RESUMO
New Biginelli adducts were rationalised, via the introduction of selected anti-tubercular (TB) pharmacophores into the dihydropyrimidine (DHPM) ring of deoxythymidine monophosphate (dTMP), the natural substrate of Mycobacterium tuberculosis thymidine monophosphate kinase (TMPKmt). Repurposing was one of the design rationale strategies for some selected mimics of the designed compounds. The anti-TB activity was screened against the Mtb H37Rv strain where 11a was superior to ethambutol (EMB), and was 9-fold more potent than pyrazinamide (PZA). Additionally, compounds 11b, 4a, 4b, 13a, 13b and 14a elicited higher anti-TB activity than PZA, showing better safety profiles than EMB against RAW 264.7 cells' growth. The in vitro TMPKmt inhibition assay released compounds 11a, 11b and 13b as the most potent inhibitors. Docking studies presumed the binding modes and molecular dynamics (MD) simulation revealed the dynamic stability of 11a-TMPKmt complex over 100 ns. In silico prediction of the chemo-informatics properties of the most active compounds was conducted.
Assuntos
Antituberculosos , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis , Núcleosídeo-Fosfato Quinase , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/enzimologia , Antituberculosos/farmacologia , Antituberculosos/química , Antituberculosos/síntese química , Núcleosídeo-Fosfato Quinase/antagonistas & inibidores , Núcleosídeo-Fosfato Quinase/metabolismo , Relação Estrutura-Atividade , Estrutura Molecular , Camundongos , Modelos Moleculares , Animais , Células RAW 264.7 , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese químicaRESUMO
Currently, as the largest family of E3 ubiquitin ligases, Skp1-Cullin 1-F-box (SCF) E3 ligase complexes have attracted extensive attention. Among SCF complexes, Skp2, ß-TrCP, and FBXW7 have undergone extensive research on their structures and functions. Previous studies suggest Skp2, ß-TrCP, and FBXW7 are overexpressed in numerous cancers. Thus, the SCF E3 ligase complex has become a significant target for the development of anti-cancer drugs. Over the past few decades, a variety of anti-tumor inhibitors targeting the SCF E3 ligase complex have been attempted. However, since almost none of the SCF E3 ligase inhibitors passed clinical trials, the design and synthesis of the new inhibitors are needed. Here, we will introduce the structure and function of Skp2, ß-TrCP, and FBXW7, their connections with cancer development, the relevant in vitro and in vivo activities, selectivity, structure-activity relationships, and the therapeutic or preventive application of small molecule inhibitors targeting these three F-box proteins reported in the patent (2010-present). This information will help develop drugs targeting the SCF E3 ubiquitin ligase, providing new strategies for future cancer treatments.
Assuntos
Antineoplásicos , Desenho de Fármacos , Neoplasias , Humanos , Relação Estrutura-Atividade , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Patentes como Assunto , Animais , Proteínas Ligases SKP Culina F-Box/metabolismo , Proteínas Ligases SKP Culina F-Box/antagonistas & inibidores , Estrutura Molecular , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Ubiquitina-Proteína Ligases/antagonistas & inibidores , Ubiquitina-Proteína Ligases/metabolismo , Proteínas Quinases Associadas a Fase S/antagonistas & inibidores , Proteínas Quinases Associadas a Fase S/metabolismo , Proteína 7 com Repetições F-Box-WD/metabolismoRESUMO
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
Vacuolar-type H+-ATPases (V-ATPases) play a crucial role in the life cycle of agricultural pests and represent a promising target for the development of novel insecticides. In this study, S18, a derivative of vanillin acquired from Specs database using a structure-based virtual screening methodology, was first identified as a V-ATPase inhibitor. It binds to subunit A of the enzyme with a Kd of 1 nM and exhibits insecticidal activity against M. separata. Subsequently, using S18 as the lead compound, a new series of vanillin derivatives were rationally designed and efficiently synthesized. and their biological activities were assessed. Among them, compound 3b-03 showed the strongest insecticidal activity against M. separata by effectively targeting the V-ATPase subunit A with Kd of 0.803 µM. Isothermal titration calorimetric measurements and docking results provided insights into its interaction with subunit A of V-ATPase, which could facilitate future research aimed at the development of novel chemical insecticides.
Assuntos
Benzaldeídos , Inseticidas , Simulação de Acoplamento Molecular , ATPases Vacuolares Próton-Translocadoras , Inseticidas/química , Inseticidas/farmacologia , Inseticidas/síntese química , Animais , Benzaldeídos/química , Benzaldeídos/farmacologia , Relação Estrutura-Atividade , ATPases Vacuolares Próton-Translocadoras/antagonistas & inibidores , ATPases Vacuolares Próton-Translocadoras/química , ATPases Vacuolares Próton-Translocadoras/metabolismo , Proteínas de Insetos/química , Proteínas de Insetos/antagonistas & inibidores , Proteínas de Insetos/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese química , Estrutura Molecular , HalogenaçãoRESUMO
Decaprenylphosphoryl-ß-D-ribose-oxidase (DprE1), a subunit of the essential decaprenylphosphoribose-2'-epimerase, plays a crucial role in the synthesis of cell wall arabinan components in mycobacteria, including the pathogen responsible for tuberculosis, Mycobacterium tuberculosis. In this study, we designed, synthesised, and evaluated 15 (BOK-1-BOK-10 and BOP-1-BOP-5) potential inhibitors of DprE1 from a series of 1,2,3-triazole ligands using a validated DprE1 inhibition assay. Two compounds, BOK-2 and BOK-3, demonstrated significant inhibition with IC50 values of 2.2 ± 0.1 and 3.0 ± 0.6 µM, respectively, whereas the standard drug (TCA-1) showed inhibition at 3.0 ± 0.2 µM. Through molecular modelling and dynamic simulations, we explored the structural relationships between selected 1,2,3-triazole compounds and DprE1, revealing key features for effective drug-target interactions. This study introduces a novel approach for designing ligands against DprE1, offering a potential therapeutic strategy for tuberculosis treatment.
Identification of 15 (BOK-1BOK-10 and BOP-1BOP-5) potent inhibitors of DprE1 enzyme from 1,2,3-triazole ligands.BOK-2 and BOK-3 exhibited significant DprE1 inhibition with IC50 values of 2.2 ± 0.1 and 3.0 ± 0.6 µM, respectively.Molecular modelling and dynamic simulations elucidated key structural features for effective drugtarget interactions.Novel approach introduced for designing DprE1 ligands, potentially aiding tuberculosis treatment.Findings offer promising candidates for future tuberculosis research.
Assuntos
Benzoxazóis , Relação Dose-Resposta a Droga , Desenho de Fármacos , Inibidores Enzimáticos , Mycobacterium tuberculosis , Triazóis , Triazóis/química , Triazóis/farmacologia , Triazóis/síntese química , Benzoxazóis/química , Benzoxazóis/farmacologia , Benzoxazóis/síntese química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Relação Estrutura-Atividade , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/enzimologia , Estrutura Molecular , Fluorometria , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/metabolismo , Modelos Moleculares , Testes de Sensibilidade Microbiana , Oxirredutases do Álcool/antagonistas & inibidores , Oxirredutases do Álcool/metabolismoRESUMO
DNA N6-methyladenine (6mA) demethylase ALKBH1 plays an important role in various cellular processes. Dysregulation of ALKBH1 is associated with the development of some cancer types, including gastric cancer, implicating a potential therapeutic target. However, there is still a lack of potent ALKBH1 inhibitors. Herein, we report the discovery of a highly potent ALKBH1 inhibitor, 1H-pyrazole-4-carboxylic acid derivative 29. The structure-activity relationship of this series of compounds was also discussed. Because of the poor cell membrane permeability of 29, we prepared a prodrug of 29 (29E), which showed excellent cellular activities. In gastric cancer cell lines HGC27 and AGS, 29E treatment significantly increased the abundance of 6mA, inhibited cell viability, and upregulated the AMP-activated protein kinase (AMPK) signaling pathway. In addition, the hydrolysis product 29 showed high exposure in mice after administration of 29E. Collectively, this research provides a new potent ALKBH1 inhibitor, which could serve as a lead compound for subsequent drug development.
Assuntos
Homólogo AlkB 1 da Histona H2a Dioxigenase , Antineoplásicos , Inibidores Enzimáticos , Pirazóis , Neoplasias Gástricas , Humanos , Relação Estrutura-Atividade , Homólogo AlkB 1 da Histona H2a Dioxigenase/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Animais , Pirazóis/farmacologia , Pirazóis/química , Pirazóis/síntese química , Camundongos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Linhagem Celular Tumoral , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacologia , Ácidos Carboxílicos/síntese química , Proliferação de Células/efeitos dos fármacos , Estrutura Molecular , Simulação de Acoplamento Molecular , Camundongos Nus , Camundongos Endogâmicos BALB CRESUMO
High levels of extracellular adenosine in tumor microenvironment (TME) has extensive immunosuppressive effect. CD73 catalyzes the conversion of AMP into adenosine and regulates its production. Inhibiting CD73 can reduce the level of adenosine and reverse adenosine-mediated immune suppression. Therefore, CD73 has emerged as a valuable target for cancer immunotherapy. Here, a new series of malonic acid non-nucleoside derivatives were designed, synthesized and evaluated as CD73 inhibitors. Among them, compounds 18 and 19 exhibited significant inhibition activities against hCD73 with IC50 values of 0.28 µM and 0.10 µM, respectively, suggesting the feasibility of replacing the benzotriazole moiety in the lead compound. This study explored the novelty and structural diversity of CD73 inhibitors.
Assuntos
5'-Nucleotidase , Desenho de Fármacos , Inibidores Enzimáticos , Malonatos , Relação Estrutura-Atividade , 5'-Nucleotidase/antagonistas & inibidores , 5'-Nucleotidase/metabolismo , Humanos , Malonatos/química , Malonatos/farmacologia , Malonatos/síntese química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Estrutura Molecular , Relação Dose-Resposta a Droga , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/metabolismoRESUMO
Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) has emerged as a promising therapeutic target for cancer treatment. However, the current PIN1 inhibitors have shown limited efficacy in animal models, leaving the question of whether PIN1 is a proper oncologic target still unanswered. By screening a 1 trillion DNA-encoded library (DEL), we identified novel nonacidic compounds. Among resynthesized DEL compounds, DEL1067-56-469 (A0) is the most potent one (KD = 430 nM, IC50 = 420 nM). Further optimization of A0 resulted in compound C10 with much improved potency (KD = 25 nM, IC50 = 150 nM). As an alternative approach, C10 was then converted into proteolysis targeting chimeras (PROTACs) in order to achieve deeper downregulation of the PIN1 protein in cancer cell lines. Unfortunately, neither PIN1 inhibitors nor PIN1 PROTACs demonstrated meaningful antiproliferation activity. In addition, siRNA knock-down experiments provided unfavorable evidence of PIN1 as an oncologic target. Our findings highlight the complexity of targeting PIN1 for cancer therapy.
Assuntos
Antineoplásicos , Proliferação de Células , Peptidilprolil Isomerase de Interação com NIMA , Peptidilprolil Isomerase de Interação com NIMA/antagonistas & inibidores , Peptidilprolil Isomerase de Interação com NIMA/metabolismo , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Proteólise/efeitos dos fármacos , Relação Estrutura-Atividade , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Quimera de Direcionamento de ProteóliseRESUMO
Acyl-CoA: cholesterol acyltransferase (ACAT), a pivotal enzyme in the absorption and metabolism of cholesterol, is primarily responsible for intracellular esterification. ACAT inhibition is expected to diminish plasma lipid levels by impeding intestinal cholesterol absorption, thereby preventing the progression of atherosclerotic lesions. A previous study shows that selective inhibition of ACAT2 significantly mitigated hypercholesterolaemia and atherosclerosis in mouse models. Therefore, the need for ACAT2 selective inhibitors becomes particularly urgent. In this study, we established a multilayer virtual screening workflow and subjected biologically evaluated representative compounds to enzyme inhibitory assays. The experimental results indicated that the two compounds, STL565001 (inhibition rate at 25 µM: 75.7 ± 27.8%, selectivity = 6) and STL528213 (inhibition rate at 25 µM: 87.8 ± 12.4%, selectivity = 13), demonstrated robust activity against ACAT2, displaying greater selectivity for ACAT2 than for ACAT1. The molecular mechanisms governing the inhibitory activities of the selected compounds were systematically elucidated using computational approaches. In addition, hotspot residues in ACAT2 that are crucial for ligand binding were successfully identified. In summary, we devised a multilayer screening scheme to expeditiously and efficiently identify compounds with enzyme inhibitory activity, offering novel scaffolds for subsequent drug design centred on ACAT2 targets.
Assuntos
Relação Dose-Resposta a Droga , Descoberta de Drogas , Inibidores Enzimáticos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Esterol O-Aciltransferase 2 , Esterol O-Aciltransferase , Relação Estrutura-Atividade , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Esterol O-Aciltransferase/antagonistas & inibidores , Esterol O-Aciltransferase/metabolismo , Humanos , Estrutura Molecular , FarmacóforoRESUMO
In this study, novel ergosterol peroxide (EP) derivatives were synthesized and evaluated to assess their antiproliferative activity against four human cancer cell lines (A549, HepG2, MCF-7, and MDA-MB-231). Compound 3g exhibited the most potent antiproliferative activity, with an IC50 value of 3.20 µM against MDA-MB-231. This value was 5.4-fold higher than that of the parental EP. Bioassay optimization further identified 3g as a novel glutaminase 1 (GLS1) inhibitor (IC50 = 3.77 µM). In MDA-MB-231 cells, 3g reduced the cellular glutamate levels by blocking the glutamine hydrolysis pathway, which triggered reactive oxygen species production and induced caspase-dependent apoptosis. Molecular docking indicated that 3g interacts with the reaction site of the variable binding pocket by forming multiple interactions with GLS1. In a mouse model of breast cancer, 3g showed remarkable therapeutic effects at a dose of 50 mg/kg, with no apparent toxicity. Based on these results, 3g could be further evaluated as a novel GLS1 inhibitor for triple-negative breast cancer (TNBC) therapy.
Assuntos
Antineoplásicos , Proliferação de Células , Ergosterol , Glutaminase , Simulação de Acoplamento Molecular , Neoplasias de Mama Triplo Negativas , Humanos , Glutaminase/antagonistas & inibidores , Glutaminase/metabolismo , Animais , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Camundongos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Ergosterol/análogos & derivados , Ergosterol/química , Ergosterol/farmacologia , Apoptose/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Ensaios Antitumorais Modelo de Xenoenxerto , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-AtividadeRESUMO
A diminutive chemical library of acyl thiotriazinoindole (ATTI) based bioactive scaffolds was synthesized, instigated by taking the economical starting material Isatin, through a series of five steps. Isatin was first nitrated followed by the attachment of pentyl moiety via nucleophilic substitution reaction. The obtained compound was reacted with thiosemicarbazide to obtain thiosemicarbazone derivative, which was eventually cyclized using basic conditions in water as solvent. Finally, the reported series was obtained through reaction of nitrated thiotriazinoindole moiety with differently substituted phenacyl bromides. The synthesized compounds were characterized using NMR spectroscopy and elemental analysis. Finally, the synthesized motifs were scrutinized for their potential to impede urease, α-glucosidase, DPPH, and α-amylase. Compound 5 h with para cyano group manifested the most pivotal biological activity among all, displaying IC50 values of 29.7 ± 0.8, 20.5 ± 0.5 and 36.8 ± 3.9 µM against urease, α-glucosidase, and DPPH assay, respectively. Simultaneously, for α-amylase compound 5 g possessing a p-CH3 at phenyl ring unfolded as most active, with calculated IC50 values 90.3 ± 1.1 µM. The scaffolds were additionally gauged for their antifungal and antibacterial activity. Among the tested strains, 5d having bromo as substituent exhibited the most potent antibacterial activity, while it also demonstrated the highest potency against Aspergillus fumigatus. Other derivatives 5b, 5e, 5i, and 5j also exhibited dual inhibition against both antibacterial and antifungal strains. The interaction pattern of derivatives clearly displayed their SAR, and their docking scores were correlated with their IC50 values. In molecular docking studies, the importance of interactions like hydrogen bonding was further asserted. The electronic factors of various substituents engendered variety of interactions between the ligands and targets implying their importance in the structures of the synthesized heterocyclic scaffolds. To conclude, the synthesized compounds had satisfactory biological activity against various important targets. Further studies are therefore encouraged by attachment of different substitutions in the structure at various positions to enhance the activity of these compounds.
Assuntos
Antioxidantes , Simulação de Acoplamento Molecular , Urease , alfa-Amilases , alfa-Glucosidases , Urease/antagonistas & inibidores , Urease/química , alfa-Amilases/antagonistas & inibidores , alfa-Amilases/química , alfa-Glucosidases/química , alfa-Glucosidases/metabolismo , Antioxidantes/química , Antioxidantes/farmacologia , Antioxidantes/síntese química , Relação Estrutura-Atividade , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Desenho de Fármacos , Indóis/química , Indóis/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Inibidores de Glicosídeo Hidrolases/síntese química , Testes de Sensibilidade MicrobianaRESUMO
Chitinases play an important role in the molting process of insects and are potential targets for the development of green insecticides. Based on the feature that the +1/+2 sites in OfChtI, OfChtII, and OfChi-h have tryptophan residues in mismatch-parallel position, a strategy to introduce indole scaffold into chitinase inhibitors was proposed, and multitarget chitinase inhibitors containing N-methylcarbamoylguanidinyl and indole scaffold were successfully synthesized. The inhibitory activity showed that compound 8u exhibited significant inhibitory activity against OfChtI, OfChtII, and OfChi-h, with IC50 values of 0.7, 0.79, and 0.58 µM, and Ki values of 0.05 ± 0.005, 0.065 ± 0.004, and 0.025 ± 0.006 µM, respectively. In vivo insecticidal activity showed that compounds 8a and 8g exhibited excellent insecticidal activity against Plutella xylostella and Mythimna separata, with LC50 values of 0.79 and 9.17 mg/L against P. xylostella, respectively, and 3.58 and 83.09 mg/L against M. separata, respectively, making them the most potent chitinase inhibitors with in vivo insecticidal activity discovered to date. The inhibition mechanism and binding free energy results suggested that N-methylcarbamoylguanidinyl binds to the -1 catalytic site, while additional interactions acquired by π-π stacking and hydrophobic interactions of the indole scaffold with tryptophan increase the binding affinity of the targets to chitinases. This work provides a new direction for the development of chitinase inhibitors with compounds 8a and 8g potentially serving as promising candidates for pesticide development.
Assuntos
Quitinases , Desenho de Fármacos , Inibidores Enzimáticos , Indóis , Inseticidas , Mariposas , Quitinases/antagonistas & inibidores , Quitinases/química , Quitinases/metabolismo , Inseticidas/química , Inseticidas/farmacologia , Inseticidas/síntese química , Animais , Mariposas/efeitos dos fármacos , Relação Estrutura-Atividade , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese química , Indóis/química , Indóis/farmacologia , Proteínas de Insetos/antagonistas & inibidores , Proteínas de Insetos/química , Proteínas de Insetos/metabolismo , Simulação de Acoplamento Molecular , Estrutura MolecularRESUMO
Transketolase (TKL; EC 2.2.1.1) is a highly promising potential target for herbicidal applications. To identify novel TKL inhibitors, we designed and synthesized a series of 3-oxopropionamide-1-methylpyrazole carboxylate analogues and assessed their herbicidal activities. Ethyl 3-((1-((2,4-dichlorophenyl)amino)-1-oxopropan-2-yl)oxy)-1-methyl-1H-pyrazole-5-carboxylate (D15) and ethyl 1-methyl-3-((1-oxo-1-((thiophen-2-ylmethyl)amino)propan-2-yl)oxy)-1H-pyrazole-5-carboxylate (D20) exhibited superior growth inhibition activities against both the root and stem of Amaranthus retroflexus (A. retroflexus) compared to nicosulfuron and mesotrione. Additionally, D15 achieved an inhibition rate of more than 90% against the roots and stems of Digitaria sanguinalis (D. sanguinalis), outperforming the four control agents at a concentration of 200 mg/L using the small cup method. In the pre-emergence herbicidal activity test, D15 effectively inhibited D. sanguinalis by more than 90% at 150 g ai/ha, surpassing the efficacy of the control, mesotrione. Conversely, in the postemergence herbicidal activity test, D20 exhibited efficient inhibition of A. retroflexus by more than 90% at 150 g ai/ha, outperforming the control agents nicosulfuron, mesotrione, and metamifop. The results of the TKL enzyme activity test showed that the IC50 values of compounds D15 and D20 were 0.384 and 0.655 mg/L, respectively, which were close to those of the control agents. Furthermore, molecular docking and molecular dynamics simulation studies revealed that D15 and D20 interacted favorably with the TKL of Setaria viridis. Such findings highlight the promising potential of D15 and D20 as lead TKL inhibitors for the optimization of new herbicides.
Assuntos
Amaranthus , Herbicidas , Simulação de Acoplamento Molecular , Pirazóis , Herbicidas/farmacologia , Herbicidas/química , Herbicidas/síntese química , Pirazóis/química , Pirazóis/farmacologia , Pirazóis/síntese química , Amaranthus/efeitos dos fármacos , Amaranthus/crescimento & desenvolvimento , Relação Estrutura-Atividade , Digitaria/efeitos dos fármacos , Digitaria/enzimologia , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacologia , Raízes de Plantas/química , Raízes de Plantas/crescimento & desenvolvimento , Estrutura Molecular , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese química , Plantas Daninhas/efeitos dos fármacos , Plantas Daninhas/crescimento & desenvolvimentoRESUMO
The discovery of natural product-derived novel nanopesticide systems can effectively address the adverse effects caused by the improper use of traditional fungicides. In this research, 33 novel 3-carene-derived amide-thiourea derivatives 5a-5zg were designed using laccase as the biological target, synthesized from natural renewable forest biomass resource 3-carene as the starting material, and structurally confirmed by Fourier-transform infrared spectroscopy, nuclear magnetic resonance, high-resolution mass spectrometry, and single crystal X-ray diffraction. The antifungal activity of the target compounds against eight plant pathogenic fungi was evaluated, and the results presented that target compound 5g exhibited excellent and broad-spectrum antifungal activity against the eight tested phytopathogenic fungi. Furthermore, the important contribution of the gem-dimethylcyclopropane structure in the antifungal activity of compound 5g was revealed through two negative controls without the gem-dimethylcyclopropane structure. Besides, compound 5g also demonstrated a prominent laccase inhibitory activity. The fluorescence quenching of the laccase with compound 5g, the chelating characteristics of compound 5g, and the interaction mode between the laccase and compound 5g presented that the target compound 5g probably exhibited excellent antifungal activity by acting on the laccase target. Cytotoxicity assay revealed that compound 5g had a low cytotoxicity for LO2 and HEK293T cell lines. On the other hand, to further improve the application potential of compound 5g, the 3-carene molecular skeleton containing gem-dimethylcyclopropane ring was grafted onto chitosan, and two nanopesticide carriers CACS and CATCS with sustained releasing performance were synthesized for loading compound 5g. 3-Carene-derived nanochitosan carrier CATCS showed a relatively regular, loose, and porous reticular structure, which displayed high dispersibility and good thermostability. In addition, this carrier had a higher drug-loading capacity and sustained releasing performance than that of the unmodified chitosan. This research identified that the target compound 5g could be used as a promising lead compound for fungicide against the laccase target, meanwhile, the complex 5g/CATCS deserved further study as a nanopesticide candidate.
Assuntos
Quitosana , Lacase , Tioureia , Lacase/química , Lacase/metabolismo , Quitosana/química , Quitosana/farmacologia , Tioureia/química , Tioureia/farmacologia , Humanos , Desenho de Fármacos , Fungos/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese química , Fungicidas Industriais/química , Fungicidas Industriais/farmacologia , Fungicidas Industriais/síntese química , Doenças das Plantas/microbiologia , Proteínas Fúngicas/química , Proteínas Fúngicas/metabolismo , Proteínas Fúngicas/antagonistas & inibidores , Preparações de Ação Retardada/química , Células HEK293RESUMO
Tyrosinase, a key enzyme in melanin synthesis, represents a crucial therapeutic target for hyperpigmentation disorders due to excessive melanin production. This study aimed to design and evaluate a series of indole-thiourea derivatives by conjugating thiosemicarbazones with strong tyrosinase inhibitory activity to indole. Among these derivatives, compound 4b demonstrated tyrosinase inhibitory activity with an IC50 of 5.9 ± 2.47 µM, outperforming kojic acid (IC50 = 16.4 ± 3.53 µM). Kinetic studies using Lineweaver-Burk plots confirmed competitive inhibition by compound 4b. Its favorable ADMET and drug-likeness properties make compound 4b a promising therapeutic candidate with a reduced risk of toxicity. Molecular docking revealed that the compounds bind strongly to mushroom tyrosinase (mTYR) and human tyrosinase-related protein 1 (TYRP1), with compound 4b showing superior binding energies of -7.0 kcal/mol (mTYR) and -6.5 kcal/mol (TYRP1), surpassing both kojic acid and tropolone. Molecular dynamics simulations demonstrated the stability of the mTYR-4b complex with low RMSD and RMSF and consistent Rg and SASA values. Persistent strong hydrogen bonds with mTYR, along with favorable Gibbs free energy and MM/PBSA calculations (-19.37 kcal/mol), further support stable protein-ligand interactions. Overall, compound 4b demonstrated strong tyrosinase inhibition and favorable pharmacokinetics, highlighting its potential for treating pigmentary disorders.
Assuntos
Inibidores Enzimáticos , Indóis , Simulação de Acoplamento Molecular , Monofenol Mono-Oxigenase , Tioureia , Monofenol Mono-Oxigenase/antagonistas & inibidores , Monofenol Mono-Oxigenase/química , Monofenol Mono-Oxigenase/metabolismo , Indóis/química , Indóis/farmacologia , Indóis/síntese química , Tioureia/química , Tioureia/farmacologia , Tioureia/análogos & derivados , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese química , Cinética , Humanos , Simulação de Dinâmica Molecular , Agaricales/enzimologia , Relação Estrutura-AtividadeRESUMO
The inhibition of the hLDHA (human lactate dehydrogenase A) enzyme has been demonstrated to be of great importance in the treatment of cancer and other diseases, such as primary hyperoxalurias. In that regard, we have designed, using virtual docking screening, a novel family of ethyl pyrimidine-quinolinecarboxylate derivatives (13-18)(a-d) as enhanced hLDHA inhibitors. These inhibitors were synthesised through a convergent pathway by coupling the key ethyl 2-aminophenylquinoline-4-carboxylate scaffolds (7-12), which were prepared by Pfitzinger synthesis followed by a further esterification, to the different 4-aryl-2-chloropyrimidines (VIII(a-d)) under microwave irradiation at 150-170 °C in a green solvent. The values obtained from the hLDHA inhibition were in line with the preliminary of the preliminary docking results, the most potent ones being those with U-shaped disposition. Thirteen of them showed IC50 values lower than 5 µM, and for four of them (16a, 18b, 18c and 18d), IC50 ≈ 1 µM. Additionally, all compounds with IC50 < 10 µM were also tested against the hLDHB isoenzyme, resulting in three of them (15c, 15d and 16d) being selective to the A isoform, with their hLDHB IC50 > 100 µM, and the other thirteen behaving as double inhibitors.
Assuntos
Inibidores Enzimáticos , L-Lactato Desidrogenase , Simulação de Acoplamento Molecular , Pirimidinas , Humanos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese química , Pirimidinas/química , Pirimidinas/farmacologia , Pirimidinas/síntese química , L-Lactato Desidrogenase/antagonistas & inibidores , L-Lactato Desidrogenase/metabolismo , L-Lactato Desidrogenase/química , Quinolinas/química , Quinolinas/farmacologia , Quinolinas/síntese química , Relação Estrutura-AtividadeRESUMO
Over the last decades, the increased incidence of metabolic disorders, such as type two diabetes and obesity, has motivated researchers to investigate new enzyme inhibitors. Inhibition of the α-amylase enzyme is one therapeutic approach in lowering glucose levels in the blood to manage diabetes mellitus. The objective of this study was to synthesize short α-/ß-mixed peptides in the solution phase. The Boc-protected α-L-leucine was converted to ß-analogue by using Arndt-Eistert synthesis with the advantage of no racemization and retention of configuration. Three novel short peptides were successfully synthesized: N(Boc)-Gly-ß-Leu-OCH3(14), N(Boc)-O(Bz)α-Ser-ß-Leu-OCH3(16), and N(Boc)-O(Bz)-α-Tyr-α-Gly-ß-Leu-OCH3(17), characterized by FTIR and 1H NMR analysis. The synthesized peptide 16 showed highest inhibitory activity (45.22%) followed by peptide 14 (18.51%) and peptide 17 (17.05%), respectively. Intriguingly, peptide 16 showed higher inhibition on α-amylase compared with other α-/ß-mixed peptides.
Assuntos
Peptídeos , alfa-Amilases , alfa-Amilases/antagonistas & inibidores , Peptídeos/química , Peptídeos/síntese química , Peptídeos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologiaRESUMO
Based on the hypothesis that the 2-mercaptoacetamide moiety chelates the copper ions of tyrosinase, 2-mercapto-N-arylacetamide (2-MAA) analogs were designed and synthesized as potential tyrosinase inhibitors. Four 2-MAA analogs showed low IC50 values ranging from 0.95 to 2.0 µM against mushroom tyrosinase, which was 12-26 times lower than that of kojic acid (IC50 value = 24.3 µM). However, according to a copper ion chelation experiment performed, the 2-MAA analogs did not participate in chelation with copper ions. To identify the mode of inhibition of the 2-MAA analogs, kinetic studies were performed, and the results were supported by docking results. In addition, docking simulation results suggested that the 2-MAA analogs strongly inhibited tyrosinase activity because of the hydrogen bonding of the amide NH group and the hydrophobic interaction of the aryl ring instead of chelation with copper ions. In experiments using B16F10 cells, 2-MAA analogs were shown to inhibit melanin production by inhibiting cellular tyrosinase activity. Western blotting showed that in addition to directly inhibiting tyrosinase activity, analog 7 also has an anti-melanogenic effect by inhibiting the expression of microphthalmia-associated transcription factor (MITF) and tyrosinase. The 2-MAA analogs showed no appreciable cytotoxicity against HaCaT and B16F10 cells, making them suitable for dermal applications. In a depigmentation experiment using zebrafish embryos, analogs 1 and 2 showed more potent depigmentation effects than kojic acid even at 1000 times lower concentration than that of kojic acid. These results suggest that the 2-MAA analogs are promising anti-melanogenic agents that can inhibit most tyrosinases in various species.
Assuntos
Acetamidas , Inibidores Enzimáticos , Melaninas , Monofenol Mono-Oxigenase , Peixe-Zebra , Animais , Monofenol Mono-Oxigenase/antagonistas & inibidores , Monofenol Mono-Oxigenase/metabolismo , Camundongos , Acetamidas/farmacologia , Acetamidas/química , Acetamidas/síntese química , Melaninas/antagonistas & inibidores , Melaninas/metabolismo , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Agaricales/enzimologia , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Linhagem Celular Tumoral , Estrutura Molecular , Relação Dose-Resposta a Droga , HumanosRESUMO
The histone lysine methyltransferase NSD2 has been recognized as an attractive target for cancer treatment, due to the functional implication of its dysregulation in the initiation and progression of many cancers. Although considerable efforts have been made to develop NSD2 small-molecule inhibitors, highly potent and selective ones are still rarely available till now. Here, we report the discovery of a series of novel NSD2 inhibitors via an extensive SAR exploration of the privileged quinazoline scaffold within compound 8. The most promising compound 42 showed excellent NSD2 enzymatic inhibitory activity and good antiproliferative activity in cells. In addition, it demonstrated favorable pharmacokinetic properties and significantly inhibited the tumor growth in a RS411 tumor xenograft model with good safety. Taken together, compound 42 could be a promising NSD2 inhibitor and deserves further investigation.
Assuntos
Histona-Lisina N-Metiltransferase , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Animais , Relação Estrutura-Atividade , Quinazolinas/farmacologia , Quinazolinas/química , Quinazolinas/síntese química , Quinazolinas/farmacocinética , Camundongos , Descoberta de Drogas , Proliferação de Células/efeitos dos fármacos , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/metabolismo , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Ensaios Antitumorais Modelo de Xenoenxerto , Camundongos Nus , RatosRESUMO
Given the considerable potential of DOT1LR231Q inhibitors in lung cancer therapy and the problematic pharmacokinetics of nucleoside inhibitors, our group launched a development program of non-nucleoside DOT1LR231Q inhibitors to improve the pharmacokinetic properties. Herein, two series of non-nucleoside compounds bearing piperidine or 3-(aminomethyl)pyrrolidin-3-ol as "ribose mimics" were designed and evaluated through antiproliferation assay and western blot analysis. The optimal TB22 inhibited the proliferation of H460R231Q cells with an IC50 value of 2.85 µM, about 13-fold more potent than SGC0946. Notably, TB22 demonstrated significant in vivo efficacy (TGI = 60.57%) in H460R231Q cell-derived xenograft models and improved pharmacokinetic properties (t1/2 = 6.06 ± 2.94 h and CL = 55.18 ± 8.56 mL/kg/min). Moreover, a mechanism study validated that TB22 suppressed malignant phenotypes of lung cancer cells harboring R231Q mutation via the MAPK/ERK signaling pathway. This work provides a promising molecule for lung cancer therapy in favor of clinical patients.