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1.
Int J Mol Sci ; 23(21)2022 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-36362328

RESUMO

Asthma, which is a chronic inflammatory disease of the airways, is usually caused by allergens in which various structures and immune cells are involved. Ephedra sinica, the most commonly used Chinese medicine, has significant clinical effects on asthma, but its components are complex and the mechanism of action has not been fully elucidated. Among its components, we identified an amide alkaloid (EB-A) and investigated its anti-asthmatic activity and the underlying mechanisms. In this study, we replicated an OVA-sensitized/challenged allergic asthma mouse model, and divided the mice into a model (OVA) group, positive drug (Y, 0.5 mg/kg/day) group, and EB-A treatment with low (Low, 10 mg/kg/day) and high dose (High, 20 mg/kg/day) groups. Asthma-related features were analyzed through the airway hyperresponsiveness (AHR), cough and wheeze indexes, allergen-specific IgE, prostaglandin D2 (PDG2), and lung histology in mice. The levels of apoptosis and reactive oxygen species (ROS) in the primary lung cells, cytokines in the serum and broncho-alveolar lavage fluid (BALF), and proteinase-activated receptor-2 (PAR2) pathway activation in the lung tissue were measured to evaluate the inflammatory injury and lung epithelial barrier damage in the mice. Dendritic cell (DC) maturation and mast cell (MC) activation were verified in vitro and in vivo. Furthermore, the effect of a PAR2 activation in lung epithelial cells on the maturation of DCs was evaluated by the co-culture system of (human bronchial epithelial cell lines) 16HBE and bone marrow-derived dendritic cells (BMDCs). The results showed that EB-A inhibited the typical asthmatic phenotypes, as well as lung injury and inflammation, MC activation and degranulation, and DC maturation in the OVA-sensitized/challenged BALB/c mice. In addition, EB-A inhibited the expression of PAR2 in the lung epithelial cells and significantly interfered with the maturation of DCs after inhibiting PAR2. Taken together, our study firstly demonstrated that EB-A could ameliorate OVA-induced allergic asthma by inhibiting MC activation and DC maturation, and the molecular mechanism of EB-A's anti-asthmatic activity might be mediated by inhibiting PAR2. Our data provide a molecular justification for the use of EB-A in the treatment of allergic asthma.


Assuntos
Alcaloides , Antiasmáticos , Asma , Ephedra sinica , Humanos , Camundongos , Animais , Ovalbumina , Mastócitos/metabolismo , Amidas/farmacologia , Asma/metabolismo , Antiasmáticos/efeitos adversos , Camundongos Endogâmicos BALB C , Líquido da Lavagem Broncoalveolar , Pulmão/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Receptor PAR-2/metabolismo , Células Dendríticas , Alcaloides/metabolismo
2.
Int J Mol Sci ; 23(21)2022 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-36362364

RESUMO

α-Lipoic acid is a sulfur-containing nutrient endowed with pleiotropic actions and a safe biological profile selected to replace the unsaturated alkyl acid of capsaicin with the aim of obtaining lipoic amides potentially active as a TRPV1 ligand and with significant antioxidant properties. Thus, nine compounds were obtained in good yields following a simple synthetic procedure and tested for their functional TRPV1 activity and radical-scavenger activity. The safe biological profile together with the protective effect against hypoxia damage as well as the in vitro antioxidant properties were also evaluated. Although less potent than capsaicin, almost all lipoic amides were found to be TRPV1 agonists and, specifically, compound 4, the lipoic analogue of capsaicin, proved to be the best ligand in terms of efficacy and potency. EPR experiments and in vitro biological assays suggested the potential protective role against oxidative stress of the tested compounds and their safe biological profile. Compounds 4, 5 and 9 significantly ameliorated the mitochondrial membrane potential caused by hypoxia condition and decreased F2-isoprostanes, known markers of oxidative stress. Thus, the experimental results encourage further investigation of the therapeutic potential of these lipoic amides.


Assuntos
Capsaicina , Canais de Cátion TRPV , Humanos , Canais de Cátion TRPV/metabolismo , Antioxidantes/farmacologia , Amidas/farmacologia , Ligantes , Estresse Oxidativo , Hipóxia
3.
J Enzyme Inhib Med Chem ; 37(1): 2725-2741, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36189734

RESUMO

The group of 18 new amide derivatives of mycophenolic acid (MPA) and selected heterocyclic amines was synthesised as potential immunosuppressive agents functioning as inosine-5'-monophosphate dehydrogenase (IMPDH) uncompetitive inhibitors. The synthesis of 14 of them employed uronium-type activating system (TBTU/HOBt/DIPEA) while 4 of them concerned phosphonic acid anhydride method (T3P/Py) facilitating amides to be obtained in moderate to excellent yields without the need of phenolic group protection. Most of optimised protocols did not require complicated reaction work-ups, including chromatographic, solvent-consuming methods. The biological activity assay was performed on the T-Jurkat cell line and peripheral mononuclear blood cells (PBMCs) which are both dedicated for antiproliferative activity determination. Each of designed derivatives was characterised by reduced cytotoxicity and benzoxazole analogue (A2) revealed the most promising activity. Subsequently, an observed structure-activity relationship was discussed.


Assuntos
Imunossupressores , Ácido Micofenólico , Amidas/farmacologia , Aminas , Anidridos , Benzoxazóis , Inibidores Enzimáticos/farmacologia , IMP Desidrogenase , Imunossupressores/química , Inosina , Ácido Micofenólico/química , Solventes
4.
Int J Biol Macromol ; 222(Pt B): 1778-1788, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36195228

RESUMO

p-Coumaric acid and caffeic acid were grafted onto chitosan through a non-radical synthesis method to improve the properties of chitosan and expand its application in food industry. Structural characterization demonstrated that the -COOH of the two phenolic acids were bonded to the -NH2 of the chitosan and formed an acylamino. The grafting ratios of p-coumaric acid-modified chitosan (Cm-CTS) and caffeic acid-modified chitosan (Cf-CTS) reached 10.30 % and 9.78 %, respectively. After modification, the water solubility of the chitosan greatly improved from 9.33 % (native chitosan, Nt-CTS) to 77.33 % (Cm-CTS) and 100 % (Cf-CTS). Besides, the involvement of phenolic acid and caffeic acid endowed the chitosan with strengthened antioxidation and antibacterial activities against Escherichia coli and Staphylococcus aureus. Nt-CTS and the modified chitosans were coated on the pork surface. The results indicated that Nt-CTS effectively inhibited pork spoilage and the modified chitosans could further prolong the shelf life of pork.


Assuntos
Quitosana , Carne de Porco , Carne Vermelha , Animais , Suínos , Quitosana/química , Amidas/farmacologia , Ácidos Cafeicos/química , Antibacterianos/farmacologia , Escherichia coli
5.
Life Sci ; 310: 121081, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36273630

RESUMO

AIMS: Sialic acid derivatives (SA-derivatives) provide a nanomedicine platform for tumor-targeted delivery and treatment, and allow modulation of immunosuppressive tumor microenvironments with excellent therapeutic effects. Further, the multi-reactive groups of sialic acid (SA) contribute to the diversity of SA derivatives, which inevitably has implications for drug delivery systems and tumor therapy. However, relevant research remains lacking at present. Therefore, this study aimed to explore the effects of SA derivatives on SA-mediated drug delivery systems. MAIN METHODS: Four SA-derivatives with different linking bonds (ester and amide bonds), different linking groups (hydroxyl and carboxyl), and different linking objects (cholesterol, octadecanoic acid, and octadecylamine) were synthesized and the respective SA derivative-modified doxorubicin liposomes were prepared. In-depth research was conducted using both cells and animals. KEY FINDINGS: We found that an SA-cholesterol conjugate (SA-CH; linking bond, amide bond; linking group, carboxyl; linking object, cholesterol) could improve liposome stability, reduce liposome adsorption to plasma proteins, and enhance the targeting of liposomes for killing tumor-associated macrophages (TAMs). Reduced TAMs in the immunosuppressive tumor microenvironment lead to enhanced tumor infiltration of CD8+ T cells. SIGNIFICANCE: The results of this experiment provide clarity for research and development on SA-derivatives and a theoretical basis for clinical trials of SA-derivative-modified nanoparticles.


Assuntos
Lipossomos , Neoplasias , Animais , Lipossomos/química , Microambiente Tumoral , Ácido N-Acetilneuramínico/química , Ácido N-Acetilneuramínico/farmacologia , Linfócitos T CD8-Positivos/metabolismo , Neoplasias/tratamento farmacológico , Colesterol/química , Amidas/farmacologia , Linhagem Celular Tumoral
6.
Sci Rep ; 12(1): 17673, 2022 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-36271103

RESUMO

Scarcity of effective treatments against sepsis is daunting, especially under the contemporary standpoints on antibiotics resistance, entailing the development of alternative treatment strategies. Here, we describe the design and antibiotic adjuvant properties of a new lipopeptide-like pentamer, decanoyl-bis.diaminobutyrate-aminododecanoyl-diaminobutyrate-amide (C10BBc12B), whose sub-maximal tolerated doses combinations with inefficient antibiotics demonstrated systemic efficacies in murine models of peritonitis-sepsis and urinary-tract infections. Attempts to shed light into the mechanism of action using membrane-active fluorescent probes, suggest outer-membrane interactions to dominate the pentamer's adjuvant properties, which were not associated with typical inner-membrane damages or with delayed bacterial growth. Yet, checkerboard titrations with low micromolar concentrations of C10BBc12B exhibited unprecedented capacities in potentiation of hydrophobic antibiotics towards Gram-negative ESKAPE pathogens, with an apparent low propensity for prompting resistance to the antibiotics. Assessment of the pentamer's potentiating activities upon efflux inhibition incites submission of a hitherto unreported, probable action mechanism implicating the pentamer's de-facto capacity to hijack bacterial efflux pumps for boosting its adjuvant activity through repetitive steps including outer-membrane adhesion, translocation and subsequent expulsion.


Assuntos
Antibacterianos , Sepse , Camundongos , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Antibacterianos/química , Bactérias Gram-Negativas , Corantes Fluorescentes/farmacologia , Lipopeptídeos/farmacologia , Lipopeptídeos/uso terapêutico , Amidas/farmacologia , Testes de Sensibilidade Microbiana , Farmacorresistência Bacteriana Múltipla
7.
Bioorg Med Chem Lett ; 78: 129021, 2022 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-36228968

RESUMO

This Letter describes our ongoing effort to improve the clearance of selective M5 antagonists. Herein, we report the replacement of the previously disclosed piperidine amide (4, disclosed in Part 1) with a pyrrolidine amide core. Several compounds within this series provided good potency, subtype selectivity, and low to moderate clearance profiles. Interestingly, the left-hand side SAR for this series diverged from our earlier efforts.


Assuntos
Amidas , Pirrolidinas , Amidas/farmacologia , Pirrolidinas/farmacologia , Cinética , Antagonistas Muscarínicos
8.
J Med Chem ; 65(20): 14180-14200, 2022 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-36256875

RESUMO

The Gram-negative pathogen Pseudomonas aeruginosa causes severe infections mainly in immunocompromised or cystic fibrosis patients and is able to resist antimicrobial treatments. The extracellular lectin LecB plays a key role in bacterial adhesion to the host and biofilm formation. For the inhibition of LecB, we designed and synthesized a set of fucosyl amides, sulfonamides, and thiourea derivatives. Then, we analyzed their binding to LecB in competitive and direct binding assays. We identified ß-fucosyl amides as unprecedented high-affinity ligands in the two-digit nanomolar range. X-ray crystallography of one α- and one ß-anomer of N-fucosyl amides in complex with LecB revealed the interactions responsible for the high affinity of the ß-anomer at atomic level. Further, the molecules showed good stability in murine and human blood plasma and hepatic metabolism, providing a basis for future development into antibacterial drugs.


Assuntos
Lectinas , Pseudomonas aeruginosa , Humanos , Camundongos , Animais , Pseudomonas aeruginosa/metabolismo , Lectinas/metabolismo , Ligantes , Amidas/farmacologia , Amidas/metabolismo , Antibacterianos/farmacologia , Antibacterianos/metabolismo , Sulfonamidas/metabolismo , Tioureia/metabolismo , Biofilmes
9.
Antiviral Res ; 208: 105444, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36243175

RESUMO

Infections by pathogenic New World mammarenaviruses (NWM)s, including Junín virus (JUNV), can result in a severe life-threatening viral hemorrhagic fever syndrome. In the absence of FDA-licensed vaccines or antivirals, these viruses are considered high priority pathogens. The mammarenavirus envelope glycoprotein complex (GPC) mediates pH-dependent fusion between viral and cellular membranes, which is essential to viral entry and may be vulnerable to small-molecule inhibitors that disrupt this process. ARN-75039 is a potent fusion inhibitor of a broad spectrum of pseudotyped and native mammarenaviruses in cell culture and Tacaribe virus infection in mice. In the present study, we evaluated ARN-75039 against pathogenic JUNV in the rigorous guinea pig infection model. The compound was well-tolerated and had favorable pharmacokinetics supporting once-per-day oral dosing in guinea pigs. Importantly, significant protection against JUNV challenge was observed even when ARN-75039 was withheld until 6 days after the viral challenge when clinical signs of disease are starting to develop. We also show that ARN-75039 combination treatment with favipiravir, a viral polymerase inhibitor, results in synergistic activity in vitro and improves survival outcomes in JUNV-challenged guinea pigs. Our findings support the continued development of ARN-75039 as an attractive therapeutic candidate for treating mammarenaviral hemorrhagic fevers, including those associated with NWM infection.


Assuntos
Arenaviridae , Febre Hemorrágica Americana , Febres Hemorrágicas Virais , Vírus Junin , Cobaias , Camundongos , Animais , Febre Hemorrágica Americana/tratamento farmacológico , Pirazinas/farmacologia , Pirazinas/uso terapêutico , Amidas/farmacologia , Amidas/uso terapêutico , Antirretrovirais/farmacologia
10.
Cell Mol Biol (Noisy-le-grand) ; 68(6): 25-30, 2022 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-36227682

RESUMO

During lung resection surgery, the blood supply to the lungs increases the intrapulmonary shunt and reduces arterial oxygenation in patients. Ventilation anesthesia of a lung may affect oxygenation. The present study aimed to compare intravenous anesthesia with and without thoracic epidural block (dezocine and ropivacaine) on oxygen saturation during lung ventilation in patients undergoing lung resection surgery. For this purpose, this study was performed as a double-blind, randomized clinical trial. Sixty patients who were candidates for lung resection were divided into two intervention groups (thoracic epidural block with dezocine and ropivacaine and intravenous anesthesia) and a control group (placebo thoracic epidural block and intravenous anesthesia). Hemodynamic variables, Aldert score, and possible complications were compared between the two groups before surgery and after recovery. Also, the expression level of the IDO gene was evaluated using the real-time PCR technique. SPSS, t-test, Mann-Whitney U, Chi-square, and Fisher performed data analysis and comparison.  The results showed that the changes in hemodynamic variables and PaO2, SaO2, and ETCO2 were not statistically significant between the two groups. Aldrete's score at entry and exit of recovery was similar between the two groups. During the recovery period, the percentage of pain or chills in the group under complete intravenous anesthesia was significantly higher. There was no significant difference between the two groups regarding the frequency of nausea and hypotension. Also, the results of IDO gene expression showed that general anesthesia with the thoracic epidural block (dezocine and ropivacaine), which is involved in inducing immunological tolerance and suppressing immune responses, has no significant effect. The stress of performing surgery before surgery can play a role in suppressing the patient's immunity, and anesthesia of the thoracic epidural block (dezocine and ropivacaine) has no significant effect on IDO expression. In general, thoracic epidural block with complete intravenous anesthesia has no significant effect on oxygen saturation in ventilated lungs compared with intravenous anesthesia alone. Nevertheless, this combination significantly reduces postoperative pain and chills.


Assuntos
Anestésicos Locais , Bloqueio Nervoso , Amidas/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes , Expressão Gênica , Humanos , Pulmão/metabolismo , Pulmão/cirurgia , Bloqueio Nervoso/métodos , Oxigênio/metabolismo , Saturação de Oxigênio , Ventilação Pulmonar , Ropivacaina/farmacologia , Ropivacaina/uso terapêutico , Tetra-Hidronaftalenos
11.
ChemMedChem ; 17(21): e202200355, 2022 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-36089546

RESUMO

To improve the metabolic stability of a 4,4'-oxybisbenzoyl-based novel and potent (nanomolar-range IC50 ) antiplasmodial agent previously described by us, in silico-guided structure-activity relationship (SAR) campaigns have been conducted to substitute its peptide decorations with more metabolically stable residues. The effects of the various structural modifications were then correlated with the antiplasmodial activity in vitro in phenotypic assays. Among the several derivatives synthetized and compared with the 3D-pharmacophoric map of the original lead, a novel compound, characterized by a western tert-butyl glycine residue and an eastern 1S,2S-aminoacyclohexanol, showed low-nanomolar-range antiplasmodial activity, no signs of cross-resistance and, most importantly, 47-fold improved Phase I metabolic stability when incubated with human liver microsomes. These results highlight the efficacy of in silico-guided SAR campaigns which will allow us to further optimize the structure of the new lead aiming at testing its efficacy in vivo using different routes of administration.


Assuntos
Antimaláricos , Malária Falciparum , Humanos , Antimaláricos/química , Plasmodium falciparum , Amidas/farmacologia , Amidas/uso terapêutico , Inibidores do Crescimento/farmacologia , Inibidores do Crescimento/uso terapêutico , Malária Falciparum/tratamento farmacológico , Relação Estrutura-Atividade
12.
Bioorg Med Chem Lett ; 76: 128988, 2022 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-36113671

RESUMO

The lack of potent and selective tool compounds with pharmaceutically favorable properties limits the in vivo understanding of muscarinic acetylcholine receptor subtype 5 (M5) biology. Previously, we presented a highly potent and selective M5 antagonist VU6019650 with a suboptimal clearance profile as our second-generation tool compound. Herein, we disclose our ongoing efforts to generate next-generation M5 antagonists with improved clearance profiles. A mix and match approach between VU6019650 (lead) and VU0500325 (HTS hit) generated a piperidine amide-based novel M5 antagonist series. Several analogs within this series, including 29f, provided good on-target potency with improved clearance profiles, though room for improvement remains.


Assuntos
Amidas , Receptores Muscarínicos , Amidas/farmacologia , Piperidinas/farmacologia , Cinética
13.
Anesthesiology ; 137(6): 687-703, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36170651

RESUMO

BACKGROUND: Long-lasting local anesthetic use for perioperative pain control is limited by possible cardiotoxicity (e.g., arrhythmias and contractile depression), potentially leading to cardiac arrest. Off-target cardiac sodium channel blockade is considered the canonical mechanism behind cardiotoxicity; however, it does not fully explain the observed toxicity variability between anesthetics. The authors hypothesize that more cardiotoxic anesthetics (e.g., bupivacaine) differentially perturb other important cardiomyocyte functions (e.g., calcium dynamics), which may be exploited to mitigate drug toxicity. METHODS: The authors investigated the effects of clinically relevant concentrations of racemic bupivacaine, levobupivacaine, or ropivacaine on human stem cell-derived cardiomyocyte tissue function. Contractility, rhythm, electromechanical coupling, field potential profile, and intracellular calcium dynamics were quantified using multielectrode arrays and optical imaging. Calcium flux differences between bupivacaine and ropivacaine were probed with pharmacologic calcium supplementation or blockade. In vitro findings were correlated in vivo using an anesthetic cardiotoxicity rat model (females; n = 5 per group). RESULTS: Bupivacaine more severely dysregulated calcium dynamics than ropivacaine in vitro (e.g., contraction calcium amplitude to 52 ± 11% and calcium-mediated repolarization duration to 122 ± 7% of ropivacaine effects, model estimate ± standard error). Calcium supplementation improved tissue contractility and restored normal beating rhythm (to 101 ± 6%, and 101 ± 26% of control, respectively) for bupivacaine-treated tissues, but not ropivacaine (e.g., contractility at 80 ± 6% of control). Similarly, calcium pretreatment mitigated anesthetic-induced arrhythmias and cardiac depression in rats, improving animal survival for bupivacaine by 8.3 ± 2.4 min, but exacerbating ropivacaine adverse effects (reduced survival by 13.8 ± 3.4 min and time to first arrhythmia by 12.0 ± 2.9 min). Calcium channel blocker nifedipine coadministration with bupivacaine, but not ropivacaine, exacerbated cardiotoxicity, supporting the role of calcium flux in differentiating toxicity. CONCLUSIONS: Our data illustrate differences in calcium dynamics between anesthetics and how calcium may mitigate bupivacaine cardiotoxicity. Moreover, our findings suggest that bupivacaine cardiotoxicity risk may be higher than for ropivacaine in a calcium deficiency context.


Assuntos
Anestésicos Locais , Cálcio , Feminino , Ratos , Humanos , Animais , Anestésicos Locais/toxicidade , Cardiotoxicidade , Miócitos Cardíacos , Amidas/farmacologia , Bupivacaína/toxicidade , Ropivacaina/toxicidade , Arritmias Cardíacas/induzido quimicamente
14.
Chembiochem ; 23(22): e202200490, 2022 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-36112057

RESUMO

Neisseria meningitidis is a Gram-negative opportunistic pathogen that is responsible for causing human diseases with high mortality, such as septicemia and meningitis. The molecular mechanisms N. meningitidis employ to manipulate the immune system, translocate the mucosal and blood-brain barriers, and exert virulence are largely unknown. Human-associated bacteria encode a variety of bioactive small molecules with growing evidence for N-acyl amides as being important signaling molecules. However, only a small fraction of these metabolites has been identified from the human microbiota thus far. Here, we heterologously expressed an N-acyltransferase encoded in the obligate human pathogen N. meningitidis and identified 30 N-acyl amides with representative members serving as agonists of the G-protein coupled receptor (GPCR) S1PR4. During this process, we also characterized two mammalian N-acyl amides derived from the bovine medium. Both groups of metabolites suppress anti-inflammatory interleukin-10 signaling in human macrophage cell types, but they also suppress the pro-inflammatory interleukin-17A+ population in TH 17-differentiated CD4+ T cells.


Assuntos
Neisseria meningitidis , Humanos , Bovinos , Animais , Esfingosina , Amidas/farmacologia , Virulência , Transdução de Sinais , Mamíferos
15.
Chem Biodivers ; 19(11): e202200231, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36152343

RESUMO

Soluble epoxide hydrolase enzyme (sEH) is one of the most promising and emerging targets to develop drugs for multiple disease indications, including hypertension, diabetes, stroke, dyslipidemia, pain, etc. Most inhibitor scaffolds have a urea or amide moiety to mimic the active-site transition state. In this regard, we developed a series of amide sEH inhibitors with a pyrimidin-2-ol ring as a new secondary pharmacophore, which was subjected to in vitro evaluation. Compound 4w (4-chloro-N-{4-[6-(4-chlorophenyl)-2-hydroxypyrimidin-4-yl]phenyl}benzamide), which contains 4-chloro substituent in both terminal phenyl rings, exhibited the most inhibitory activity against sEH with an IC50 value of 1.2 nM. Molecular docking analysis of the synthesized compounds revealed that the greater number of hydrogen bonding interactions of the amide group as the primary pharmacophore with Asp-353, Tyr-383, and Tyr-466 as the key catalytic residue triad of the enzyme played a critical role and led to a more favorable binding affinity. Pharmacokinetic properties of the synthesized compounds were calculated in silico, and all ADMET indices fell within acceptable ranges. Altogether, the results of this work could provide useful information on 4,6-diphenylpyrimidin-2-olas sEH inhibitors which can be utilized in further development in this area.


Assuntos
Amidas , Epóxido Hidrolases , Epóxido Hidrolases/química , Epóxido Hidrolases/metabolismo , Amidas/farmacologia , Amidas/química , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Ureia/farmacologia , Ureia/química , Inibidores Enzimáticos/química , Solubilidade
16.
J Enzyme Inhib Med Chem ; 37(1): 2598-2604, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36131622

RESUMO

Human respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infection worldwide. Until now, there are no licenced vaccines or effective antiviral drugs against RSV infections. In our previous work, we found 2-((1H-indol-3-yl)thio/sulfinyl)-N-pheny acetamide derivatives (4-49 C and 1-HB-63) being a novel inhibitor against RSV in vitro. Here, we explored the underlying mechanism of 2-((1H-indol-3-yl)thio/sulfinyl)-N-pheny acetamide derivatives to inhibit RSV replication in vitro and disclosed that 4-49 C worked as the inhibitor of membrane fusion and 1-HB-63 functioned at the stage of RSV genome replication/transcription. Yet, both of them could not inhibit RSV infection of BALB/c mice by using RSV-Luc, in vivo imaging and RT-qPCR analyses, for which it may be due to the fast metabolism in vivo. Our work suggests that further structural modification and optimisation of 2-((1H-indol-3-yl) thio/sulfinyl)-N-pheny acetamide derivative are needed to obtain drug candidates with effective anti-RSV activities in vivo.


Assuntos
Infecções por Vírus Respiratório Sincicial , Vírus Sincicial Respiratório Humano , Acetamidas/farmacologia , Amidas/farmacologia , Animais , Antivirais/farmacologia , Antivirais/uso terapêutico , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Vírus Sincicial Respiratório Humano/genética , Replicação Viral
17.
J Enzyme Inhib Med Chem ; 37(1): 2679-2701, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36154552

RESUMO

A new series of vinyl amide-, imidazolone-, and triazinone-linked combretastatin A-4 analogues have been designed and synthesised. These compounds have been evaluated for their cytotoxic activity against MDA-MB-231 breast cancer cells. The triazinone-linked combretastatin analogues (6 and 12) exhibited the most potent cytotoxic activity, in sub-micromolar concentration compared with combretastatin A-4 as a reference standard. The results of ß-tubulin polymerisation inhibition assay appear to correlate well with the ability to inhibit ß-tubulin polymerisation. Additionally, these compounds were subjected to biological assays relating to cell cycle aspects and apoptosis induction. In addition, the most potent compound 6 was loaded on PEG-PCL modified diamond nanoparticles (PEG-PCL-NDs) and F4 was picked as the optimum formula. F4 exhibited enhanced solubility and release over the drug suspension. In the comparative cytotoxic activity, PEG-PCL modified F4 was capable of diminishing the IC50 by around 2.89 times for nude F4, while by 3.48 times relative to non-formulated compound 6.


Assuntos
Antineoplásicos , Nanopartículas , Amidas/farmacologia , Antineoplásicos/farmacologia , Bibenzilas , Linhagem Celular Tumoral , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Estrutura Molecular , Solubilidade , Estilbenos , Relação Estrutura-Atividade , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/farmacologia
18.
Int J Biol Macromol ; 219: 1337-1350, 2022 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-36057297

RESUMO

Massive bleeding is a great threat to the life safety of patients, which is a challenging clinical problem. Therefore, it is urgent to develop a kind of multifunctional dressing material with hemostatic ability and antibacterial performance to promote wound healing and repair. To resolve this issue, in this study, a carboxymethyl chitosan (CMCS)/sodium alginate (SA)/oxidized dextran (ODE) (CSO) multifunctional hydrogel was developed. The hydrogel could rapidly gel through Schiff base reaction and amide reaction and firmly adhere to the skin at the wound, to realize the fast hemostasis. Importantly, it was verified that the hydrogel could prevent the Staphylococcus aureus-caused wound infection, owing to the antibacterial effect of CMCS and ODE. In addition, the CSO hydrogel had good water retention capacity and was able to mimic the three-dimensional structure of the natural extracellular matrix, thereby promoting wound repair in mice. In vitro whole-blood clotting assay demonstrated that red blood cells could be adhered to the surface of hydrogel, showing good hemostasis in rat liver injury and tail amputation models. Together with the biocompatible feature, CSO hydrogel holds a great application prospect in hemostasis and wound healing.


Assuntos
Quitosana , Hemostáticos , Infecção dos Ferimentos , Alginatos/química , Amidas/farmacologia , Animais , Antibacterianos/farmacologia , Bandagens , Quitosana/química , Dextranos/farmacologia , Hemostasia , Hemostáticos/farmacologia , Hidrogéis/química , Hidrogéis/farmacologia , Camundongos , Ratos , Bases de Schiff/farmacologia , Água/farmacologia , Cicatrização
19.
Sci Rep ; 12(1): 16246, 2022 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-36171229

RESUMO

Many benzoxazole-based and similar scaffolds were reported to have wide-range of anticancer activities. In this study, four series of benzoxazole derivatives were designed by combining benzoxazole scaffold with different amines via a reversed phenyl amide linker to produce the compounds of series A, B and C. A fourth new hybrid of benzoxazole with 1,2,3 triazole ring (series D) was also designed. The designed compounds were synthesized and screened for their anti-breast cancer activity against MDA-MB-231 and MCF-7 cell lines using MTT assay. The most potent cytotoxic compounds; 11-14, 21, 22, 25-27 were further evaluated for their in vitro PARP-2 enzyme inhibition. Compounds 12 and 27 proved to be the most active PARP-2 inhibitors with IC50 values of 0.07 and 0.057 µM, respectively. Compounds 12 and 27 caused cell cycle arrest in mutant MCF-7 cell line at G2/M and G1/S phase, respectively and they possessed significant apoptosis-promoting activity. Docking results of compounds 12 and 27 into PARP-2 pocket demonstrated binding interactions comparable to those of olaparib. Their predicted pharmacokinetic parameters and oral bioavailability appeared to be appropriate. Collectively, it could be concluded that compounds 12 and 27 are promising anti-breast cancer agents that act as PARP-2 inhibitors with potent apoptotic activity.


Assuntos
Antineoplásicos , Neoplasias da Mama , Amidas/farmacologia , Aminas/farmacologia , Antineoplásicos/química , Benzoxazóis/química , Benzoxazóis/farmacologia , Neoplasias da Mama/tratamento farmacológico , Proliferação de Células , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Relação Estrutura-Atividade , Triazóis/farmacologia
20.
Phytochemistry ; 203: 113340, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35987401

RESUMO

Medicinal plants have been used to treat different diseases throughout the human history namely in traditional medicine. Most of the plants mentioned in this review article belong among them, including those that are widely spread in the nature, counted frequently to be food and nutrition plants and producing pharmacologically important secondary metabolites. Triterpenoids represent an important group of plant secondary metabolites displaying emerging pharmacological importance. This review article sheds light on four selected triterpenoids, oleanolic, ursolic, betulinic and platanic acid, and on their amide derivatives as important natural or semisynthetic agents in cancer treatment, and, in part, in pathogenic microbe treatment. A literature search was made in the Web of Science for the given key words covering the required area of secondary plant metabolites and their amide derivatives. The most recently published findings on the biological activity of the selected triterpenoids, and on the structures and biological activity of their relevant amide derivatives have been summarized therein. Mainly anti-cancer effects, and, in part, antimicrobial and other effects of the four selected triterpenoids and their amide derivatives have also been reviewed. A comparison of the effects of the parent plant products and those of their amide derivatives has been made.


Assuntos
Neoplasias , Ácido Oleanólico , Plantas Medicinais , Triterpenos , Amidas/farmacologia , Amidas/uso terapêutico , Humanos , Neoplasias/tratamento farmacológico , Ácido Oleanólico/química , Plantas Medicinais/metabolismo , Triterpenos/química , Triterpenos/farmacologia , Triterpenos/uso terapêutico
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