives of 3-benzamidopyrazine-2-carboxamides, previously identified as potent antimycobacterial compounds with predicted binding to mycobacterial prolyl-transfer RNA synthetase. New urea derivatives (Series-1) were generally inactive, probably due to their preference for cis-trans conformation (confirmed by density functional theory calculations and experimentally by nuclear overhauser effect spectroscopy NMR). Series-2 (3-benzamidopyrazine-2-carboxamides with disubstituted benzene ring) demonstrated that substituents larger than fluorine are not tolerated in the ortho position of the benzene ring. This series brought two new compounds (21: R = 2-F, 4-Cl and 22: R = 2-F, 4-Br) with in vitro activity against Mycobacterium tuberculosis H37Rv as well as multidrug-resistant clinical isolates, with minimum inhibitory concentration ranging from 6.25 to 25 µg/mL. The lactone-type derivatives 4H-pyrazino[2,3-d][1,3]oxazin-4-ones (Series-3) were inactive, but solvent stability studies of compound 29 indicated that they might be developed to usable lactone prodrugs of inhibitors of mycobacterial aspartate decarboxylase (PanD).
Assuntos
Antituberculosos , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis , Relação Estrutura-Atividade , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/enzimologia , Antituberculosos/farmacologia , Antituberculosos/química , Antituberculosos/síntese química , Estrutura Molecular , Aminoacil-tRNA Sintetases/antagonistas & inibidores , Aminoacil-tRNA Sintetases/metabolismo , Pirazinas/farmacologia , Pirazinas/química , Pirazinas/síntese química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Relação Dose-Resposta a DrogaRESUMO
The synthesis of a collection of enantiomerically pure, systematically substituted hydantoins as structural privileged universal mimetic scaffolds is presented. It relies on a chemoselective condensation/cyclization domino process between isocyanates of quaternary or unsubstituted α-amino esters and N-alkyl aspartic acid diesters followed by standard hydrolysis/coupling reactions with amines, using liquid-liquid acid/base extraction protocols for the purification of the intermediates. Besides the nature of the α carbon on the isocyanate moiety, either a quaternary carbon or a more flexible methylene group, conformational studies in silico (molecular modeling), in solution (NMR, circular dichroism (CD), Fourier transform infrared (FTIR)), and in solid state (X-ray) showed that the presented hydantoin-based peptidomimetics are able to project their substituents in positions superimposable to the side chains of common protein secondary structures such as α-helix and ß-turn, being the open α-helix conformation slightly favorable according to molecular modeling, while the closed ß-turn conformation preferred in solution and in solid state.
Assuntos
Hidantoínas , Peptidomiméticos , Hidantoínas/química , Conformação Molecular , Modelos Moleculares , Ciclização , Dicroísmo Circular , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) infections is one of the most crucial challenges currently faced by the scientific community. Developments in the fundamental understanding of their underlying mechanisms may open new perspectives in drug discovery. In this review, we conducted a systematic literature search in PubMed, Web of Science, and Scopus, to collect information on innovative strategies to hinder iron acquisition in bacteria. In detail, we discussed the most interesting targets from iron uptake and metabolism pathways, and examined the main chemical entities that exhibit anti-infective activities by interfering with their function. The mechanism of action of each drug candidate was also reviewed, together with its pharmacodynamic, pharmacokinetic, and toxicological properties. The comprehensive knowledge of such an impactful area of research will hopefully reflect in the discovery of newer antibiotics able to effectively tackle the antimicrobial resistance issue.
Assuntos
Antibacterianos , Anti-Infecciosos , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Anti-Infecciosos/farmacologia , Anti-Infecciosos/uso terapêutico , Bactérias , Descoberta de Drogas , FerroRESUMO
Bispidines are a family of ligands that plays a pivotal role in various areas of coordination chemistry, with applications in medicinal chemistry, molecular catalysis, coordination polymers synthesis, and molecular magnetism. In the present work, triazole moieties were introduced using the CuAAC click-reaction, with the aim of expanding the number of coordination sites on the bispidine core. The 1,2,3-triazole rings were thus synthesized on propargyl-derived bispidines after reaction with different alkyl azides. The new class of triazole-bispidines was characterized, and their chelation capabilities were evaluated with different metals through NMR titration, ESI-MS spectrometry, and single-crystal X-ray diffraction (SC-XRD). Finally, the suitability of these molecules as metal ligands for the catalytic Henry reaction was demonstrated with copper and zinc.
RESUMO
Elagolix sodium salt is the first marketed orally active non-peptide gonadotropin-releasing hormone receptor antagonist (GnRHR-ant) for the management of hormone dependent diseases, such as endometriosis and uterine fibroids. Despite its presence on the market since 2018, a thorough NMR analysis of this drug, together with its synthetic intermediates, is still lacking. Hence, with the aim of filling this literature gap, we here performed a detailed NMR investigation, which allowed the complete assignment of the 1H, 13C, and 15N NMR signals. These data allowed, with the support of the conformational analysis, the determination of the stereochemical profile of the two atropisomers, detectable in solution. Moreover, these latter were also detected by means of cellulose-based chiral HPLC, starting from a sample prepared through an implemented synthetic procedure with respect to the reported ones. Overall, these results contribute to further understanding of the topic of atropisomerism in drug discovery and could be applied in the design of safe and stable analogs, endowed with improved target selectivity.
Assuntos
Endometriose , Hormônio Liberador de Gonadotropina , Feminino , Humanos , Hidrocarbonetos Fluorados , Pirimidinas , Cloreto de Sódio , Cloreto de Sódio na Dieta , Álcoois GraxosRESUMO
SIRT5 is a member of the Sirtuin family, a class of deacetylating enzymes consisting of seven isoforms, involved in the regulation of several processes, including gene expression, metabolism, stress response, and aging. Considering that the anomalous activity of SIRT5 is linked to many pathological conditions, we present herein an overview of the most interesting modulators, with the aim of contributing to further development in this field.
Assuntos
Sirtuínas , Isoformas de Proteínas/genética , Sirtuínas/genética , Sirtuínas/metabolismoRESUMO
The elucidation of the structure of enzymes and their complexes with ligands continues to provide invaluable insights for the development of drugs against many diseases, including bacterial infections. After nearly three decades since the World Health Organization's (WHO) declaration of tuberculosis (TB) as a global health emergency, Mycobacterium tuberculosis (Mtb) continues to claim millions of lives, remaining among the leading causes of death worldwide. In the last years, several efforts have been devoted to shortening and improving treatment outcomes, and to overcoming the increasing resistance phenomenon. The structural elucidation of enzyme-ligand complexes is fundamental to identify hot-spots, define possible interaction sites, and elaborate strategies to develop optimized molecules with high affinity. This review offers a critical and comprehensive overview of the most recent structural information on traditional and emerging mycobacterial enzymatic targets. A selection of more than twenty enzymes is here discussed, with a special emphasis on the analysis of their binding sites, the definition of the structure-activity relationships (SARs) of their inhibitors, and the study of their main intermolecular interactions. This work corroborates the potential of structural studies, substantiating their relevance in future anti-mycobacterial drug discovery and development efforts.
Assuntos
Antituberculosos/química , Proteínas de Bactérias/química , Desenho de Fármacos/métodos , Descoberta de Drogas/métodos , Inibidores Enzimáticos/química , Mycobacterium tuberculosis/enzimologia , Tuberculose/tratamento farmacológico , Domínio Catalítico , Cristalografia/métodos , Humanos , Ligação de Hidrogênio , Mycobacterium tuberculosis/efeitos dos fármacos , Relação Estrutura-Atividade , Tuberculose/microbiologiaRESUMO
Ergometrine and methylergometrine are two alkaloids that are used as maleate salts for the prevention and control of postpartum hemorrhage. Although the two molecules have been known for a long time, few and discordant crystallographic and NMR spectroscopic data are available in the literature. With the aim of providing more conclusive data, we performed a careful NMR study for the complete assignment of the 1H, 13C, and 15N NMR signals of ergometrine, methylergometrine, and their maleate salts. This information allowed for a better definition of their conformational equilibria. In addition, the stereochemistry and the intermolecular interactions in the solid state of the two maleate salts were deeply investigated by means of single-crystal X-ray diffraction, showing the capability of these derivatives to act as both hydrogen-bond donors and acceptors, and evidencing a correlation between the number of intermolecular interactions and their different solubility.
Assuntos
Claviceps/metabolismo , Ergonovina/química , Alcaloides de Claviceps/química , Metilergonovina/química , Cristalografia por Raios X , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Estrutura MolecularRESUMO
Signal transducer and activator of transcription 3 (STAT3) is a validated anticancer target due to the relationship between its constitutive activation and malignant tumors. Through a virtual screening approach on the STAT3-SH2 domain, 5,6-dimethyl-1H,3H-2,1,3-benzothiadiazole-2,2-dioxide (1) was identified as a potential STAT3 inhibitor. Some benzothiadiazole derivatives were synthesized by employing a versatile methodology, and they were tested by an AlphaScreen-based assay. Among them, benzosulfamide 1 showed a significant activity with an IC50 = 15.8 ± 0.6 µM as a direct STAT3 inhibitor. Notably, we discovered that compound 1 was also able to interact with cysteine residues located around the SH2 domain. By applying mass spectrometry, liquid chromatography, NMR, and UV spectroscopy, an in-depth investigation was carried out, shedding light on its intriguing and unexpected mechanism of interaction.
Assuntos
Fator de Transcrição STAT3/metabolismo , Tiadiazóis/química , Sítios de Ligação , Desenho de Fármacos , Humanos , Simulação de Acoplamento Molecular , Mutagênese Sítio-Dirigida , Domínios e Motivos de Interação entre Proteínas/efeitos dos fármacos , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/genética , Relação Estrutura-Atividade , Tiadiazóis/metabolismo , Tiadiazóis/farmacologia , Domínios de Homologia de srcRESUMO
Considering aryl azides as electrophilic partners for the TosMIC mediated Van Leusen reaction, a novel multicomponent synthesis of 4-tosyl-1-arylimidazoles is reported. In this transformation, two molecules of TosMIC participate in the reaction mechanism in two different ways, with the second molecule undergoing a novel type of fragmentation resulting in the incorporation of a C-H into the final product.
RESUMO
Starting from the analysis of the hypothetical binding mode of our previous furan-based hit (I), we successfully achieved our objective to replace the nitro moiety, leading to the disclosure of a new lead exhibiting a strong activity against MbtI. Our best candidate 1 h displayed a Ki of 8.8 µM and its antimycobacterial activity (MIC99 = 250 µM) is conceivably related to mycobactin biosynthesis inhibition. These results support the hypothesis that 5-phenylfuran-2-carboxylic derivatives are a promising class of MbtI inhibitors.
Assuntos
Antituberculosos/química , Antituberculosos/farmacologia , Inibidores Enzimáticos/farmacologia , Furanos/química , Liases/antagonistas & inibidores , Sítios de Ligação , Inibidores Enzimáticos/química , Liases/química , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Mycobacterium bovis/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
New N-substituted-2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridine derivatives were synthesized employing a convenient one-pot three-component method and their structures were characterized by 1 H-NMR and single crystal X-ray diffraction analysis. All the synthesized compounds were inâ vitro screened for antimicrobial activity against Gram-positive (Sarcina lutea) and Gram-negative bacteria (Escherichia coli). In this work, we introduced a chiral residue on the tetrahydropyridine nitrogen, the hitherto the less investigated position on this pharmacophore in order to explore the effect. The antibacterial results showed that the synthesized compounds were active only against Gram-positive bacteria and the (R)-enantiomers displayed a greater antimicrobial potency than their (S)-counterparts. The structure-activity relationship here investigated may provide some interesting clues for future development of tetrahydrothienopyridine derivatives with higher antimicrobial activity.
Assuntos
Anti-Infecciosos/síntese química , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Cristalografia por Raios X , Fungos/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Conformação Molecular , Piridinas/síntese química , Piridinas/química , Piridinas/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A novel one-pot multicomponent reaction to synthesize substituted imidazopyrazines is described. In brief, 1H-(imidazol-5-yl)-N-substituted methanamines react with aldehydes and isocyanides in methanol at room temperature to give imidazopyrazine derivatives in excellent yields. The imidazole nitrogen atom was able to intercept the nascent nitrilium ion, channeling the reaction toward to the sole formation of imidazopyrazines, suppressing the competitive formation of other possible side products deriving from the reaction with the high-energy nitrilium ion. The number of examples and the variability of the nature of isocyanides, aldehydes, and amine components herein employed, witness the robustness of this novel methodology.
Assuntos
Cianetos/química , Imidazóis/síntese química , Nitrogênio/química , Pirazinas/síntese química , Aldeídos/química , Imidazóis/química , Estrutura Molecular , Pirazinas/químicaRESUMO
Tuberculosis is the leading cause of death from a single infectious agent worldwide; therefore, the need for new antitubercular drugs is desperate. The recently validated target salicylate synthase MbtI is the first enzyme involved in the biosynthesis of mycobactins, compounds able to chelate iron, an essential cofactor for the survival of Mycobacterium tuberculosis in the host. Here, we report on the synthesis and biological evaluation of chromane-based compounds as new potential inhibitors of MbtI. Our approach successfully allowed the identification of a novel lead compound (1), endowed with a promising activity against this enzyme (IC50 = 55 µM). Molecular modeling studies were performed in order to evaluate the binding mode of 1 and rationalize the preliminary structure-activity relationships, thus providing crucial information to carry out further optimization studies.
Assuntos
Antituberculosos/química , Proteínas de Bactérias/antagonistas & inibidores , Ácido Corísmico/química , Cromanos/química , Inibidores Enzimáticos/química , Liases/antagonistas & inibidores , Mycobacterium tuberculosis/química , Motivos de Aminoácidos , Antituberculosos/síntese química , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Domínio Catalítico , Ácido Corísmico/metabolismo , Cromanos/síntese química , Inibidores Enzimáticos/síntese química , Expressão Gênica , Cinética , Liases/química , Liases/genética , Liases/metabolismo , Simulação de Acoplamento Molecular , Mycobacterium tuberculosis/enzimologia , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Estrutura Secundária de Proteína , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade , Especificidade por Substrato , TermodinâmicaRESUMO
With the aim to discover new STAT3 direct inhibitors, potentially useful as anticancer agents, a set of methanethiosulfonate drug hybrids were synthesized. The in vitro tests showed that all the thiosulfonic compounds were able to strongly and selectively bind STAT3-SH2 domain, whereas the parent drugs were completely devoid of this ability. In addition, some of them showed a moderate antiproliferative activity on HCT-116 cancer cell line. These results suggest that methanethiosulfonate moiety can be considered a useful scaffold in the preparation of new direct STAT3 inhibitors. Interestingly, an unusual kind of organo-sulfur derivative, endowed with valuable antiproliferative activity, was occasionally isolated. [Formula: see text].
Assuntos
Mesilatos/farmacologia , Fator de Transcrição STAT3/metabolismo , Linhagem Celular Tumoral , Cristalografia por Raios X , Humanos , Ligantes , Mesilatos/química , Mesilatos/metabolismo , Domínios de Homologia de srcRESUMO
The first asymmetric, Brønsted acid catalyzed Biginelli-like reaction of a ketone has been developed, employing N-substituted isatins as carbonyl substrates, and urea and alkyl acetoacetates as further components. BINOL-derived phosphoric acid catalysts have been used to achieve the synthesis of a small library of chiral, enantioenriched spiro(indoline-pyrimidine)-diones derivatives. The absolute configuration of the new spiro stereocenter was assessed on diastereoisomeric derivatives through computer-assisted NMR spectroscopy. X-ray diffractometry allowed the disclosure of the overall molecular conformation in the solid state and the characterization of the crystal packing of a Br-substituted Biginelli-like derivative, while computational studies on the reaction transition state allowed us to rationalize the stereochemical outcome.
RESUMO
Three chiral derivatives of the alkaloid sparteine (bispidines), characterized by the 3,7-diazabicyclo[3.3.1]nonane moiety, were designed as efficient ligands in a number of enantioselective reactions due to their metal coordination properties. A full evaluation of the 3D properties of the compounds was carried out, as the geometrical features of the bicyclic framework are strictly related to the efficiency of the ligands in the asymmetric catalysis. The selected molecules have different molecular complexity for investigating the effects of different chiral groups on the bicycle conformation. We report here a thorough analysis of their molecular arrangement, by NMR spectroscopy, single crystal X-ray crystallography, and computational techniques, which put in evidence their conformational preferences and the parameters needed for the design of more efficient ligands in asymmetric synthetic routes. The results confirmed the high molecular flexibility of the compounds, and indicated how to achieve a control of the chair-chair/boat-chair conformational ratio, by adjusting the relative size of the substituents on the piperidine nitrogens.
Assuntos
Compostos Aza/química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Metais/química , Piperidinas/química , Catálise , Cristalografia por Raios X , Ligantes , Espectroscopia de Ressonância Magnética , Conformação Molecular , EstereoisomerismoRESUMO
Synthetically useful aminodioximes are prepared via a novel three-component reaction among Z-chlorooximes, isocyanides, and hydroxylamines by exploiting the preferential attack of isocyanides to nitrile N-oxides via a [3 + 1] cycloaddition reaction. The results of quantum mechanical studies of the reaction mechanism are also discussed. Furthermore, the one-pot conversion of aminodioximes to 1,2,3-oxadiazole-5-amines via Mitsunobu-Beckmann rearrangement is reported for the first time.