RESUMO
In search for new molecules of diterpene origin with promising anticancer activity, two amino-derivatives (methyl maleopimarate aminoimide and methyl 1ß,13-epoxydihydroquinopimarate C4-hydrazone) were involved in the 4-component Ugi reaction (Ugi-4CR) and pseudo-7-component azido-Ugi condensation (azido-Ugi-7CR) to afford a series of adducts holding α-aminoacylamide and bis-1,5-disubstituted tetrazole substituents. The NCI-60 cancer cell panel screening revealed diterpene-type Ugi adducts 2, 5, and 6 with strong antiproliferative potency with GI50 in range of 1.2-15.4 µM. The high positive correlations with standard anticancer drugs suggest microtubules or progesterone and androgen receptors as possible targets of the synthesized compounds.
Assuntos
Antineoplásicos , Diterpenos , Tetrazóis , Humanos , Tetrazóis/química , Tetrazóis/síntese química , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Diterpenos/química , Diterpenos/farmacologia , Diterpenos/síntese química , Ensaios de Seleção de Medicamentos Antitumorais , Proliferação de Células/efeitos dos fármacos , Relação Estrutura-Atividade , Amidas/químicaRESUMO
For the approval of a drug, the stability data must be submitted to regulatory authorities. Such analyses are often time-consuming and cost-intensive. Forced degradation studies are mainly carried out under harsh conditions in the dissolved state, often leading to extraneous degradation profiles for a solid drug. Oxidative mechanochemical degradation offers the possibility of generating realistic degradation profiles. In this study, a sustainable mechanochemical procedure is presented for the degradation of five active pharmaceutical ingredients (APIs) from the sartan family: losartan potassium, irbesartan, valsartan, olmesartan medoxomil, and telmisartan. High-resolution mass spectrometry enabled the detection of impurities already present in untreated APIs and allowed the elucidation of degradation products. Significant degradation profiles could already be obtained after 15-60 min of ball milling time. Many of the identified degradation products are described in the literature and pharmacopoeias, emphasizing the significance of our results and the applicability of this approach to predict degradation profiles for drugs in the solid state.
Assuntos
Benzimidazóis , Compostos de Bifenilo , Losartan , Telmisartan , Tetrazóis , Valsartana , Benzimidazóis/química , Benzimidazóis/análise , Tetrazóis/química , Telmisartan/química , Valsartana/química , Losartan/química , Losartan/análise , Compostos de Bifenilo/química , Irbesartana/química , Irbesartana/análise , Imidazóis/química , Benzoatos/química , Valina/química , Valina/análise , Solventes/química , Estabilidade de MedicamentosRESUMO
This research summaries the development, optimization and validation of liquid chromatography tandem mass spectrometric (LC-MS/MS) method for concurrent measurement of seven nitrosamines viz; NDMA, NDEA, NDIPA, NDPA, NEIPA, NMPA & NMBA in Olmesartan tablet. Controlling these nitrosamines at trace levels is imperative for ensuring the safety of drug substances and products for consumption. Various regulatory authorities stress the significance of utilizing highly sensitive analytical methods to precisely measure nitrosamines at trace levels. The method applied effective chromatographic separation and optimized parameters for mass spectrometric detection. Detection was carried out using APCI positive ion mode. Chromatographic separation was achieved using a Thermo Accucore PFP column (150 mm x 4.6 mm, 2.6 µ), with a simple gradient elution of mobile phase consisting of 0.1 % formic acid in water (mobile phase A) and methanol (mobile phase B). The total run time was 20 min, with a flow rate of 0.800 mL/min. The method was validated according to the International Council on Harmonisation (ICH Q2 (R2)) guidelines. The established method demonstrated excellent linearity (R2> 0.99) and sensitivity for all the nitrosamines. Detection and quantification limits were sufficiently low for trace nitrosamine levels having good S/N ratio. The method showed good accuracy in Olmesartan tablet samples, with recoveries ranges between 80 % to 120 %. The new analytical approach has exceptional repeatability and reliability, making it possible to precisely quantify the levels of seven nitrosamines in Olmesartan medoxomil tablets in a single analytical run.
Assuntos
Imidazóis , Nitrosaminas , Espectrometria de Massas em Tandem , Tetrazóis , Imidazóis/análise , Imidazóis/química , Limite de Detecção , Espectrometria de Massa com Cromatografia Líquida/métodos , Nitrosaminas/análise , Reprodutibilidade dos Testes , Comprimidos , Espectrometria de Massas em Tandem/métodos , Tetrazóis/análise , Tetrazóis/químicaRESUMO
Tetrazoles are five-membered ring aromatic heterocyclic molecules that consist of one carbon and four nitrogen atoms. Several tetrazole-based drugs have shown promising activities against bacteria, fungi, asthma, cancer, hypertension etc. The overall aim of this study was to determine anti-Acanthamoebic properties of tetrazoles and tetrazole-conjugated silver nanoparticles. Tetrazole-conjugated silver nanoparticles were synthesized and confirmed using ultraviolet-visible spectrometry, Dynamic light scattering, and Fourier-transform infrared spectroscopy. Using amoebicidal, encystment, and excystment assays, the findings revealed that tetrazoles exhibited antiamoebic properties and these effects were enhanced when conjugated with silver nanoparticles. Importantly, conjugation with silver nanoparticles inhibited parasite-mediated human cell death in vitro, as measured by lactate dehydrogenase release, but it reduced toxic effects of drugs alone on human cells. Overall, these results showed clearly that tetrazoles exhibit potent antiamoebic properties which can be enhanced by conjugation with silver nanoparticles and these potential in the rational development of therapeutic interventions against parasitic infections such as keratitis and granulomatous amoebic encephalitis due to pathogenic Acanthamoeba.
Assuntos
Nanopartículas Metálicas , Prata , Tetrazóis , Prata/farmacologia , Prata/química , Humanos , Nanopartículas Metálicas/química , Tetrazóis/farmacologia , Tetrazóis/química , Espectroscopia de Infravermelho com Transformada de Fourier , Espectrofotometria Ultravioleta , Amebicidas/farmacologia , Amebicidas/química , Difusão Dinâmica da Luz , Acanthamoeba castellanii/efeitos dos fármacos , L-Lactato Desidrogenase/metabolismoRESUMO
A synthetic strategy for obtaining a new series of 1,5-disubstituted tetrazole-benzofuran hybrid systems via a one-pot five-component reaction is described. This process involves a Ugi-azide multicomponent reaction coupled to an intramolecular cyclization catalyzed by Pd/Cu, resulting in low to moderate yields from 21 to 67%. This protocol allowed the synthesis of highly substituted benzofurans at the 2-position through an operationally simple process under mild reaction conditions and with high bond forming efficiency due to the formation of six new bonds (two C-C, two C-N, one N-N, and one C-O). Besides, to evaluate the antifungal activity of 1,5-disubstituted tetrazole-benzofurans 9a-n, in vitro studies against Mucor lusitanicus were performed, finding that compound 9b exhibits bioactivity comparable to the commercial antifungal drug Amphotericin B. These results suggest potential for use in controlling mucormycosis infections in animal models, highlighting the importance of these findings given the limited antifungal drug options and high mortality rates associated with this infection.
Assuntos
Antifúngicos , Benzofuranos , Testes de Sensibilidade Microbiana , Mucor , Tetrazóis , Benzofuranos/farmacologia , Benzofuranos/química , Benzofuranos/síntese química , Mucor/efeitos dos fármacos , Antifúngicos/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Tetrazóis/farmacologia , Tetrazóis/química , Tetrazóis/síntese química , Relação Estrutura-Atividade , Estrutura MolecularRESUMO
3-Tetrazolyl-ß-carbolines were prepared by the Pictet-Spengler approach using a tryptophan analogue as building block, in which the carboxylic acid was replaced by the bioisosteric tetrazole group. Knowing that ß-carbolines are often associated with psychopharmacological effects, the study of the 3-tetrazolyl-ß-carbolines as potential neuroprotective agents against Parkinson's disease was investigated. The evaluation of neuroprotective effects against 1-methyl-4-phenylpyridin-1-ium (MPP+)-induced cytotoxicity allowed to identify compounds with relevant neuroprotective activity. One derivative, 3-(1-benzyl-1H-tetrazol-5-yl)-1-(p-dimethylaminophenyl)-ß-carboline, stood out for its low cytotoxicity and excellent performance, preventing cell death induced by this neurotoxin. The most promising compounds were also evaluated for their neuroprotective properties against iron (III)-induced cytotoxicity. However, only one 3-tetrazolyl-ß-carboline derivative slightly reduced iron-induced cytotoxicity. Overall, the neuroprotective properties of 3-tetrazolyl-ß-carbolines have been demonstrated and this finding may contribute to the development of new therapies for Parkinson's disease.
Assuntos
Carbolinas , Fármacos Neuroprotetores , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/síntese química , Carbolinas/química , Carbolinas/farmacologia , Carbolinas/síntese química , Relação Estrutura-Atividade , Humanos , Estrutura Molecular , Sobrevivência Celular/efeitos dos fármacos , Tetrazóis/química , Tetrazóis/farmacologia , Tetrazóis/síntese química , Relação Dose-Resposta a Droga , AnimaisRESUMO
Human tryptophan dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) are two important targets in cancer immunotherapy. Extensive research has led to a large number of potent IDO inhibitors; in addition, 52 structures of IDO in complex with inhibitors with a wide array of chemical scaffolds have been documented. In contrast, progress in the development of TDO inhibitors has been limited. Only four structures of TDO in complex with competitive inhibitors that compete with the substrate L-tryptophan for binding to the active site have been reported to date. Here we systematically evaluated the structures of TDO in complex with competitive inhibitors with three types of pharmacophores, imidazo-isoindole, indole-tetrazole, and indole-benzotriazole. The comparative assessment of the protein-inhibitor interactions sheds new light into the structure-based design of enzyme-selective inhibitors.
Assuntos
Inibidores Enzimáticos , Indolamina-Pirrol 2,3,-Dioxigenase , Triptofano Oxigenase , Humanos , Triptofano Oxigenase/antagonistas & inibidores , Triptofano Oxigenase/metabolismo , Triptofano Oxigenase/química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenase/química , Relação Estrutura-Atividade , Indóis/química , Indóis/farmacologia , Indóis/metabolismo , Modelos Moleculares , Tetrazóis/química , Tetrazóis/farmacologia , Tetrazóis/metabolismo , Triptofano/química , Triptofano/metabolismo , Imidazóis/química , Imidazóis/farmacologia , Imidazóis/metabolismo , Ligação ProteicaRESUMO
KDM4 histone demethylases became an exciting target for inhibitor development as the evidence linking them directly to tumorigenesis mounts. In this study, we set out to better understand the binding cavity using an X-ray crystallographic approach to provide a detailed landscape of possible interactions within the under-investigated region of KDM4. Our design strategy was based on utilizing known KDM binding motifs, such as nicotinic acid and tetrazolylhydrazides, as core motifs that we decided to enrich with flexible tails to map the distal histone binding site. The resulting X-ray structures of the novel compounds bound to KDM4D, a representative of the KDM4 family, revealed the interaction pattern with distal residues in the histone-binding site. The most prominent protein rearrangement detected upon ligand binding is the loop movement that blocks the accessibility to the histone binding site. Apart from providing new sites that potential inhibitors can target, the novel compounds may prove helpful in exploring the capacity of ligands to bind in sites distal to the cofactor-binding site of other KDMs or 2-oxoglutarate (2OG)-dependent oxygenases. The case study proves that combining a strong small binding motif with flexible tails to probe the binding pocket will facilitate lead discovery in classical drug-discovery campaigns, given the ease of accessing X-ray quality crystals.
Assuntos
Histonas , Histona Desmetilases com o Domínio Jumonji , Piridinas , Tetrazóis , Histona Desmetilases com o Domínio Jumonji/metabolismo , Histona Desmetilases com o Domínio Jumonji/antagonistas & inibidores , Histona Desmetilases com o Domínio Jumonji/química , Tetrazóis/química , Tetrazóis/farmacologia , Tetrazóis/metabolismo , Tetrazóis/síntese química , Piridinas/química , Piridinas/farmacologia , Piridinas/metabolismo , Piridinas/síntese química , Humanos , Sítios de Ligação , Cristalografia por Raios X , Relação Estrutura-Atividade , Histonas/metabolismo , Histonas/química , Estrutura Molecular , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese química , Modelos Moleculares , Relação Dose-Resposta a DrogaRESUMO
The binding affinities and interactions between eight drug candidates, both commercially available (candesartan; losartan; losartan carboxylic acid; nirmatrelvir; telmisartan) and newly synthesized benzimidazole-N-biphenyltetrazole (ACC519T), benzimidazole bis-N,N'-biphenyltetrazole (ACC519T(2) and 4-butyl-N,N-bis([2-(2H-tetrazol-5-yl)biphenyl-4-yl]) methyl (BV6), and the active site of angiotensin-converting enzyme-2 (ACE2) were evaluated for their potential as inhibitors against SARS-CoV-2 and regulators of ACE2 function through Density Functional Theory methodology and enzyme activity assays, respectively. Notably, telmisartan and ACC519T(2) exhibited pronounced binding affinities, forming strong interactions with ACE2's active center, favorably accepting proton from the guanidinium group of arginine273. The ordering of candidates by binding affinity and reactivity descriptors, emerged as telmisartan > ACC519T(2) > candesartan > ACC519T > losartan carboxylic acid > BV6 > losartan > nirmatrelvir. Proton transfers among the active center amino acids revealed their interconnectedness, highlighting a chain-like proton transfer involving tyrosine, phenylalanine, and histidine. Furthermore, these candidates revealed their potential antiviral abilities by influencing proton transfer within the ACE2 active site. Furthermore, through an in vitro pharmacological assays we determined that candesartan and the BV6 derivative, 4-butyl-N,N0-bis[20-2Htetrazol-5-yl)bipheyl-4-yl]methyl)imidazolium bromide (BV6(K+)2) also contain the capacity to increase ACE2 functional activity. This comprehensive analysis collectively underscores the promise of these compounds as potential therapeutic agents against SARS-CoV-2 by targeting crucial protein interactions.
Assuntos
Antagonistas de Receptores de Angiotensina , Enzima de Conversão de Angiotensina 2 , Teoria da Densidade Funcional , SARS-CoV-2 , Enzima de Conversão de Angiotensina 2/metabolismo , Enzima de Conversão de Angiotensina 2/química , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/enzimologia , Humanos , Antagonistas de Receptores de Angiotensina/farmacologia , Antagonistas de Receptores de Angiotensina/química , Compostos de Bifenilo/farmacologia , Compostos de Bifenilo/química , Antivirais/farmacologia , Antivirais/química , Antivirais/síntese química , COVID-19/virologia , Relação Estrutura-Atividade , Estrutura Molecular , Benzimidazóis/farmacologia , Benzimidazóis/química , Tetrazóis/farmacologia , Tetrazóis/química , Tetrazóis/síntese química , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/química , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Tratamento Farmacológico da COVID-19RESUMO
Gelatin polymers made from partially degraded collagen are important biomaterials, but their in-situ analysis suffers from uncontrollable covalent labelling and poor spatial-temporal imaging resolution. Herein, three tetrazolate-tagged tetraphenylethylene fluorophores (TPE-TAs) are introduced for practical fluorogenic labelling of gelatin in aqueous phase and hydrogels. These probes with aggregation-induced emission characteristics offer negligible background and elicit turn-on fluorescence by simply mixing with the gelatin in aqueous phase, giving a detection limit of 0.15â mg/L over a linear dynamic range up to 100â mg/L. This method does not work for collagens and causes minimal interference with gelatin properties. Mechanistic studies reveal a key role for multivalent electrostatic interactions between the abundant basic residues in gelatin (e. g., lysine, hydroxylysine, arginine) and anionic tetrazolate moieties of the lipophilic fluorophore synergistically in spatially rigid macromolecular encapsulation to achieve fluorogenic labelling. The AIE strategy by forming non-covalent fluorophore-gelatin complexes was developed for novel hydrogels that exhibited reversible fluorescence in response to dynamic microstructural changes in the hydrogel scaffold upon salting-in/out treatments, and enabled high spatial-temporal imaging of the fiber network in lyophilized samples. This work may open up avenues for in-situ imaging analysis and evaluation of gelatin-based biomaterials during processes such as inâ vivo degradation and mineralization.
Assuntos
Corantes Fluorescentes , Gelatina , Hidrogéis , Gelatina/química , Hidrogéis/química , Corantes Fluorescentes/química , Água/química , Polímeros/química , Estilbenos/química , Materiais Biocompatíveis/química , Tetrazóis/químicaRESUMO
BACKGROUND: Candesartan cilexetil (CC) is a selective angiotensin II receptor antagonist widely used to treat hypertension. CC is a substrate of P-glycoprotein (P-gp), causing its efflux to the intestinal lumen. It is also practically insoluble in water and has low oral bioavailability (14%). Thus, the current study aims to improve the in vitro dissolution of CC by developing solid dispersion systems (SDSs) and corroborating the in vitro results using a simulated pharmacokinetics study. METHODS: The SDSs were prepared using polyvinyl pyrrolidone (PVP) as a water-soluble polymer, Eudragit E100 (EE100) as a pH-dependent soluble carrier, and a combination of these two polymers. The saturation solubility and the dissolution rate studies of the prepared systems in three dissolution media were performed. The optimized system SE-EE5 was selected for further investigations, including DSC, XRD, FTIR, FESEM, DLS, TSEM, IVIVC convolution study, and stability studies. RESULTS: The solubility of CC significantly increased by a factor of 27,037.344 when formulated as a solid dispersion matrix using EE100 at a ratio of 1:5 (w/w) drug to polymer (SE-EE5 SD), compared to the solubility of the pure drug. The mechanism of solubility and dissolution rate enhancement of CC by the optimized SDS was found to be via the conversion of the crystalline CC into the amorphous form as well as nanoparticles formation upon dissolution at a pH below 5. The instrumental analysis tests showed good compatibility between CC and EE100 and there was no chemical interaction between the drug and the polymer. Moreover, the stability tests confirmed that the optimized system was stable after three months of storage at 25°C. CONCLUSION: The utilization of the solid dispersion technique employing EE 100 polymer as a matrix demonstrates significant success in enhancing the solubility, dissolution, and subsequently, the bioavailability of water-insoluble drugs like CC.
Assuntos
Benzimidazóis , Compostos de Bifenilo , Polímeros , Solubilidade , Tetrazóis , Benzimidazóis/química , Benzimidazóis/farmacocinética , Tetrazóis/química , Tetrazóis/farmacocinética , Compostos de Bifenilo/química , Compostos de Bifenilo/farmacocinética , Polímeros/química , Polímeros/farmacocinética , Povidona/química , Água/química , Concentração de Íons de Hidrogênio , Disponibilidade Biológica , Estabilidade de Medicamentos , Liberação Controlada de Fármacos , AcrilatosRESUMO
As a hybrid weapon, two novel series of pyrazoles, 16a-f and 17a-f, targeting both COX-2 and ACE-1-N-domain, were created and their anti-inflammatory, anti-hypertensive, and anti-fibrotic properties were evaluated. In vitro, 17b and 17f showed COX-2 selectivity (SI = 534.22 and 491.90, respectively) compared to celecoxib (SI = 326.66) and NF-κB (IC50 1.87 and 2.03 µM, respectively). 17b (IC50 0.078 µM) and 17 f (IC50 0.094 µM) inhibited ACE-1 comparable to perindopril (PER) (IC50 0.048 µM). In vivo, 17b decreased systolic blood pressure by 18.6%, 17b and 17f increased serum NO levels by 345.8%, and 183.2%, respectively, increased eNOS expression by 0.97 and 0.52 folds, respectively and reduced NF-κB-p65 and P38-MAPK expression by -0.62, -0.22, -0.53, and -0.24 folds, respectively compared to l-NAME (-0.34, -0.45 folds decline in NF-κB-p65 and P38-MAPK, respectively). 17b reduced ANG-II expression which significantly reversed the cardiac histological changes induced by L-NAME.
Assuntos
Inibidores da Enzima Conversora de Angiotensina , Anti-Inflamatórios , Anti-Hipertensivos , Inibidores de Ciclo-Oxigenase 2 , Pirazóis , Tetrazóis , Pirazóis/farmacologia , Pirazóis/química , Animais , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/química , Anti-Hipertensivos/síntese química , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/química , Inibidores da Enzima Conversora de Angiotensina/síntese química , Tetrazóis/farmacologia , Tetrazóis/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/síntese química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Ratos , Desenho de Fármacos , Masculino , Antifibróticos/farmacologia , Antifibróticos/química , Ciclo-Oxigenase 2/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Humanos , Peptidil Dipeptidase A/metabolismoRESUMO
The solidification of deep eutectic solvent (DES) through wet impregnation techniques on inert solid carriers is an interesting approach that offers better processing attributes and excellent stability. Herein, DES of Fimasartan (FS) was developed to improve its solubility and bioavailability. The selected DES-FS was solidified by wet impregnation method employing Nesulin US2 and Aerosil 200. The SeDeM-SLA (solid-liquid adsorption) system was employed to investigate flow attributes of solidified DES-FS. Further, the selected solidified DES-FS (A) was characterized by Fourier transforms infrared spectroscopy (FTIR), Powder X-ray diffraction (PXRD), Differential scanning calorimetry (DSC), Scanning electron microscopy (SEM). The DES comprising Choline Chloride (ChCl): Glycerol (Gly) (1:3) revealed maximum drug solubility (35.6 ± 2.2 mg/mL) and thus opted for solidification. Solidification through wet impregnation was employed using 1:0.5 ratios (DES-FS to carriers). The Index of Good Flow (IGF) value was calculated from the SeDeM-SLA expert system, which indicates the better flow characteristics of solidified DES-FS, particularly with Neusilin US2 [SDES-FS (A)]. The solid-state evaluation data of SDS-FS (A) suggested a transition of FS to an amorphous form, resulting in an increment in solubility and dissolution. A similar trend was reported in the in vivo pharmacokinetic study, which indicated a 2.9 folds increment in the oral bioavailability of FS. Furthermore, excellent stability, i.e., a shelf life of 28.44 months, reported by SDES-FS (A) in accelerated stability studies, suggests better formulation perspectives. In a nutshell, the present study evokes the potentiality of performing solidification through wet impregnation and successful implementation of the SeDeM-SLA expert model, which could find wide applications in pharmaceutical science.
Assuntos
Disponibilidade Biológica , Pirimidinas , Solubilidade , Solventes , Tetrazóis , Solventes/química , Animais , Tetrazóis/química , Tetrazóis/administração & dosagem , Tetrazóis/farmacocinética , Pirimidinas/química , Pirimidinas/farmacocinética , Pirimidinas/administração & dosagem , Varredura Diferencial de Calorimetria/métodos , Ratos , Masculino , Compostos de Bifenilo/química , Química Farmacêutica/métodos , Difração de Raios X/métodos , Composição de Medicamentos/métodos , Glicerol/química , Portadores de Fármacos/química , Colina/química , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Estabilidade de Medicamentos , Microscopia Eletrônica de Varredura/métodosRESUMO
In this investigation, we successfully isolated and purified natural diarylheptanoids using an orthogonal offline two-dimensional RPLC × SFC approach, employing only the phenyl/tetrazole stationary phase. First, a styrene-divinylbenzene matrix medium pretreatment liquid chromatography system effectively processed chlorophyll-containing plant extract solution with a recovery rate of 33.8 %, obviating the need for concentration steps. Subsequently, an offline two-dimensional RPLC × SFC employing only the phenyl/tetrazole stationary phase achieved a remarkable 96.38 % orthogonality and was established and utilized in the preparative separation and purification of natural products. Finally, the constructed single stationary phase highly orthogonal RPLC × SFC system was successfully applied in the preparative separation and purification of natural diarylheptanoids from the Saxifraga tangutica target fraction and yielded four diarylheptanoids with purities exceeding 95 %.
Assuntos
Cromatografia de Fase Reversa , Cromatografia com Fluido Supercrítico , Diarileptanoides , Tetrazóis , Diarileptanoides/química , Diarileptanoides/isolamento & purificação , Cromatografia de Fase Reversa/métodos , Cromatografia com Fluido Supercrítico/métodos , Tetrazóis/química , Tetrazóis/isolamento & purificação , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificaçãoRESUMO
Thirty-one novel albaconazole derivatives were designed and synthesized based on our previous work. All compounds exhibited potent in vitro antifungal activities against seven pathogenic fungi. Among them, tetrazole compound D2 was the most potent antifungal with MIC values of <0.008, <0.008, and 2 µg/mL against Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus, respectively, the three most common and critical priority pathogenic fungi. In addition, compound D2 also exhibited potent activity against fluconazole-resistant C. auris isolates. Notably, compound D2 showed a lower inhibitory activity in vitro against human CYP450 enzymes as well as a lower inhibitory effect on the hERG K+ channel, indicating a low risk of drug-drug interactions and QT prolongation. Moreover, with improved pharmacokinetic profiles, compound D2 showed better in vivo efficacy than albaconazole at reducing fungal burden and extending the survival of C. albicans-infected mice. Taken together, compound D2 will be further investigated as a promising candidate.
Assuntos
Antifúngicos , Candida albicans , Cryptococcus neoformans , Testes de Sensibilidade Microbiana , Tetrazóis , Antifúngicos/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Antifúngicos/uso terapêutico , Tetrazóis/farmacologia , Tetrazóis/química , Tetrazóis/síntese química , Tetrazóis/farmacocinética , Tetrazóis/uso terapêutico , Animais , Humanos , Candida albicans/efeitos dos fármacos , Camundongos , Cryptococcus neoformans/efeitos dos fármacos , Relação Estrutura-Atividade , Aspergillus fumigatus/efeitos dos fármacos , Descoberta de Drogas , Farmacorresistência Fúngica/efeitos dos fármacos , Candidíase/tratamento farmacológico , Inibidores das Enzimas do Citocromo P-450/farmacologia , Inibidores das Enzimas do Citocromo P-450/síntese química , Inibidores das Enzimas do Citocromo P-450/química , Sistema Enzimático do Citocromo P-450/metabolismoRESUMO
Neurological disorders are the leading cause of a large number of mortalities and morbidities. Nitrogen heterocyclic compounds have been pivotal in exhibiting wide array of therapeutic applications. Among them, tetrazole is a ubiquitous class of organic heterocyclic compounds that have attracted much attention because of its unique structural and chemical properties, and a wide range of pharmacological activities comprising anti-convulsant effect, antibiotic, anti-allergic, anti-hypertensive to name a few. Owing to significant chemical and biological properties, the present review aimed at highlighting the recent advances in tetrazole derivatives with special emphasis on their role in the management of neurological diseases. Besides, in-depth structure-activity relationships, molecular docking studies, and associated modes of action of tetrazole derivatives evident in in vitro, in vivo preclinical, and clinical studies have been discussed.
Assuntos
Doenças do Sistema Nervoso , Tetrazóis , Animais , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Doenças do Sistema Nervoso/tratamento farmacológico , Relação Estrutura-Atividade , Tetrazóis/química , Tetrazóis/farmacologia , Tetrazóis/síntese química , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologiaRESUMO
Carboxylic acids are key pharmacophoric elements in many molecules. They can be seen as a problem by some, due to perceived permeability challenges, potential for high plasma protein binding and the risk of forming reactive metabolites due to acyl-glucuronidation. By others they are viewed more favorably as they can decrease lipophilicity by adding an ionizable center which can be beneficial for solubility, and can add enthalpic interactions with the target protein. However, there are many instances where the replacement of a carboxylic acid with a bioisosteric group is required. This has led to the development of a number of ionizable groups which sufficiently mimic the carboxylic acid functionality whilst improving, for example, the metabolic profile of the molecule in question. An alternative strategy involves replacement of the carboxylate by neutral functional groups. This review initially details carefully selected examples whereby tetrazoles, acyl sulfonamides or isoxazolols have been beneficially utilized as carboxylic acid bioisosteres altering physicohemical properties, interactions with the target and metabolism and/or pharmacokinetics, before delving further into the binding mode of carboxylic acid derivatives with their target proteins. This analysis highlights new ways to consider the replacement of carboxylic acids by neutral bioisosteric groups which either rely on hydrogen bonds or cation-π interactions. It should serve as a useful guide for scientists working in drug discovery.
Assuntos
Ácidos Carboxílicos , Ácidos Carboxílicos/química , Descoberta de Drogas , Ligação Proteica , Sulfonamidas/química , Tetrazóis/químicaRESUMO
It was found that Argentatins A and B triterpenoids make up approximately 20-30 % of the waste resin produced from the industrial processes to isolate rubber from P. argentatum. We have developed an efficient protocol for synthesizing cycloartane-16ß-ol derivatives by opening the oxepane ring of argentatin B acetate (2) with BF3-OEt2. Although three new cycloartenol derivatives showed high cytotoxicity against PC-3 and HCT-15 cancer cell lines, nevertheless, the best results were obtained for (16ß,24R) -(16,24-epoxy-cycloartan-2(1H)-ylidene) acetate (14), compound with intact oxepane ring. These results indicate that the substituents in the argentatin nucleus and a side chain account for the cytotoxic activity. However, according to the selectivity index (SI), 14 did not show selectivity activity to cancer cell lines over the HaCat noncancerous cell line. The compound 3ß,16ß-Dihydroxy-cycloartan-24-one (5), synthesized by oxepane opening, demonstrated high cytotoxic activity to cancer cell lines and showed a remarkable selectivity to cancer cell lines over the noncancerous ones. These results suggest that 5 could lead to the development of new anticancer compounds.
Assuntos
Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Relação Estrutura-Atividade , Proliferação de Células/efeitos dos fármacos , Triterpenos/farmacologia , Triterpenos/química , Triterpenos/síntese química , Tetrazóis/farmacologia , Tetrazóis/síntese química , Tetrazóis/química , Estrutura Molecular , Relação Dose-Resposta a Droga , Sobrevivência Celular/efeitos dos fármacosRESUMO
Bioconjugation chemistry has emerged as a powerful tool for the modification of diverse biomolecules under mild conditions. Tetrazole, initially proposed as a bioorthogonal photoclick handle for 1,3-dipolar cyclization with alkenes, was later demonstrated to possess broader photoreactivity with carboxylic acids, serving as a versatile bioconjugation and photoaffinity labeling probe. In this study, we unexpectedly discovered and validated the photoreactivity between tetrazole and primary amine to afford a new 1,2,4-triazole cyclization product. Given the significance of functionalized N-heterocycles in medicinal chemistry, we successfully harnessed the serendipitously discovered reaction to synthesize both pharmacologically relevant DNA-encoded chemical libraries (DELs) and small molecule compounds bearing 1,2,4-triazole scaffolds. Furthermore, the mild reaction conditions and stable 1,2,4-triazole linkage found broad application in photoinduced bioconjugation scenarios, spanning from intramolecular peptide macrocyclization and templated DNA reaction cross-linking to intermolecular photoaffinity labeling of proteins. Triazole cross-linking products on lysine side chains were identified in tetrazole-labeled proteins, refining the comprehensive understanding of the photo-cross-linking profiles of tetrazole-based probes. Altogether, this tetrazole-amine bioconjugation expands the current bioconjugation toolbox and creates new possibilities at the interface of medicinal chemistry and chemical biology.
Assuntos
Aminas , Proteínas , Aminas/química , Ciclização , Proteínas/química , Tetrazóis/química , DNA , Química ClickRESUMO
Nitrile imines produced by photodissociation of 2,5-diaryltetrazoles undergo cross-linking reactions with amide groups in peptide-tetrazole (tet-peptide) conjugates and a tet-peptide-dinucleotide complex. Tetrazole photodissociation in gas-phase ions is efficient, achieving ca. 50% conversion with 2 laser pulses at 250 nm. The formation of cross-links was detected by CID-MS3 that showed structure-significant dissociations by loss of side-chain groups and internal peptide segments. The structure and composition of cross-linking products were established by a combination of UV-vis action spectroscopy and cyclic ion mobility mass spectrometry (c-IMS). The experimental absorption bands were found to match the bands calculated for vibronic absorption spectra of nitrile imines and cross-linked hydrazone isomers. The calculated collision cross sections (CCSth) for these ions were related to the matching experimental CCSexp from multipass c-IMS measurements. Loss of N2 from tet-peptide conjugates was calculated to be a mildly endothermic reaction with ΔH0 = 80 kJ mol-1 in the gas phase. The excess energy in the photolytically formed nitrile imine is thought to drive endothermic proton transfer, followed by exothermic cyclization to a sterically accessible peptide amide group. The exothermic nitrile imine reaction with peptide amides is promoted by proton transfer and may involve an initial [3 + 2] cycloaddition followed by cleavage of the oxadiazole intermediate. Nucleophilic groups, such as cysteine thiol, did not compete with the amide cyclization. Nitrile imine cross-linking to 2'-deoxycytidylguanosine was found to be >80% efficient and highly specific in targeting guanine. The further potential for exploring nitrile-imine cross-linking for biomolecular structure analysis is discussed.