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1.
Drug Des Devel Ther ; 16: 4021-4039, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36439378

RESUMO

Purpose: This study aims to determine the analgesic activity of 1,4-dihydropyridine hybrid benzamide derivatives. These hybrid derivatives were synthesized, and their analgesic activity was studied. The synthesis method applied was a one-step reaction involving a green chemistry approach. Methods: The compounds were prepared via the amination method with a yield ranging between 82% and 93%. The title compounds were confirmed by means of IR, 1H and 13C NMR, and mass spectral analyses. The pharmacological activity of all the synthesized compounds was evaluated, and the analgesic activities were monitored in vivo (by tail immersion methods), with a digital analgesiometer. The drug response and damage of tail ata concentration of 10 mg/kg were measured by tail-flicking latency. Results: The activity of compound 2c (81.35% activity at 5mg/kg) can be correlated with its salicylamidemoiety (13.99% activity at 5mg/kg), and diclofenac showed comparable activity (79.21% activity at 5mg/kg reference drugs). Compound 2c has a higher potential to inhibit COX proteins compared to diclofenac. The drug-like nature of the molecule 2c corresponds to its ADME properties. Conclusion: In this study, all the synthesized compounds were found to possess significant analgesic activities; particularly, the performance of compound 2c is excellent. Thus, the preparative method described is an apt route for developing novel therapeutic formulations.


Assuntos
Diclofenaco , Compostos Heterocíclicos , Simulação de Acoplamento Molecular , Anti-Inflamatórios não Esteroides/química , Analgésicos/química , Benzamidas/farmacologia
2.
Int J Mol Sci ; 23(19)2022 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-36232394

RESUMO

To find novel herbicidal compounds with high activity and broad spectrum, a series of phenylpyridine moiety-containing α-trifluoroanisole derivatives were designed, synthesized, and identified via nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS). Greenhouse-based herbicidal activity assays revealed that compound 7a exhibited > 80% inhibitory activity against Abutilon theophrasti, Amaranthus retroflexus, Eclipta prostrate, Digitaria sanguinalis, and Setaria viridis at a dose of 37.5 g a.i./hm2, which was better than fomesafen. Compound 7a further exhibited excellent herbicidal activity against Abutilon theophrasti and Amaranthus retroflexus in this greenhouse setting, with respective median effective dose (ED50) values of 13.32 and 5.48 g a.i./hm2, both of which were slightly superior to fomesafen (ED50 = 36.39, 10.09 g a.i./hm2). The respective half-maximal inhibitory concentration (IC50) for compound 7a and fomesafen when used to inhibit the Nicotiana tabacum protoporphyrinogen oxidase (NtPPO) enzyme, were 9.4 and 110.5 nM. The docking result of compound 7a indicated that the introduction of 3-chloro-5-trifluoromethylpyridine and the trifluoromethoxy group was beneficial to the formation of stable interactions between these compounds and NtPPO. This work demonstrated that compound 7a could be further optimized as a PPO herbicide candidate to control various weeds.


Assuntos
Amaranthus , Herbicidas , Benzamidas/farmacologia , Herbicidas/química , Herbicidas/farmacologia , Plantas Daninhas , Protoporfirinogênio Oxidase/química , Relação Estrutura-Atividade , Tabaco
3.
Eur J Med Chem ; 243: 114790, 2022 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-36183505

RESUMO

Poly(ADP-ribose) polymerase-1 (PARP-1) is one of the key members of DNA repair enzymes that is responsible for the repair of DNA single-strand breaks. Inhibition of PARP-1 has been demonstrated to be a promising strategy to selectively kill tumor cells by targeting DNA repair pathway. Herein, a series of novel urea-based benzamide derivatives were designed and synthesized based on the structure-based drug design strategy. The anticancer activities against five human cancer cell lines including HCT116, MDA-MB-231, HeLa, A579 and A375 were evaluated and the preliminary structure-activity relationships were summarized. Among them, compounds 23f and 27f exhibited potent antiproliferative effects against HCT116 cells with IC50 values of 7.87 µM and 8.93 µM, respectively. Moreover, both compounds displayed excellent PARP-1 inhibitory activities with IC50 values of 5.17 nM and 6.06 nM, respectively. Mechanistic investigations showed that 23f and 27f could effectively inhibit colony formation and cell migration of HCT116 cells. Furthermore, 23f and 27f could cause cell cycle arrest at G2/M phase, and induce apoptosis by upregulating the expression of Bax and cleaved Caspase-3 and downregulating the expression of Caspase-3 and Bcl-2 in HCT116 cells. In addition, molecular docking studies provided the rational binding modes of these compounds in complex with PARP-1. Collectively, these results suggested that 23f and 27f could serve as promising drug candidates for further investigation.


Assuntos
Antineoplásicos , Inibidores de Poli(ADP-Ribose) Polimerases , Humanos , Inibidores de Poli(ADP-Ribose) Polimerases/química , Simulação de Acoplamento Molecular , Caspase 3/metabolismo , Poli(ADP-Ribose) Polimerases/metabolismo , Ureia/farmacologia , Linhagem Celular Tumoral , Antineoplásicos/química , Proliferação de Células , Poli(ADP-Ribose) Polimerase-1 , Relação Estrutura-Atividade , Benzamidas/farmacologia
4.
Int J Biol Macromol ; 222(Pt A): 1487-1499, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36195231

RESUMO

Chronic myelogenous leukemia (CML) is characterized by Philadelphia translocation arising from Bcr-Abl fusion gene, which encodes abnormal oncoprotein showing tyrosine kinase (TK) function. Certain mutations in kinase domain, off-target effects and resistance problems of current TK inhibitors require the discovery of novel Abl TK inhibitors. For this purpose, herein, we synthesized new gypsogenin derivatives (6a-l) and evaluated their anticancer effects towards CML cells along with healthy cell line and different leukemic cells. Among these compounds, compound 6l was found as the most active anti-leukemic agent against K562 CML cells compared to imatinib exerting less cytotoxicity towards PBMCs (healthy). This compound also revealed significant anti-leukemic effects against Jurkat cell line. Besides, compound 6l enhanced apoptosis in CML cells with 52.4 % when compared with imatinib (61.8 %) and inhibited Abl TK significantly with an IC50 value of 13.04 ± 2.48 µM in a large panel of kinases accentuating Abl TK-mediated apoptosis of compound 6l in CML cells. Molecular docking outcomes showed that compound 6l formed mainly crucial interactions in the ATP-binding cleft of Abl TK similar to that of imatinib. Ultimately, in silico pharmacokinetic evaluation of compound 6l indicated that this compound was endowed with anti-leukemic drug candidate features.


Assuntos
Proteínas de Fusão bcr-abl , Leucemia Mielogênica Crônica BCR-ABL Positiva , Humanos , Mesilato de Imatinib/farmacologia , Proteínas de Fusão bcr-abl/genética , Proteínas de Fusão bcr-abl/metabolismo , Simulação de Acoplamento Molecular , Benzamidas/farmacologia , Pirimidinas/farmacologia , Piperazinas , Resistencia a Medicamentos Antineoplásicos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Apoptose , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química
5.
Bioorg Med Chem ; 74: 117069, 2022 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-36283251

RESUMO

C-Abl is involved in various biological processes and plays an important role in neurodegenerative diseases, especially Parkinson's disease (PD). Previous studies have found that nilotinib shows a neuroprotective effect in cell and animal models of PD by inhibiting the activation of c-Abl. But the low blood-brain barrier permeability and potential toxicity limit the further use of nilotinib in PD. Based on molecular modeling studies, a series of 4-methyl-3-(pyridin-2-ylamino)benzamide derivatives were designed and synthesized. In particular, compound 9a exhibited significant inhibitory activity against c-Abl and a potent neuroprotective effect against MPP+-induced SH-SY5Y cell death. Moreover, 9a not only displayed lower cell toxicity compared with nilotinib, but also showed higher oral bioavailability and proper permeability of the blood-brain barrier. This paper provides 4-methyl-3-(pyridin-2-ylamino)benzamide derivatives as a new scaffold for c-Abl inhibitor with potential neuroprotective effect.


Assuntos
Neuroblastoma , Fármacos Neuroprotetores , Doença de Parkinson , Animais , Humanos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/metabolismo , Neuroblastoma/metabolismo , Barreira Hematoencefálica/metabolismo , Doença de Parkinson/metabolismo , Benzamidas/farmacologia , Benzamidas/metabolismo , Linhagem Celular Tumoral
6.
Bioorg Chem ; 129: 106192, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36265355

RESUMO

Capsid assembly modulators (CAMs) represent a novel class of antiviral agents targeting hepatitis B virus (HBV) capsid to disrupt the assembly process. NVR 3-778 is the first CAM to demonstrate antiviral activity in patients infected with HBV. However, the relatively low aqueous solubility and moderate activity in the human body halted further development of NVR 3-778. To improve the anti-HBV activity and the drug-like properties of NVR 3-778, we designed and synthesized a series of NVR 3-778 derivatives. Notably, phenylboronic acid-bearing compound 7b (EC50 = 0.83 ± 0.33 µM, CC50 = 19.4 ± 5.0 µM) displayed comparable anti-HBV activity to NVR 3-778 (EC50 = 0.73 ± 0.20 µM, CC50 = 23.4 ± 7.0 µM). Besides, 7b showed improved water solubility (328.8 µg/mL, pH 7) compared to NVR 3-778 (35.8 µg/mL, pH 7). Size exclusion chromatography (SEC) and quantification of encapsidated viral RNA were used to demonstrate that 7b behaves as a class II CAM similar to NVR 3-778. Moreover, molecular dynamics (MD) simulations were conducted to rationalize the structure-activity relationships (SARs) of these novel derivatives and to understand their key interactions with the binding pocket, which provide useful indications for guiding the further rational design of more effective anti-HBV drugs.


Assuntos
Antivirais , Benzamidas , Capsídeo , Desenho de Fármacos , Vírus da Hepatite B , Montagem de Vírus , Humanos , Antivirais/síntese química , Antivirais/química , Antivirais/farmacologia , Benzamidas/síntese química , Benzamidas/química , Benzamidas/farmacologia , Capsídeo/efeitos dos fármacos , Capsídeo/metabolismo , Proteínas do Capsídeo/metabolismo , Vírus da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/fisiologia , Montagem de Vírus/efeitos dos fármacos
7.
J Agric Food Chem ; 70(43): 13839-13848, 2022 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-36270026

RESUMO

A series of pyrazol-5-yl-benzamide derivatives containing the oxazole group were designed and synthesized as potential SDH inhibitors. According to the results of the bioassays, most target compounds displayed moderate-to-excellent in vitro antifungal activities against Valsa mali, Sclerotinia scleotiorum, Alternaria alternata, and Botrytis cinerea. Among them, compounds C13, C14, and C16 exhibited more excellently inhibitory activities against S. sclerotiorum than boscalid (EC50 = 0.96 mg/L), with EC50 values of 0.69, 0.26, and 0.95 mg/L, respectively. In vivo experiments on rape leaves and cucumber leaves showed that compounds C13 and C14 exhibited considerable protective effects against S. sclerotiorum than boscalid. SEM analysis indicated that compounds C13 and C14 significantly destroyed the typical structure and morphology of S. scleotiorum hyphae. In the respiratory inhibition effect assays, compounds C13 (28.0%) and C14 (33.9%) exhibited a strong inhibitory effect on the respiration rate of S. sclerotiorum mycelia, which was close to boscalid (30.6%). The results of molecular docking indicated that compounds C13 and C14 could form strong interactions with the key residues TRP O:173, ARG P:43, TYR Q:58, and MET P:43 of the SDH. Furthermore, the antifungal mechanism of these derivatives was demonstrated by the SDH enzymatic inhibition assay. These results demonstrate that compounds C13 and C14 can be developed into novel SDH inhibitors for crop protection.


Assuntos
Rhizoctonia , Succinato Desidrogenase , Succinato Desidrogenase/metabolismo , Antifúngicos/farmacologia , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Oxazóis/farmacologia , Benzamidas/farmacologia
8.
Clin Lymphoma Myeloma Leuk ; 22 Suppl 2: S395-S396, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36164121

RESUMO

CONTEXT: Covalent Bruton's Tyrosine Kinase (BTK) inhibitors (BTKi) have transformed the management of relapsed mantle cell lymphoma (MCL), but many patients will require additional treatment. Pirtobrutinib is a highly selective, non-covalent (reversible) BTKi that inhibits both wild type and C481-mutated BTK with equal low nM potency. OBJECTIVE: Determine whether pirtobrutinib is superior to investigator's choice of covalent BTKi in patients with previously treated, BTKi-naïve MCL. DESIGN: BRUIN MCL-321 is a randomized, open-label, global phase 3 study comparing pirtobrutinib monotherapy versus investigator's choice of covalent BTKi monotherapy (ibrutinib, acalabrutinib, or zanubrutinib) in patients with previously treated, BTKi-naïve MCL. Approximately 500 patients will be randomized 1:1. Randomization will be stratified by sMIPI risk (low/intermediate vs high), comparator BTKi (ibrutinib vs acalabrutinib/zanubrutinib), and number of prior lines of therapy (1 vs ≥ 2). SETTING: Global; community hospitals, academic medical centers. PATIENTS: Eligible patients are adults aged ≥18 years with a confirmed diagnosis of MCL who received ≥ 1 prior line of systemic therapy for MCL that did not include a prior BTKi. Patients must have measurable disease per Lugano criteria and must have progressed on or relapsed following the most recent line of therapy prior to study enrollment. Key exclusion criteria include a history of current or prior CNS involvement, significant cardiovascular disease, stroke, or intracranial hemorrhage within 6 months of randomization, and allogeneic stem cell transplant (SCT), autologous SCT or chimeric antigen receptor (CAR) T-cell therapy within 60 days of randomization. INTERVENTIONS: Pirtobrutinib monotherapy versus investigator's choice of covalent BTKi monotherapy. MAIN OUTCOME MEASURES: The primary endpoint is progression-free survival (PFS) per Lugano criteria assessed by an independent review committee, with the goal of demonstrating the superiority of pirtobrutinib over the investigator's choice of covalent BTKi. Secondary endpoints include overall response rate, duration of response, investigator-assessed PFS per Lugano criteria, overall survival, event-free survival, time to treatment failure, time to next treatment, PFS2 (time from randomization to disease progression on next line of treatment or death from any cause), safety and tolerability, and patient-reported outcomes. This global study is currently enrolling patients (NCT04662255). RESULTS: Trial in Progress. CONCLUSIONS: Trial in Progress.


Assuntos
Linfoma de Célula do Manto , Receptores de Antígenos Quiméricos , Adolescente , Adulto , Tirosina Quinase da Agamaglobulinemia , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Humanos , Linfoma de Célula do Manto/patologia , Pirazinas
9.
Plant J ; 112(3): 664-676, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36069460

RESUMO

Vacuolar H+ -ATPase (V-ATPase) has diverse functions related to plant development and growth. It creates the turgor pressure that drives cell growth by generating the energy needed for the active transport of solutes across the tonoplast. V-ATPase is a large protein complex made up of multiheteromeric subunits, some of which have unknown functions. In this study, a forward genetics-based strategy was employed to identify the vab3 mutant, which displayed resistance to isoxaben, a cellulose synthase inhibitor that could induce excessive transverse cell expansion. Map-based cloning and genetic complementary assays demonstrated that V-ATPase B subunit 3 (VAB3) is associated with the observed insensitivity of the mutant to isoxaben. Analysis of the vab3 mutant revealed defective ionic homeostasis and hypersensitivity to salt stress. Treatment with a V-ATPase inhibitor exacerbated ionic tolerance and cell elongation defects in the vab3 mutant. Notably, exogenous low-dose Ca2+ or Na+ could partially restore isoxaben resistance of the vab3 mutant, suggesting a relationship between VAB3-regulated cell growth and ion homeostasis. Taken together, the results of this study suggest that the V-ATPase subunit VAB3 is required for cell growth and ion homeostasis in Arabidopsis.


Assuntos
Arabidopsis , ATPases Vacuolares Próton-Translocadoras , Arabidopsis/metabolismo , ATPases Vacuolares Próton-Translocadoras/genética , ATPases Vacuolares Próton-Translocadoras/metabolismo , Benzamidas/farmacologia , Benzamidas/metabolismo , Homeostase
10.
J Biol Chem ; 298(11): 102539, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36179791

RESUMO

Recent studies have reported that the peroxisome proliferator-activated receptor gamma (PPARγ) pathway is activated in approximately 40% of patients with muscle-invasive bladder cancer. This led us to investigate pharmacological repression of PPARγ as a possible intervention strategy. Here, we characterize PPARγ antagonists and inverse agonists and find that the former behave as silent ligands, whereas inverse agonists (T0070907 and SR10221) repress downstream PPARγ target genes leading to growth inhibition in bladder cancer cell lines. To understand the mechanism, we determined the ternary crystal structure of PPARγ bound to T0070907 and the corepressor (co-R) peptide NCOR1. The structure shows that the AF-2 helix 12 (H12) rearranges to bind inside the ligand-binding domain, where it forms stabilizing interactions with the compound. This dramatic movement in H12 unveils a large interface for co-R binding. In contrast, the crystal structure of PPARγ bound to a SR10221 analog shows more subtle structural differences, where the compound binds and pushes H12 away from the ligand-binding domain to allow co-R binding. Interestingly, we found that both classes of compound promote recruitment of co-R proteins in biochemical assays but with distinct conformational changes in H12. We validate our structural models using both site-directed mutagenesis and chemical probes. Our findings offer new mechanistic insights into pharmacological modulation of PPARγ signaling.


Assuntos
PPAR gama , Neoplasias da Bexiga Urinária , Humanos , PPAR gama/metabolismo , Ligantes , Benzamidas/farmacologia
11.
Proc Natl Acad Sci U S A ; 119(39): e2205509119, 2022 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-36129942

RESUMO

Androgen receptor (AR) messenger RNA (mRNA) alternative splicing variants (AR-Vs) are implicated in castration-resistant progression of prostate cancer (PCa), although the molecular mechanism underlying the genesis of AR-Vs remains poorly understood. The CDK12 gene is often deleted or mutated in PCa and CDK12 deficiency is known to cause homologous recombination repair gene alteration or BRCAness via alternative polyadenylation (APA). Here, we demonstrate that pharmacological inhibition or genetic inactivation of CDK12 induces AR gene intronic (intron 3) polyadenylation (IPA) usage, AR-V expression, and PCa cell resistance to the antiandrogen enzalutamide (ENZ). We further show that AR binds to the CCNK gene promoter and up-regulates CYCLIN K expression. In contrast, ENZ decreases AR occupancy at the CCNK gene promoter and suppresses CYCLIN K expression. Similar to the effect of the CDK12 inhibitor, CYCLIN K degrader or ENZ treatment promotes AR gene IPA usage, AR-V expression, and ENZ-resistant growth of PCa cells. Importantly, we show that targeting BRCAness induced by CYCLIN K down-regulation with the PARP inhibitor overcomes ENZ resistance. Our findings identify CYCLIN K down-regulation as a key driver of IPA usage, hormonal therapy-induced AR-V expression, and castration resistance in PCa. These results suggest that hormonal therapy-induced AR-V expression and therapy resistance are vulnerable to PARP inhibitor treatment.


Assuntos
Antineoplásicos , Ciclinas , Inibidores de Poli(ADP-Ribose) Polimerases , Neoplasias de Próstata Resistentes à Castração , Receptores Androgênicos , Antagonistas de Androgênios/farmacologia , Antineoplásicos/farmacologia , Benzamidas/farmacologia , Linhagem Celular Tumoral , Ciclinas/genética , Regulação para Baixo , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Íntrons , Masculino , Nitrilas/farmacologia , Feniltioidantoína/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Poliadenilação/genética , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , RNA Mensageiro/genética , Receptores Androgênicos/genética
12.
Int J Mol Sci ; 23(18)2022 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-36142591

RESUMO

Combined inhibition of vascular endothelial growth factor receptor (VEGFR) and the programmed cell death protein 1 (PD-1) pathways has shown efficacy in multiple cancers; however, the clinical outcomes show limited benefits and the unmet clinical needs still remain and require improvement in efficacy. Using murine colon carcinoma (CT26) allograft models, we examined the efficacy and elucidated novel tumor microenvironment (TME) remodeling mechanisms underlying the combination of chidamide (a benzamide-based class l histone deacetylase inhibitor; brand name in Taiwan, Kepida®) with VEGF receptor tyrosine kinase inhibitor (TKIs; cabozantinib/regorafenib, etc.) and immune checkpoint inhibitors (ICIs; anti-PD-1/anti-PD-L1/anti-CTLA-4 antibodies). The TME was assessed using flow cytometry and RNA-sequencing to determine the novel mechanisms and their correlation with therapeutic effects in mice with significant treatment response. Compared with ICI alone or cabozantinib/regorafenib + ICI, combination of chidamide + cabozantinib/regorafenib + ICI increased the tumor response and survival benefits. In particular, treatment of CT26-bearing mice with chidamide + regorafenib + anti-PD-1 antibody showed a better objective response rate (ORR) and overall survival (OS). Similar results were observed in anti-PD-1 treatment-resistant mice. After treatment with this optimal combination, in the TME, RNA-sequencing revealed that downregulated mRNAs were correlated with leukocyte migration, cell chemotaxis, and macrophage gene sets, and flow cytometry analysis showed that the cell numbers of myeloid-derived polymorphonuclear suppressor cells and tumor-associated macrophages were decreased. Accordingly, chidamide + regorafenib + anti-PD-1 antibody combination therapy could trigger a novel TME remodeling mechanism by attenuating immunosuppressive cells, and restoring T-cell activation to enhance ORR and OS. Our studies also showed that the addition of Chidamide to the regorafenib + anti-PD-1 Ab combination could induce a durable tumor-specific response by attenuating immune suppression in the TME. In addition, this result suggests that TME remodeling, mediated by epigenetic immunomodulator combined with TKI and ICI, would be more advantageous for achieving a high objective response rate, when compared to TKI plus ICI or ICI alone, and maintaining long-lasting antitumor activity.


Assuntos
Neoplasias do Colo , Microambiente Tumoral , Aminopiridinas , Anilidas , Animais , Benzamidas/farmacologia , Linhagem Celular Tumoral , Neoplasias do Colo/tratamento farmacológico , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Camundongos , Compostos de Fenilureia , Receptor de Morte Celular Programada 1 , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas , RNA , Receptores de Fatores de Crescimento do Endotélio Vascular/uso terapêutico , Fator A de Crescimento do Endotélio Vascular
13.
Life Sci ; 309: 121014, 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-36179814

RESUMO

Positive allosteric modulators (PAMs) of metabotropic glutamate receptor type 5 (mGluR5) potentiate positive receptor response and may be effective for the treatment of schizophrenia and cognitive disorders. Although crystal structures of mGluR5 complexed with the negative allosteric modulators (NAMs) are available, no crystal structure of mGluR5 complexed with PAM has been reported to date. Thus, conformational changes associated with the binding of PAMs to mGluR5 remain elusive. Here, a PAM CDPPB, and two NAMs MTEP and MFZ10-7 used as a negative control, were docked to the crystal structure. The docked complexes were submitted to molecular dynamics simulations to examine the activation of the PAM system. An MM/GBSA binding energy calculation was performed to estimate binding strength. Furthermore, molecular switch analysis was done to get insights into conformational changes of the receptor. The PAM CDPPB displays a stronger binding affinity for mGluR5 and induces conformational changes. Also, a salt bridge between TM3 and TM7, corresponding to the ionic lock switch in class A GPCRs is found to be broken. The PAM-induced receptor conformation is more like the agonist-induced conformation than the antagonist-induced conformation, suggesting that PAM works by inducing conformation change and stabilizing the active receptor conformation.


Assuntos
Benzamidas , Simulação de Dinâmica Molecular , Regulação Alostérica , Benzamidas/farmacologia , Pirazóis/farmacologia
14.
J Am Chem Soc ; 144(36): 16638-16646, 2022 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-36044733

RESUMO

A variety of diseases are associated with tyrosine kinase enzymes that activate many proteins via signal transduction cascades. The similar ATP-binding pockets of these tyrosine kinases make it extremely difficult to design selective covalent inhibitors. The present study explores the contribution of the chemical reaction steps to the selectivity of the commercialized inhibitor acalabrutinib over the Bruton's tyrosine kinase (BTK) and the interleukin-2-inducible T-cell kinase (ITK). Ab initio and empirical valence bond (EVB) simulations of the two kinases indicate that the most favorable reaction path involves a water-assisted mechanism of the 2-butynamide reactive group of acalabrutinib. BTK reacts with acalabrutinib with a substantially lower barrier than ITK, according to our calculated free-energy profile and kinetic simulations. Such a difference is due to the microenvironment of the active site, as further supported by a sequence-based analysis of specificity determinants for several commercialized inhibitors. Our study involves a new approach of simulating directly the IC50 and inactivation efficiency keff, instead of using the standard formulas. This new strategy is particularly important in studies of covalent inhibitors with a very exothermic bonding step. Overall, our results demonstrate the importance of understanding the chemical reaction steps in designing selective covalent inhibitors for tyrosine kinases.


Assuntos
Benzamidas , Inibidores de Proteínas Quinases , Tirosina Quinase da Agamaglobulinemia , Benzamidas/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Pirazinas , Tirosina
15.
J Med Chem ; 65(16): 11365-11387, 2022 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-35969197

RESUMO

Herein, we report a series of selective sub-nanomolar inhibitors against butyrylcholinesterase (BChE). These compounds, bearing a novel N-benzyl benzamide scaffold, inhibited BChE with IC50 from picomolar to nanomolar. The inhibitory activity was confirmed by the surface plasmon resonance assay, showing a sub-nanomolar KD value, which revealed that the compounds exert the inhibitory effect through directly binding to BChE. Several compounds showed neuroprotective effects verified by the oxidative damage model. Furthermore, the safety of S11-1014 and S11-1033 was demonstrated by the in vivo acute toxicity test. In the behavior study, 0.5 mg/kg S11-1014 or S11-1033 exhibited a marked therapeutic effect, which was almost equal to the treatment with 1 mg/kg rivastigmine, against the cognitive impairment induced by Aß1-42. The pharmacokinetics studies characterized the metabolic stability of S11-1014. Thus, N-benzyl benzamide inhibitors are promising compounds with drug-like properties for improving cognitive dysfunction, providing a potential strategy for the treatment of Alzheimer's disease.


Assuntos
Doença de Alzheimer , Fármacos Neuroprotetores , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Relação Estrutura-Atividade
16.
J Med Chem ; 65(15): 10481-10505, 2022 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-35868003

RESUMO

Given the close association between inflammation and cancer, combining anti-inflammation therapy is prominent to improve the anticancer effect. Based on I-1, a series of agents targeting COX-2 and Topo I were designed by combining fenamates and phenols. The optimal compound 1H-30 displayed an enhanced inhibitory effect on COX-2 compared to tolfenamic acid and I-1 and showed better inhibition of Topo I than I-1. Importantly, 1H-30 showed potential anticancer effects and suppressed the activation of the NF-κB pathway in cancer cells. 1H-30 inhibited the nuclear translocation of NF-κB and suppressed the production of NO, COX-2, and IL-1ß in RAW264.7. In vivo, 1H-30 showed acceptable pharmacokinetic parameters, decreased the tumor growth without affecting the body weight, down-regulated COX-2 and MMP-9, and induced apoptosis in the CT26.WT tumor-bearing mice. Accordingly, 1H-30 as a potential Topo I/COX-2 inhibitor which possessed anti-inflammatory and anticancer effects, with inhibition of the NF-κB pathway, is promising for gastrointestinal cancer therapy.


Assuntos
Inibidores Enzimáticos/farmacologia , Neoplasias Gastrointestinais , NF-kappa B , Animais , Anti-Inflamatórios/farmacologia , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Ciclo-Oxigenase 2/metabolismo , DNA Topoisomerases Tipo I/farmacologia , Dinoprostona , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos , NF-kappa B/metabolismo , Transdução de Sinais , Inibidores da Topoisomerase I
17.
Sci Rep ; 12(1): 11954, 2022 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-35831379

RESUMO

Plant-parasitic nematodes (PPN) are responsible for severe yield losses in crop production. Management is challenging as effective and safe means are rare. Recently, it has been discovered that the succinate dehydrogenase (SDH) inhibitor fluopyram is highly effective against PPN while accompanying an excellent safety profile. Here we show that fluopyram is a potent inhibitor of SDH in nematodes but not in mammals, insects and earthworm, explaining the selectivity on molecular level. As a consequence of SDH inhibition, fluopyram impairs ATP generation and causes paralysis in PPN and Caenorhabditis elegans. Interestingly, efficacy differences of fluopyram amongst PPN species can be observed. Permanent exposure to micromolar to nanomolar amounts of fluopyram prevents Meloidogyne spp. and Heterodera schachtii infection and their development at the root. Preincubation of Meloidogyne incognita J2 with fluopyram followed by a recovery period effectively reduces gall formation. However, the same procedure does not inhibit H. schachtii infection and development. Sequence comparison of sites relevant for ligand binding identified amino acid differences in SDHC which likely mediate selectivity, coincidently revealing a unique amino acid difference within SDHC conserved among Heterodera spp. Docking and C. elegans mutant studies suggest that this minute difference mediates altered sensitivity of H. schachtii towards fluopyram.


Assuntos
Caenorhabditis elegans , Tylenchoidea , Aminoácidos/farmacologia , Animais , Benzamidas/farmacologia , Mamíferos , Piridinas
18.
Bioorg Chem ; 127: 105898, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35792317

RESUMO

The elevation of epoxy-fatty acids through inhibition of soluble epoxide hydrolase (sEH) is efficient for the treatment of inflammatory and pain-related diseases. Herein, we reported the discovery of a series of benzamide derivatives containing urea moiety as sEH inhibitors. Intensive structural modifications led to the identification of compound A34 as a potent sEH inhibitor with good physicochemical properties. Molecular docking revealed an additional hydrogen-bonding interaction between the unique amide scaffold and Phe497, contributing to sEH inhibition potency enhancement. Compound A34 exhibited outstanding inhibitory activity against human sEH, with an IC50 value of 0.04 ± 0.01 nM and a Ki value of 0.2 ± 0.1 nM. It also showed moderate systemic drug exposure and oral bioavailability in vivo metabolism studies. In carrageenan-induced inflammatory pain rat model, compound A34 exhibited a better therapeutic effect compared to t-AUCB and Celecoxib. Metabolism studies in vivo together with an inflammatory pain evaluation suggest that A34 may be a viable lead compound for the development of highly potent sEH inhibitors.


Assuntos
Inibidores Enzimáticos , Epóxido Hidrolases , Animais , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Humanos , Simulação de Acoplamento Molecular , Dor , Ratos , Solubilidade , Ureia/farmacologia
19.
Cell Mol Biol (Noisy-le-grand) ; 67(4): 115-120, 2022 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-35809296

RESUMO

High-dose chemotherapy and stem cell transplantation are the best treatment options in patients with multiple myeloma. Numerous medicines have been studied as a maintenance treatment after transplantation. Still, the use of medications that, in addition to their maintenance properties, eliminate or delay relapse of the disease has always been researchers' purpose. Therefore, this study was performed to evaluate the efficacy of MST-312 after stem cell transplantation in patients with multiple myeloma. For this purpose, 73 patients with multiple myeloma after stem cell transplantation were studied. Thirty-five patients were in the case group, and 37 patients were in the control group. The case group was treated with 100 mg/day MST-312. Stem cell survival was evaluated in the two groups. Also, the expression of TNFα and IL-6 genes were evaluated by the Real-time PCR technique. The results showed no significant difference between the two groups in terms of stem cell survival in the first year (P=0.72) and second years of treatment (P=0.66). But there was a significant difference between the two groups regarding progression-free survival (PFS) in the first year (P=0.041) and the second year (P=0.029). These results indicate that MST-312 inhibits the progress of the disease by inhibiting the telomerase activity of myeloma cells. Genetic evaluations also showed that IL-6 and TNF-α genes were significantly reduced in the case group. Therefore, it could be suggested that MST-312 has a selective inhibitory effect on myeloma cell growth and can be indicated as a suitable candidate for treating multiple myeloma.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo , Telomerase , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzamidas/farmacologia , Inibidores Enzimáticos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Interleucina-6/genética , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/etiologia , Transplante de Células-Tronco , Telomerase/antagonistas & inibidores , Telomerase/genética , Transplante Autólogo/métodos
20.
Pflugers Arch ; 474(10): 1091-1106, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35819489

RESUMO

Acetylcholine (ACh), which activates muscarinic ACh receptors (mAChRs) and nicotinic ACh receptors (nAChRs), enhances airway ciliary beating by increasing the intracellular Ca2+ concentration ([Ca2+]i). The mechanisms enhancing airway ciliary beating by nAChRs have remained largely unknown, although those by mAChRs are well understood. In this study, we focused on the effects of α7-nAChRs and voltage-gated Ca2+ channels (CaVs) on the airway ciliary beating. The activities of ciliary beating were assessed by frequency (CBF, ciliary beat frequency) and amplitude (CBD, ciliary bend distance) measured by high-speed video microscopy. ACh enhanced CBF and CBD by 25% mediated by an [Ca2+]i increase stimulated by mAChRs and α7-nAChRs (a subunit of nAChR) in airway ciliary cells of mice. Experiments using PNU282987 (an agonist of α7-nAChR) and MLA (an inhibitor of α7-nAChR) revealed that CBF and CBD enhanced by α7-nAChR are approximately 50% of those enhanced by ACh. CBF, CBD, and [Ca2+]i enhanced by α7-nAChRs were inhibited by nifedipine, suggesting activation of CaVs by α7-nAChRs. Experiments using a high K+ solution with/without nifedipine (155.5 mM K+) showed that the activation of CaVs enhances CBF and CBD via an [Ca2+]i increase. Immunofluorescence and immunoblotting studies demonstrated that Cav1.2 and α7-nAChR are expressed in airway cilia. Moreover, IL-13 stimulated MLA-sensitive increases in CBF and CBD in airway ciliary cells, suggesting an autocrine regulation of ciliary beating by CaV1.2/α7-nAChR/ACh. In conclusion, a novel Ca2+ signalling pathway in airway cilia, CaV1.2/α7-nAChR, enhances CBF and CBD and activates mucociliary clearance maintaining healthy airways.


Assuntos
Acetilcolina , Canais de Cálcio Tipo L , Cílios , Mucosa Respiratória , Receptor Nicotínico de Acetilcolina alfa7 , Acetilcolina/metabolismo , Acetilcolina/farmacologia , Animais , Benzamidas/farmacologia , Compostos Bicíclicos com Pontes/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo L/metabolismo , Colinérgicos/farmacologia , Cílios/efeitos dos fármacos , Cílios/fisiologia , Interleucina-13/metabolismo , Camundongos , Agonistas Nicotínicos/farmacologia , Nifedipino/farmacologia , Mucosa Respiratória/metabolismo , Mucosa Respiratória/fisiologia , Receptor Nicotínico de Acetilcolina alfa7/antagonistas & inibidores , Receptor Nicotínico de Acetilcolina alfa7/metabolismo
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