RESUMO
New antibacterial compounds are urgently needed, especially for infections caused by the top-priority Gram-negative bacteria that are increasingly difficult to treat. Lipid A is a key component of the Gram-negative outer membrane and the LpxH enzyme plays an important role in its biosynthesis, making it a promising antibacterial target. Inspired by previously reported ortho-N-methyl-sulfonamidobenzamide-based LpxH inhibitors, novel benzamide substitutions were explored in this work to assess their in vitro activity. Our findings reveal that maintaining wild-type antibacterial activity necessitates removal of the N-methyl group when shifting the ortho-N-methyl-sulfonamide to the meta-position. This discovery led to the synthesis of meta-sulfonamidobenzamide analogs with potent antibacterial activity and enzyme inhibition. Moreover, we demonstrate that modifying the benzamide scaffold can alter blocking of the cardiac voltage-gated potassium ion channel hERG. Furthermore, two LpxH-bound X-ray structures show how the enzyme-ligand interactions of the meta-sulfonamidobenzamide analogs differ from those of the previously reported ortho analogs. Overall, our study has identified meta-sulfonamidobenzamide derivatives as promising LpxH inhibitors with the potential for optimization in future antibacterial hit-to-lead programs.
Assuntos
Antibacterianos , Benzamidas , Desenho de Fármacos , Testes de Sensibilidade Microbiana , Antibacterianos/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Benzamidas/farmacologia , Benzamidas/química , Benzamidas/síntese química , Relação Estrutura-Atividade , Humanos , Sulfonamidas/química , Sulfonamidas/farmacologia , Sulfonamidas/síntese química , Estrutura Molecular , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Relação Dose-Resposta a Droga , Amidoidrolases/antagonistas & inibidores , Amidoidrolases/metabolismo , Modelos MolecularesRESUMO
Viral infectivity factor (Vif) has been recognized as a new therapeutic target for human immunodeficiency virus-1 (HIV-1) infected patients. In our previous work, we have synthesized a novel class of Vif inhibitors with 2-amino-N-(5-hydroxy-2-methoxyphenyl)-6-((4-nitrophenyl)thio)benzamide scaffold, which show obvious activity in HIV-1 infected cells and are also effective against drug-resistant strains. Proteolytic targeting chimera (PROTAC) utilizes the ubiquitin-proteasome system to degrade target proteins, which is well established in the field of cancer, but the antiviral PROTAC molecules are rarely reported. In order to explore the effectiveness of PROTAC in the antiviral area, we designed and synthesized a series of degrader of HIV-1 Vif based on 2-amino-N-(5-hydroxy-2-methoxyphenyl)-6-((4-nitrophenyl)thio)benzamide scaffold. Among them, L15 can degrade Vif protein obviously in a dose-dependent manner and shows certain antivirus activity. Meanwhile, molecular dynamics simulation indicated that the ternary complex formed by L15, Vif, and E3 ligase adopted a reasonable binding mode and maintained a stable interaction. This provided a molecular basis and prerequisite for the selective degradation of the Vif protein by L15. This study reports the HIV-1 Vif PROTAC for the first time and represents the proof-of-concept of PROTACs-based antiviral drug discovery in the field of HIV/ acquired immune deficiency syndrome (AIDS).
Assuntos
Fármacos Anti-HIV , HIV-1 , Produtos do Gene vif do Vírus da Imunodeficiência Humana , HIV-1/efeitos dos fármacos , Produtos do Gene vif do Vírus da Imunodeficiência Humana/antagonistas & inibidores , Produtos do Gene vif do Vírus da Imunodeficiência Humana/metabolismo , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Humanos , Relação Estrutura-Atividade , Estrutura Molecular , Benzamidas/farmacologia , Benzamidas/química , Benzamidas/síntese química , Descoberta de Drogas , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Proteólise/efeitos dos fármacos , Simulação de Dinâmica MolecularRESUMO
In this work, molecular descriptors of N-(1-(2-bromobenzoyl)-4-cyano-1H-pyrazol-5-yl) halogenated benzamides (1a-h) have been computed using a quantum chemical technique through DFT. Prior work involved the synthesis of compounds (1a-h) and the assessment of their anticancer activity on breast, colon, and liver tumors: MCF-7, HCT-116, and HepG-2 cell lines respectively. Since 1a, 1b, and 1d showed the most potential anticancer impact, their ability to inhibit EGFRWT was investigated. Based on the biological data, 1b inhibited EGFRWT the most. According to the docking evaluation, an H-bond with the threonine residue was one of the main non-covalent contacts between 1b and the EGFRWT active site residues. PES, MESP, HOMOs, LUMOs, energy band gap, global reactivity indices [electron affinity (A), ionization energies (I), electrophilicity index (ω), nucleophilicity index (ε), chemical potential (µ), electronegativity (χ), hardness (η), and softness (S)], condensed Fukui functions, NBO, and NCIs are the molecular descriptors of 1a-h that were computed using DFT technique. According to the theoretical investigation results, compounds (1a-h) might have anticancer effects; these findings are consistent with the biological findings from our previous research. Compound 1b had the lowest binding energy, according to an assessment of the binding energies between the threonine and the three most active compounds (1a, 1b, and 1d). This is consistent with the outcomes of the docking study and the biological examination of the influence of 1a, 1b, and 1d on EGFRWT.
Assuntos
Antineoplásicos , Teoria da Densidade Funcional , Receptores ErbB , Simulação de Acoplamento Molecular , Pirazóis , Humanos , Pirazóis/química , Pirazóis/farmacologia , Pirazóis/síntese química , Receptores ErbB/metabolismo , Receptores ErbB/química , Receptores ErbB/antagonistas & inibidores , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Benzamidas/química , Benzamidas/farmacologia , Benzamidas/síntese química , Linhagem Celular Tumoral , Ligação de HidrogênioRESUMO
Glucose-regulated protein 94 (Grp94) is an isoform of the heat shock protein 90 kDa (Hsp90) family of molecular chaperones. Inhibiting Grp94 has been implicated for many diseases. Co-crystal structures of two generations of Grp94 inhibitors revealed the importance of investigating the ester group, which is projected into the site 2 pocket unique to Grp94. Therefore, a series of KUNG65 benzamide analogs was designed and synthesized to evaluate their impact on the affinity and selectivity for Grp94. The data demonstrated that substituents with small and saturated ring systems that contain hydrogen bond acceptors exhibited increased affinity for Grp94, whereas larger saturated ring system manifested increased selectivity for Grp94 over Hsp90α.
Assuntos
Benzamidas , Benzamidas/química , Benzamidas/síntese química , Benzamidas/farmacologia , Relação Estrutura-Atividade , Humanos , Sítios de Ligação , Estrutura Molecular , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/antagonistas & inibidores , Glicoproteínas de Membrana/química , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Proteínas de Choque Térmico HSP90/metabolismoRESUMO
In modern cancer therapy, blockage of more than one target is a standard approach, and there are already many dual-target drugs that can achieve multiple inhibition through a single molecule. Herein, we designed and synthesized a series of novel derivatives with signal transducer and activator of transcription 3 (STAT3) and histone deacetylase (HDAC) inhibitory activity through strategy of combining pharmacophore based on the STAT3 inhibitor E28 and HDAC inhibitor MS-275. Among them, compound 24 (IC50 = 8.22 ± 0.27 µM) showed better anti-tumor activity than the clinical Class I HDAC inhibitor MS-275 (IC50 = 14.65 ± 0.24 µM) in MCF-7 breast cancer cells. Furthermore, the dual inhibition to HDAC and STAT3 of compound 24 was validated by western blot analysis. The study provides new tool compounds for further exploration of STAT3-HDAC pathway inhibitor achieved with a single molecule.
Assuntos
Antineoplásicos , Inibidores de Histona Desacetilases , Fator de Transcrição STAT3 , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/metabolismo , Humanos , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Células MCF-7 , Histona Desacetilases/metabolismo , Benzamidas/farmacologia , Benzamidas/química , Benzamidas/síntese química , Piridinas/química , Piridinas/farmacologia , Piridinas/síntese química , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Proliferação de Células/efeitos dos fármacosRESUMO
Both cyclopropyl amide and piperazine sulfonamide functional groups are known for their various biological properties used for drug development. Herein, we synthesized nine new derivatives with different substituent groups incorporating these moieties and screened them for their anti-osteoclast differentiation activity. After analyzing the structure-activity relationship (SAR), the inhibitory effect against osteoclastogenesis was determined to be dependent on the lipophilicity of the compound. Derivative 5b emerged as the most effective dose-dependent inhibitor after TRAP staining with an IC50 of 0.64 µM against RANKL-induced osteoclast cells. 5b was also able to suppress F-acting ring formation and bone resorption activity of osteoclasts in vitro. Finally, well-acknowledged gene and protein osteoclast-specific marker expression levels were decreased after 5b administration on primary murine osteoclast cells.
Assuntos
Benzamidas , Diferenciação Celular , Osteoclastos , Ligante RANK , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Diferenciação Celular/efeitos dos fármacos , Animais , Relação Estrutura-Atividade , Ligante RANK/farmacologia , Ligante RANK/antagonistas & inibidores , Camundongos , Benzamidas/farmacologia , Benzamidas/síntese química , Benzamidas/química , Estrutura Molecular , Relação Dose-Resposta a DrogaRESUMO
Due to its severe damage, Spodoptera frugiperda is receiving attention as one of the biggest dangers to world food security. Although there are numerous insecticides that are widely and successfully used to control S.â frugiperda, they do not have an immediate effect. In our work focusing for synthesized twelve novel benzamide derivatives and examined their insecticidal effectiveness against S.â frugiperda larvae in their second & fourth larvae instars, with the aim of further improving the insecticidal activity based on combination principles. Several spectroscopic methods, including elemental analysis, NMR & infrared spectroscopy, were employed for confirming the structure of the newly designed products. It has been discovered that most compounds show good of promising efficacy. With an LC50 of 24.8â mg/L for larvae in the second instar & 56.2â mg/L for larvae in the fourth instar, compound 23 was the most active. Among all compounds 11, 22 and 20 exhibited excellent results. Furthermore, a number of biological and histopathological properties of the demonstration compounds of the produced goods under laboratory conditions were also examined. This work further demonstrates the anti-proliferation of S.â frugiperda and offers fresh ideas for the manufacture of benzamide derivatives.
Assuntos
Benzamidas , Inseticidas , Larva , Spodoptera , Animais , Benzamidas/farmacologia , Benzamidas/síntese química , Benzamidas/química , Inseticidas/farmacologia , Inseticidas/química , Inseticidas/síntese química , Spodoptera/efeitos dos fármacos , Larva/efeitos dos fármacos , Relação Estrutura-Atividade , Estrutura Molecular , Relação Dose-Resposta a DrogaRESUMO
Imidazoles are crucial structural components in a variety of small-molecule inhibitors designed to target different kinases in anticancer treatment. However, the effectiveness of such inhibitors is often hampered by nonspecific effects and the development of resistance. Photopharmacology provides a compelling solution by enabling external control over drug activity with spatiotemporal precision. Herein, we introduce a novel strategy for caging bioactive triarylimidazole-based drug molecules. This approach involves introducing a dialkylamino group as a photoremovable group on the carbon atom of the imidazole ring, which intrinsically modulates the core structure from planar imidazole to tetrahedral 2H-imidazole, enabling the caged compound to be selectively uncaged upon visible light exposure. We applied this innovative caging technique to SB431542, a triarylimidazole-based small-molecule inhibitor that targets the pivotal TGF-ß signaling pathway, the dysregulation of which is linked to several human diseases, including cancer. Our results demonstrated the selective inhibition of human breast cancer cell migration in vitro upon light activation, highlighting the potential of our approach to transform triarylimidazole-based drug molecules into visible light-activatable drugs, thereby facilitating spatiotemporal regulation of their pharmacological activity.
Assuntos
Imidazóis , Luz , Humanos , Imidazóis/química , Imidazóis/farmacologia , Imidazóis/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Movimento Celular/efeitos dos fármacos , Estrutura Molecular , Linhagem Celular Tumoral , Benzamidas/farmacologia , Benzamidas/química , Benzamidas/síntese químicaRESUMO
Orphan GPR52 is emerging as a promising neurotherapeutic target. Optimization of previously reported lead 4a employing an iterative drug design strategy led to the identification of a series of unique GPR52 agonists, such as 10a (PW0677), 15b (PW0729), and 24f (PW0866), with improved potency and efficacy. Intriguingly, compounds 10a and 24f showed greater bias for G protein/cAMP signaling and induced significantly less in vitro desensitization than parent compound 4a, indicating that reducing GPR52 ß-arrestin activity with biased agonism results in sustained GPR52 activation. Further exploration of compounds 15b and 24f indicated improved potency and efficacy, and excellent target selectivity, but limited brain exposure warranting further optimization. These balanced and biased GPR52 agonists provide important pharmacological tools to study GPR52 activation, signaling bias, and therapeutic potential for neuropsychiatric and neurological diseases.
Assuntos
Benzamidas , Receptores Acoplados a Proteínas G , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/metabolismo , Humanos , Animais , Relação Estrutura-Atividade , Benzamidas/farmacologia , Benzamidas/química , Benzamidas/síntese química , Células HEK293 , Descoberta de Drogas , Camundongos , Ratos , Transdução de Sinais/efeitos dos fármacosRESUMO
Second-generation AR antagonists, such as enzalutamide, are the primary therapeutic agents for advanced prostate cancer. However, the development of both primary and secondary drug resistance leads to treatment failures and patient mortality. Bifunctional agents that simultaneously antagonize and degrade AR block the AR signaling pathway more completely and exhibit excellent antiproliferative activity against wild-type and drug-resistant prostate cancer cells. Here, we reported the discovery and optimization of a series of biphenyl derivatives as androgen receptor antagonists and degraders. These biphenyl derivatives exhibited potent antiproliferative activity against LNCaP and 22Rv1 cells. Our discoveries enrich the diversity of small molecule AR degraders and offer insights for the development of novel AR degraders for the treatment of enzalutamide-resistant prostate cancer.
Assuntos
Antagonistas de Receptores de Andrógenos , Antineoplásicos , Benzamidas , Compostos de Bifenilo , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Nitrilas , Feniltioidantoína , Neoplasias da Próstata , Receptores Androgênicos , Humanos , Masculino , Benzamidas/farmacologia , Benzamidas/química , Benzamidas/síntese química , Nitrilas/química , Nitrilas/farmacologia , Feniltioidantoína/farmacologia , Feniltioidantoína/análogos & derivados , Feniltioidantoína/química , Compostos de Bifenilo/farmacologia , Compostos de Bifenilo/antagonistas & inibidores , Receptores Androgênicos/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Proliferação de Células/efeitos dos fármacos , Relação Estrutura-Atividade , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Neoplasias da Próstata/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Estrutura Molecular , Antagonistas de Receptores de Andrógenos/farmacologia , Antagonistas de Receptores de Andrógenos/química , Antagonistas de Receptores de Andrógenos/síntese química , Antagonistas de Receptores de Andrógenos/uso terapêutico , Descoberta de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Relação Dose-Resposta a Droga , Linhagem Celular TumoralRESUMO
Here, a series of 3-(6-aminopyridin-3-yl) benzamide derivatives were designed and synthesized. Cell viability assay indicated that most compounds exhibited potent antiproliferative activity against all the tested cancer cells. Among them, compound 7l displayed the best antiproliferative activity particularly in A549 cells, with an IC50 value of 0.04 ± 0.01 µM. RNA-seq analysis was employed to explore the potential pathways related to the antiproliferative activity of compound 7l. The data revealed that 7l exerted antiproliferative activity mainly by regulating cell cycle, DNA replication and p53 signaling pathway. Indeed, compound 7l induced G2/M phase arrest by AURKB transcription inhibition and resulted in cell apoptosis via p53 signaling pathway. Most importantly, compound 7l demonstrated potent antitumor activity in A549 xenograft tumor model. Collectively, 7l might be a promising lead compound for the development of new therapeutic agents for AURKB overexpressed or mutated cancers.
Assuntos
Antineoplásicos , Apoptose , Benzamidas , Pontos de Checagem do Ciclo Celular , Proliferação de Células , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Benzamidas/farmacologia , Benzamidas/síntese química , Benzamidas/química , Proliferação de Células/efeitos dos fármacos , Relação Estrutura-Atividade , Estrutura Molecular , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Animais , Camundongos , Camundongos Nus , Linhagem Celular Tumoral , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Transcrição Gênica/efeitos dos fármacos , Camundongos Endogâmicos BALB CRESUMO
Oligonucleotides carrying 3'-terminal phosphates and conjugates are important tools in molecular biology and diagnostic purposes. We described the preparation of solid supports carrying the base labile linker 4-((2-hydroxyethyl)sulfonyl)benzamide for the solid-phase synthesis of 3'-phosphorylated oligonucleotides. These supports are fully compatible with the phosphoramidite chemistry yielding the desired 3'-phosphate oligonucleotides in excellent yields. The use of mild deprotection conditions allows the generation of partially protected DNA fragments.
Assuntos
Oligonucleotídeos , Técnicas de Síntese em Fase Sólida , Oligonucleotídeos/química , Oligonucleotídeos/síntese química , Fosfatos/química , Benzamidas/química , Benzamidas/síntese química , Compostos Organofosforados/química , Compostos Organofosforados/síntese química , Fosforilação , Estrutura MolecularRESUMO
Enhancer of zeste homolog 2 (EZH2) is a promising therapeutic target for diffuse large B-cell lymphoma. In this study, based on the binding model of 1 (tazemetostat) with polycomb repressive complex 2 (PRC2), we designed and synthesized a series of tazemetostat analogs bearing a 1-methyl-2-benzimidazolinone moiety to improve the inhibitory activity of EZH2 wild-type (WT) and Y641 mutants and enhance metabolic stability. After the assessment of the structure-activity relationship at enzymatic and cellular levels, compound N40 was identified. Biochemical assays showed that compound N40 (IC50â¯=â¯0.32â¯nM) exhibited superior inhibitory activity against EZH2 WT, compared with 1 (IC50â¯=â¯1.20â¯nM), and high potency against EZH2 Y641 mutants (EZH2 Y641F, IC50â¯=â¯0.03â¯nM; EZH2 Y641N, IC50â¯=â¯0.08â¯nM), which were approximately 10-fold more active than those of 1 (EZH2 Y641F, IC50â¯=â¯0.37â¯nM; EZH2 Y641N, IC50â¯=â¯0.85â¯nM). Furthermore, compound N40 (IC50â¯=â¯3.52⯱â¯1.23â¯nM) effectively inhibited the proliferation of Karpas-422 cells and was more potent than 1 (IC50â¯=â¯35.01⯱â¯1.28â¯nM). Further cellular experiments showed that N40 arrested Karpas-422 cells in the G1 phase and induced apoptosis in a dose-dependent manner. Moreover, N40 inhibited the trimethylation of lysine 27 on histone H3 (H3K27Me3) in Karpas-422 cells bearing the EZH2 Y641N mutant. Additionally, N40 (T1/2â¯=â¯177.69â¯min) showed improved metabolic stability in human liver microsomes compared with 1 (T1/2â¯=â¯7.97â¯min). Our findings suggest N40 as a promising EZH2 inhibitor; further investigation remains warranted to confirm our findings and further develop N40.
Assuntos
Antineoplásicos , Benzamidas , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Proteína Potenciadora do Homólogo 2 de Zeste , Piridonas , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Humanos , Relação Estrutura-Atividade , Benzamidas/química , Benzamidas/farmacologia , Benzamidas/síntese química , Piridonas/farmacologia , Piridonas/química , Piridonas/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Proliferação de Células/efeitos dos fármacos , Estrutura Molecular , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/metabolismo , Linfoma de Células B/patologia , Relação Dose-Resposta a Droga , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Descoberta de Drogas , Benzimidazóis/química , Benzimidazóis/farmacologia , Benzimidazóis/síntese químicaRESUMO
To promote the development and exploitation of novel antifungal agents, a series of thiazol-2-ylbenzamide derivatives (3A-3V) and thiazole-2-ylbenzimidoyl chloride derivatives (4A-4V) were designed and selective synthesis. The bioassay results showed that most of the target compounds exhibited excellent in vitro antifungal activities against five plant pathogenic fungi (Valsa mali, Sclerotinia scleotiorum, Botrytis cinerea, Rhizoctonia solani and Trichoderma viride). The antifungal effects of compounds 3B (EC50 = 0.72 mg/L) and 4B (EC50 = 0.65 mg/L) against S. scleotiorum were comparable to succinate dehydrogenase inhibitors (SDHIs) thifluzamide (EC50 = 1.08 mg/L) and boscalid (EC50 = 0.78 mg/L). Especially, compounds 3B (EC50 = 0.87 mg/L) and 4B (EC50 = 1.08 mg/L) showed higher activity against R. solani than boscalid (EC50 = 2.25 mg/L). In vivo experiments in rice leaves revealed that compounds 3B (86.8 %) and 4B (85.3 %) exhibited excellent protective activities against R. solani comparable to thifluzamide (88.5 %). Scanning electron microscopy (SEM) results exhibited that compounds 3B and 4B dramatically disrupted the typical structure and morphology of R. solani mycelium. Molecular docking demonstrated that compounds 3B and 4B had significant interactions with succinate dehydrogenase (SDH). Meanwhile, SDH inhibition assay results further proved their potential as SDHIs. In addition, acute oral toxicity tests on A. mellifera L. showed only low toxicity for compounds 3B and 4B to A. mellifera L. populations. These results suggested that these two series of compounds had merit for further investigation as potential low-risk agricultural SDHI fungicides.
Assuntos
Antifúngicos , Benzamidas , Desenho de Fármacos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Tiazóis , Relação Estrutura-Atividade , Benzamidas/farmacologia , Benzamidas/síntese química , Benzamidas/química , Tiazóis/farmacologia , Tiazóis/química , Tiazóis/síntese química , Antifúngicos/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Estrutura Molecular , Relação Dose-Resposta a Droga , Succinato Desidrogenase/antagonistas & inibidores , Succinato Desidrogenase/metabolismo , Animais , Ascomicetos/efeitos dos fármacos , Rhizoctonia/efeitos dos fármacos , BotrytisRESUMO
A series of novel chromone derivatives of (N-(4-oxo-2-(trifluoromethyl)-4H-chromen-6-yl) benzamides) were synthesized by treating 7-amino-2-(trifluoromethyl)-4H-chromen-4-one with K2CO3 and/or NaH, suitable alkyl halides and acetonitrile and/or 1,4-dioxane. The obtained products are in high yields (87 to 96%) with various substituents in short reaction times with no more by-products and confirmed by FT-IR, 1H, and 13C-NMR Spectral data. The in vitro cytotoxic activity was examined against two human cancer cell lines, namely the human lung adenocarcinoma (A-549) and the human breast (MCF-7) cancer cell line. Compound 4h showed promising cytotoxicity against both cell lines with IC50 values of 22.09 and 6.40 ± 0.26 µg/mL respectively, compared to that of the standard drug. We also performed the in vitro antioxidant activity by DPPH radical, hydrogen peroxide, NO scavenging, and total antioxidant capacity (TAC) assay methods, and they showed significant activities. The possible binding interactions of all the synthesized chromone derivatives are also investigated against selective pharmacological targets of human beings, such as HERA protein for cytotoxic activity and Peroxiredoxins (3MNG) for antioxidant activity which showed closer binding free energies than the standard drugs and evidencing the above two types of activities.
Assuntos
Antineoplásicos , Antioxidantes , Benzamidas , Simulação de Acoplamento Molecular , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antioxidantes/farmacologia , Antioxidantes/síntese química , Antioxidantes/química , Benzamidas/farmacologia , Benzamidas/química , Benzamidas/síntese química , Células MCF-7 , Células A549 , Cromonas/química , Cromonas/farmacologia , Cromonas/síntese química , Linhagem Celular Tumoral , Relação Estrutura-AtividadeRESUMO
Background: Histone deacetylase inhibitors (HDACIs) are important as anticancer agents. Objective: This study aimed to investigate some key structural features of HDACIs via the design, synthesis and biological evaluation of novel benzamide-based derivatives. Methods: Novel structures, designed using a molecular modification approach, were synthesized and biologically evaluated. Results: The results indicated that a subset of molecules with CH3/NH2 at R2 position possess selective antiproliferative activity. However, only those with an NH2 group showed HDACI activity. Importantly, the shorter the molecule length, the stronger HDACI. Among all, 7j was the most potent HDAC1-3 inhibitor and antiproliferative compound. Conclusion: The results of the present investigation could provide valuable structural knowledge applicable for the development of the HDACIs and benzamide-based antiproliferative agents in the future.
[Box: see text].
Assuntos
Antineoplásicos , Benzamidas , Proliferação de Células , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores de Histona Desacetilases , Histona Desacetilases , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/síntese química , Humanos , Benzamidas/farmacologia , Benzamidas/química , Benzamidas/síntese química , Proliferação de Células/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Relação Estrutura-Atividade , Histona Desacetilases/metabolismo , Estrutura Molecular , Linhagem Celular Tumoral , Simulação de Acoplamento MolecularRESUMO
As we work to transition the modern society that is based on non-renewable chemical feedstocks to a post-modern society built around renewable sources of energy, fuels, and chemicals, there is a need to identify the renewable resources and processes for converting them to platform chemicals. Herein, we explore a strategy for utilizing the p-hydroxybenzoate in biomass feedstocks (e. g., poplar and palm trees) and converting it into a portfolio of commodity chemicals. The targeted bio-derived product in the first processing stage is p-hydroxybenzamide produced from p-hydroxybenzoate esters found in the plant. In the second stage a continuous reaction process converts the p-hydroxybenzamide to p-aminophenol via the Hofmann rearrangement and recovers the unreacted p-hydroxybenzamide. In the third stage the p-aminophenol can be acetylated to form paracetamol, which is readily isolated by liquid/liquid extraction at >95 % purity and an overall p-hydroxybenzamide-to-paracetamol process yield of ~90 %. We explore how utilization of protecting groups alters the challenges in this process and expands the portfolio of possible products to include p-(methoxymethoxy)aniline and N-acetyl-p-(methoxymethoxy)aniline. These target compounds could become value-added renewably-sourced platform chemicals that could be used to produce biodegradable plastics, pigments, and pharmaceuticals.
Assuntos
Acetaminofen , Aminofenóis , Biomassa , Aminofenóis/química , Acetaminofen/química , Acetaminofen/síntese química , Benzamidas/química , Benzamidas/síntese química , Técnicas de Química Sintética , Parabenos/químicaRESUMO
The inhibitory effects of veralipride, a benzamide-class antipsychotic acting as dopamine D2 receptors antagonist incorporates a primary sulfonamide moiety and was investigated for its interactions with carbonic anhydrase (CA) isoforms. In vitro profiling using the stopped-flow technique revealed that veralipride exhibited potent inhibitory activity across all tested hCA isoforms, with exception of hCA III. Comparative analysis with standard inhibitors, acetazolamide (AAZ), and sulpiride, provided insights for understanding the relative efficacy of veralipride as CA inhibitor. The study reports the X-ray crystal structure analysis of the veralipride adduct with three human (h) isoforms, hCA I, II, and CA XII mimic, allowing the understanding of the molecular interactions rationalizing its inhibitory effects against each isoform. These findings contribute to our understanding of veralipride pharmacological properties and for the design of structural analogs endowed with polypharmacological properties.
Assuntos
Inibidores da Anidrase Carbônica , Anidrases Carbônicas , Humanos , Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/farmacologia , Inibidores da Anidrase Carbônica/síntese química , Cristalografia por Raios X , Anidrases Carbônicas/metabolismo , Anidrases Carbônicas/química , Antagonistas dos Receptores de Dopamina D2/farmacologia , Antagonistas dos Receptores de Dopamina D2/química , Antagonistas dos Receptores de Dopamina D2/síntese química , Benzamidas/química , Benzamidas/farmacologia , Benzamidas/síntese química , Receptores de Dopamina D2/metabolismo , Estrutura Molecular , Modelos Moleculares , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Relação Estrutura-AtividadeRESUMO
BACKGROUND: The elucidation of molecular pathways associated with adipogenesis has evidenced the relevance of estrogen and estrogen receptor beta (ERß). The positive effects of ERß ligands on adipogenesis, energy expenditure, lipolysis, food intake, and weight loss, make ERß an attractive target for obesity control. From ligand-based virtual screening, molecular docking, and molecular dynamic simulations, six new likely ERß ligands (C1 to C6) have been reported with potential for pharmacological obesity treatment. OBJECTIVE: In this study, the effect of molecules C1-C6 on adipogenesis using the murine 3T3-L1 cell line was evaluated. METHODS: Cell viability was assessed by MTT assays. Lipid accumulation and gene expression were investigated by ORO staining and real-time quantitative RT-PCR experiments, respectively. RESULTS: Cell viability was not significantly affected by C1-C6 at concentrations up to 10 µM. Interestingly, treatment with 10 µM of C1 (S-Dihydrodaidzein) and C2 (3-(1,3-benzoxazol-2-yl)- benzamide) for 72 h inhibited adipocyte differentiation; moreover, ORO staining evidenced a reduced intracellular lipid accumulation (40% at day 7). Consistently, mRNA expression of the adipogenic markers, PPARγ and C/EBPα, was reduced by 50% and 82%, respectively, in the case of C1, and by 83% and 59%, in the case of C2. CONCLUSION: Altogether, these results show the two new potential ß-estrogen receptor ligands, C1 and C2, to exhibit anti-adipogenic activity. They could further be used as lead structures for the development of more efficient drugs for obesity control.
Assuntos
Adipogenia , Benzamidas , Receptor beta de Estrogênio , Animais , Camundongos , Células 3T3-L1 , Adipogenia/efeitos dos fármacos , Fármacos Antiobesidade/farmacologia , Fármacos Antiobesidade/química , Fármacos Antiobesidade/síntese química , Benzamidas/farmacologia , Benzamidas/química , Benzamidas/síntese química , Benzoxazóis/farmacologia , Benzoxazóis/química , Benzoxazóis/síntese química , Sobrevivência Celular/efeitos dos fármacos , Receptor beta de Estrogênio/metabolismo , Receptor beta de Estrogênio/genética , Isoflavonas/farmacologia , Isoflavonas/química , Ligantes , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
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.