RESUMO
A series of 19 novel α-aminophosphonate-tetrahydroisoquinoline hybrids were synthesized through a cross dehydrogenative coupling reaction between N-aryl-tetrahydroisoquinolines and dialkylphosphites, using tert-butyl hydroperoxide as oxidazing agent. This simple procedure provided products with high atom economy and moderate to high yields. In vitro cholinesterase inhibitory activity of these compounds was evaluated. All the synthesized compounds showed good to excellent selective inhibition against butyrylcholinesterase. Compound 3bc was found to be the most active derivative with an IC50 of 9 nM. Molecular modelling studies suggested that the inhibitor is located in the peripheral anionic site (PAS) of the enzyme and interacts with some residue of the catalytic anionic site. Kinetic studies revealed that 3bc acts as a non-competitive inhibitor. Predicted ADME showed good pharmacokinetics and drug-likeness properties for most hybrids. Each newly synthesized compound was characterized by IR, 1H NMR, 13C NMR, 31P NMR spectral studies and also HRMS. The results of this study suggest that α-aminophosphonate-tetrahydroisoquinoline hybrids can be promising lead compounds in the discovery of new and improved drugs for the treatment of Alzheimer's disease and related neurodegenerative disorders.
Assuntos
Doença de Alzheimer , Tetra-Hidroisoquinolinas , Humanos , Inibidores da Colinesterase/química , Butirilcolinesterase/metabolismo , Cinética , Acetilcolinesterase/metabolismo , Relação Estrutura-Atividade , Simulação de Acoplamento Molecular , Tetra-Hidroisoquinolinas/farmacologia , Doença de Alzheimer/tratamento farmacológicoRESUMO
Microbial contamination remains a significant economic challenge in the food industry, emphasizing the need for innovative antimicrobial solutions. In this study, we synthesized N-sulfonyl-1,2,3,4-tetrahydroisoquinolines (NSTHIQ) derivatives using an environmentally friendly Preyssler heteropolyacid catalyst, obtaining moderate to high yields (35-91 %) under mild conditions. Two derivatives (5 and 6) exhibited significant antifungal properties against various fungal species, including Aspergillus spp, Penicillium spp, and Botrytis cinerea. ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) analysis revealed the absence of hepatic toxicity in all compounds, making derivatives 2, 3, 4, and 5 potential candidates for further development. However, derivatives 6 and 7 exhibited immunotoxicity. In support of our experimental findings, reactivity indices were computed using Density Functional Theory principles, deriving valuable insights into the chemical properties of these derivatives. This study underscores the potential of NSTHIQ compounds as potent antifungal agents, coupled with the importance of employing environmentally friendly catalysts in drug discovery.
Assuntos
Anti-Infecciosos , Tetra-Hidroisoquinolinas , Testes de Sensibilidade Microbiana , Anti-Infecciosos/química , Antifúngicos/farmacologia , Antifúngicos/química , Aspergillus , Tetra-Hidroisoquinolinas/farmacologia , Relação Estrutura-AtividadeRESUMO
The oxidative α-functionalization of 2-aryl-1,2,3,4-tetrahydroisoquinolines (THIQs) promoted by a versatile heterogeneous nanocatalyst consisting of copper nanoparticles immobilized on silica-coated maghemite (CuNPs/MagSilica) has been accomplished. The methodology was successfully applied in the cross-dehydrogenative coupling (CDC) reaction of N-aryl THIQs and other tertiary amines with nitromethane as a pro-nucleophile (aza-Henry reaction) and the α-oxidation of THIQs with O2 as a green oxidant. Phosphite, alkyne, or indole derivatives were also shown to be suitable candidates for their use as pro-nucleophiles in the CDC reaction with THIQs. The catalyst, with very low copper loading (0.4-1.0 mol % Cu), could be easily recovered by means of an external magnet and reused in four cycles without significant loss of activity.
Assuntos
Fosfitos , Tetra-Hidroisoquinolinas , Cobre , Catálise , Alcinos , Dióxido de Silício , Oxidantes , Aminas , Estresse Oxidativo , IndóisRESUMO
The combined allergic rhinitis and asthma syndrome (CARAS) is a chronic airway inflammation of allergic individuals, with a type 2 immune response. Pharmacotherapy is based on drugs with relevant side effects. Thus, the goal of this study was to evaluate the synthetic alkaloid, MHTP in the experimental model of CARAS. Therefore, BALB/c mice were ovalbumin (OVA) -sensitized and -challenged and treated with MHTP by intranasal or oral routes. Treated animals showed a decrease (p < 0.05) of sneezing, nasal rubbings, and histamine nasal hyperactivity. Besides, MHTP presented binding energy and favorable interaction for adequate anchoring in the histamine H1 receptor. MHTP treatment inhibited the eosinophil migration into the nasal (NALF) and the bronchoalveolar (BALF) fluids. Histological analysis showed that the alkaloid decreased the inflammatory cells in the subepithelial and perivascular regions of nasal tissue and in the peribronchiolar and perivascular regions of lung tissue. The MHTP treatment also reduced the pulmonary hyperactivity by decreasing the smooth muscle layer hypertrophy and the collagen fiber deposition in the extracellular matrix. The immunomodulatory effect of the alkaloid was due to the decrease of cytokines like IL-5 and IL-17A (type 2 and 3), TSLP (epithelial), and the immunoregulatory cytokine, TGF-ß. These MHTP effects on granulocytes were dependent on the p38/ERK1/2 MAP kinase signaling pathway axis. Indeed, the synthetic alkaloid reduced the frequency of activation of both kinases independent of the NF-κB (p65) pathway indicating that the molecule shut down the intracellular transduction signals underlie the cytokine gene transcription.
Assuntos
Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Rinite Alérgica/tratamento farmacológico , Tetra-Hidroisoquinolinas/uso terapêutico , Alérgenos/imunologia , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Sistema de Sinalização das MAP Quinases , Camundongos , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Ovalbumina/imunologia , Receptores Histamínicos H1/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
CD44 promotes metastasis, chemoresistance, and stemness in different types of cancer and is a target for the development of new anti-cancer therapies. All CD44 isoforms share a common N-terminal domain that binds to hyaluronic acid (HA). Herein, we used a computational approach to design new potential CD44 antagonists and evaluate their target-binding ability. By analyzing 30 crystal structures of the HA-binding domain (CD44HAbd), we characterized a subdomain that binds to 1,2,3,4-tetrahydroisoquinoline (THQ)-containing compounds and is adjacent to residues essential for HA interaction. By computational combinatorial chemistry (CCC), we designed 168,190 molecules and compared their conformers to a pharmacophore containing the key features of the crystallographic THQ binding mode. Approximately 0.01% of the compounds matched the pharmacophore and were analyzed by computational docking and molecular dynamics (MD). We identified two compounds, Can125 and Can159, that bound to human CD44HAbd (hCD44HAbd) in explicit-solvent MD simulations and therefore may elicit CD44 blockage. These compounds can be easily synthesized by multicomponent reactions for activity testing and their binding mode, reported here, could be helpful in the design of more potent CD44 antagonists.
Assuntos
Desenho de Fármacos , Descoberta de Drogas , Receptores de Hialuronatos , Simulação de Dinâmica Molecular , Tetra-Hidroisoquinolinas , Animais , Sítios de Ligação , Humanos , Receptores de Hialuronatos/antagonistas & inibidores , Receptores de Hialuronatos/química , Ácido Hialurônico/metabolismo , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Ligação Proteica , Tetra-Hidroisoquinolinas/químicaRESUMO
Two new strategies for the efficient synthesis of racemic 1,2,3,4-tetrahydroisoquinoline-3-phosphonic acid (TicP) (±)-2 have been developed. The first strategy involves the electron-transfer reduction of the easily obtained α,ß-dehydro phosphonophenylalanine followed by a Pictet-Spengler cyclization. The second strategy involves a radical decarboxylation-phosphorylation reaction on 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic). In both strategies, the highly electrophilic N-acyliminium ion is formed as a key intermediate, and the target compound is obtained in good yield using mild reaction conditions and readily available starting materials, complementing existing methodologies and contributing to the easy accessibility of (±)-2 for further research.
Assuntos
Ácidos Fosforosos/síntese química , Tetra-Hidroisoquinolinas/síntese química , Ciclização , Descarboxilação , Estrutura Molecular , Peptidomiméticos/síntese química , Peptidomiméticos/química , Ácidos Fosforosos/química , Fosforilação , Estereoisomerismo , Tetra-Hidroisoquinolinas/químicaRESUMO
INTRODUCTION: This study investigated the mechanism of action of a synthetic tetrahydroisoquinoline alkaloid, MHTP, in an experimental model of acute lung injury (ALI) in two distinct moments: 72 h and 10 days. METHODOLOGY: To realize this study, 2.5 mg/kg of lipopolysaccharide (LPS) was intranasally administered in BALB/c mice, and nasal instillation of MHTP (1.25; 2.5; 5.0; 10 or 20 mg/kg) was administrated at 1, 24, and 48 h after LPS challenge. The data were statistically analyzed and p < 0.05 was considered statistically significant. RESULTS: MHTP treatment (2.5, 5.0, 10 or 20 mg/kg) significantly decreased neutrophil migration into the bronchoalveolar lavage fluid (BALF), tissue inflammatory cell infiltration, edema, and hemorrhage as well as collagen fiber deposition on the perialveolar regions at both moments. TNF-α and IL-6 levels were significantly diminished in the MHTP-treated animals at 72 h and maintained them, at a basal level, at 10-day observation. These effects of MHTP are due to downregulating p38MAPkinese/p65NFκB signaling pathway-TLR4 dependent. Also, the MHTP treatment promoted a survival rate at 100% and improved their body weights during the 10-day observation. Unlike, the LPS group (non-treated LPS challenged animals) presented less than 50% of surviving rate at 72 h and the animals that survived did not improve their physiological state at 10-day observation. CONCLUSIONS: These data showed for the first time the beneficial and effective activity of a nasal treatment with a synthetic tetrahydroisoquinoline alkaloid on an experimental model of ALI and pointed out the molecular mechanism related to it.
Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Tetra-Hidroisoquinolinas/uso terapêutico , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/patologia , Administração Intranasal , Animais , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Interleucina-6/imunologia , Lipopolissacarídeos , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Masculino , Camundongos Endogâmicos BALB C , Tetra-Hidroisoquinolinas/farmacologia , Fator de Transcrição RelA/imunologia , Fator de Necrose Tumoral alfa/imunologia , Proteínas Quinases p38 Ativadas por Mitógeno/imunologiaRESUMO
MHTP [2-methoxy-4-(7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl) phenol], a synthetic isoquinolinic alkaloid, presented anti-inflammatory activity in several experimental models of acute inflammation as lipopolysaccharide (LPS)-induced acute lung injury and phlogistic agent-induced edema and presented low preclinical toxicity. The aim of this study was to determine the MHTP effect on ovalbumin (OVA)-induced pulmonary allergic inflammation. In other to realize this study, female BALFB/c mice were sensitized and challenged with OVA (OVA group) and treated with MHTP (MHTP group) by nasal instillation. Inflammatory, allergic, and immunomodulatory parameters such as migration of inflammatory cells to the lung tissue, pulmonary histological analysis, serum level of IgE-allergen specific, cytokine secretion, and lung T cell population characterization were analyzed and the data were considered statistically significant with p < 0.05. OVA-sensitized and OVA-challenged and MHTP (5.0 mg/kg)-treated mice presented reduction on total leukocyte migration into the bronchoalveolar lavage (BALF) dependent of lymphocyte and eosinophil migration (p < 0.001 and p < 0.01) as compared with the OVA group. Flow cytometric analysis showed that MHTP treatment decreased the percentage of granulocytes (p < 0.001) into the BALF and lung tissue histological analyzes demonstrated that the MHTP treatment decreased leukocyte migration and mucus production. In addition, treatment with MHTP decreased the number of CD3+CD4+ T cells independently of CD8+ T cell reduction into the BALF. The treatment also reduced significantly (p < 0.05) the serum level of IgE-OVA specific followed by reduction of IL-4, IL-13, and IL-17 production. Surprisingly, the MHTP treatment increased significantly (p < 0.05) the IFN-γ production in the BALF of these animals. Therefore, the results presented here showed that MHTP treatment, by nasal instillation, in a mouse model of OVA-induced pulmonary allergy has anti-allergic and immunomodulatory effects dependent on a Th1-skewed cytokine production that ameliorate the pulmonary allergic inflammation.
Assuntos
Asma/metabolismo , Interferon gama/biossíntese , Tetra-Hidroisoquinolinas/farmacologia , Animais , Asma/tratamento farmacológico , Asma/patologia , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Citocinas/efeitos dos fármacos , Feminino , Granulócitos/citologia , Granulócitos/efeitos dos fármacos , Inflamação/tratamento farmacológico , Interferon gama/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Células Th1/imunologiaRESUMO
Because P-glycoprotein (P-gp) plays an absorptive role in the skin, its pharmacological inhibition represents a strategy to promote cutaneous localization of anticancer agents that serve as its substrates, improving local efficacy while reducing systemic exposure. Here, we evaluated the ability of a nanoemulsion (NE) coencapsulating a P-gp inhibitor (elacridar) with the antitumor drug paclitaxel to promote epidermal targeting. Loaded NE displayed a nanometric size (45.2 ± 4.0 nm) and negative zeta potential (-4.2 ± 0.8 mV). Elacridar improved NE ability to inhibit verapamil-induced ATPase activity of P-gp; unloaded NE-inhibited P-gp when used at a concentration of 1500 µM, while elacridar encapsulation decreased this concentration by 3-fold (p <0.05). Elacridar-loaded NE reduced paclitaxel penetration into the dermis of freshly excised mice skin and its percutaneous permeation by 1.5- and 1.7-fold (p <0.05), respectively at 6 h, whereas larger drug amounts (1.4-fold, p <0.05) were obtained in viable epidermis. Assessment of cutaneous distribution of a fluorescent paclitaxel derivative confirmed the smaller delivery into the dermis at elacridar presence. In conclusion, we have provided novel evidence that NE containing elacridar exhibited a clear potential for P-gp inhibition and enabled epidermal targeting of paclitaxel, which in turn, can potentially reduce adverse effects associated with systemic exposure to anticancer therapy.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Acridinas/farmacologia , Antineoplásicos/farmacologia , Portadores de Fármacos/química , Proteínas de Membrana Transportadoras/metabolismo , Nanopartículas/química , Pele/efeitos dos fármacos , Tetra-Hidroisoquinolinas/farmacologia , Acridinas/química , Administração Cutânea , Animais , Antineoplásicos/química , Transporte Biológico/efeitos dos fármacos , Emulsões/química , Emulsões/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Paclitaxel/química , Paclitaxel/farmacologia , Tamanho da Partícula , Tetra-Hidroisoquinolinas/química , Verapamil/química , Verapamil/farmacologiaRESUMO
A series of tetrahydroisoquinolines functionalized with carbamates is reported here as highly selective ligands on the dopamine D2 receptor. These compounds were selected by means of a molecular modeling study. The studies were carried out in three stages: first an exploratory study was carried out using combined docking techniques and molecular dynamics simulations. According to these results, the bioassays were performed; these experimental studies corroborated the results obtained by molecular modeling. In the last stage of our study, a QTAIM analysis was performed in order to determine the main molecular interactions that stabilize the different ligand-receptor complexes. Our results show that the adequate use of combined simple techniques is a very useful tool to predict the potential affinity of new ligands at dopamine D1 and D2 receptors. In turn the QTAIM studies show that they are very useful to evaluate in detail the molecular interactions that stabilize the different ligand-receptor complexes; such information is crucial for the design of new ligands.