RESUMO
Neurodegenerative diseases with progressive cellular loss of the central nervous system and elusive disease etiology provide a continuous impetus to explore drug discovery programmes aiming at identifying robust and effective inhibitors of cholinesterase and monoamine oxidase enzymes. We herein present a concise library of anthranilamide derivatives involving a palladium-catalyzed Suzuki-Miyaura cross-coupling reaction to install the diverse structural diversity required for the desired biological action. Using Ellman's method, cholinesterase inhibitory activity was performed against AChE and BuChE enzymes. In vitro assay results demonstrated that anthranilamides are potent inhibitors with remarkable potency. Compound 6k emerged as the lead candidate and dual inhibitor of both enzymes with IC50 values of 0.12 ± 0.01 and 0.49 ± 0.02 µM against AChE and BuChE, respectively. Several other compounds were found as highly potent and selective inhibitors. Anthranilamide derivatives were also tested against monoamine oxidase (A and B) enzymes using fluorometric method. In vitro data revealed compound 6h as the most potent inhibitor against MAO-A, showing an IC50 value of 0.44 ± 0.02 µM, whereas, compound 6k emerged as the top inhibitor of MAO-B with an IC50 value of 0.06 ± 0.01 µM. All the lead inhibitors were analyzed for the identification of their mechanism of action using Michaelis-Menten kinetics experiments. Compound 6k and 6h depicted a competitive mode of action against AChE and MAO-A, whereas, a non-competitive and mixed-type of inhibition was observed against BuChE and MAO-B by compounds 6k. Molecular docking analysis revealed remarkable binding affinities of the potent inhibitors with specific residues inside the active site of receptors. Furthermore, molecular dynamics simulations were performed to explore the ability of potent compounds to form energetically stable complexes with the target protein. Finally, in silico ADME calculations also demonstrated that the potent compounds exhibit promising pharmacokinetic profile, satisfying the essential criteria for drug-likeness. Altogether, the findings reported in the current work clearly suggest that the identified anthranilamide derivatives have the potential to serve as effective drug candidates for future investigations.
Assuntos
Inibidores da Colinesterase , Desenho de Fármacos , Simulação de Acoplamento Molecular , Inibidores da Monoaminoxidase , Monoaminoxidase , Doenças Neurodegenerativas , ortoaminobenzoatos , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , ortoaminobenzoatos/química , ortoaminobenzoatos/farmacologia , Monoaminoxidase/metabolismo , Monoaminoxidase/química , Humanos , Inibidores da Monoaminoxidase/química , Inibidores da Monoaminoxidase/farmacologia , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/enzimologia , Relação Estrutura-Atividade , Descoberta de Drogas , Colinesterases/metabolismo , Colinesterases/química , Simulação de Dinâmica MolecularRESUMO
Paclitaxel (PTX) is considered the blockbuster chemotherapy treatment for cancer. Paclitaxel's (PTX) oral administration has proven to be extremely difficult, mostly because of its susceptibility to intestinal P-glycoprotein (P-gp) and cytochrome P450 (CYP3A4). The concurrent local inhibition of intestinal P-gp and CYP3A4 is a promising approach to improve the oral bioavailability of paclitaxel while avoiding potential unfavorable side effects of their systemic inhibition. Herein, we report the rational design and evaluation of novel dual potent inhibitors of P-gp and CYP3A4 using an anthranilamide derivative tariquidar as a starting point for their structural optimizations. Compound 14f, bearing N-imidazolylbenzyl side chain, was found to have potent and selective P-gp (EC50 = 28 nM) and CYP3A4 (IC50 = 223 nM) inhibitory activities with low absorption potential (Papp (A-to-B) <0.06). In vivo, inhibitor 14f improved the oral absorption of paclitaxel by 6 times in mice and by 30 times in rats as compared to vehicle, while 14f itself remained poorly absorbed. Compound 14f, possessing dual P-gp and CYP3A4 inhibitory activities, offered additional enhancement in paclitaxel oral absorption compared to tariquidar in mice. Evaluating the CYP effect of 14f on oral absorption of paclitaxel requires considering the variations in CYP expression between animal species. This study provides further medicinal chemistry advice on strategies for resolving concerns with the oral administration of chemotherapeutic agents.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Inibidores do Citocromo P-450 CYP3A , Citocromo P-450 CYP3A , Desenho de Fármacos , ortoaminobenzoatos , Citocromo P-450 CYP3A/metabolismo , Humanos , Animais , ortoaminobenzoatos/farmacologia , ortoaminobenzoatos/química , ortoaminobenzoatos/síntese química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Camundongos , Inibidores do Citocromo P-450 CYP3A/farmacologia , Inibidores do Citocromo P-450 CYP3A/síntese química , Inibidores do Citocromo P-450 CYP3A/química , Relação Estrutura-Atividade , Estrutura Molecular , Modelos Moleculares , Ratos , Relação Dose-Resposta a Droga , Paclitaxel/farmacologia , Paclitaxel/química , MasculinoRESUMO
The biocatalytic aerobic "in-water" reduction of anthranilic acid to 2-aminobenzaldehyde by growing cultures of the basidiomycetous white-rot fungus Bjerkandera adusta has been studied. The high specific activity of Bjerkandera adusta towards the carboxylic group of anthranilic acid that allows avoiding the formation of the corresponding alcohol has been demonstrated using different substrate concentrations. The presence of ethanol as co-solvent allows increasing the yield of target product. In contrast to chemical reducing agents that usually yield 2-aminobenzyl alcohol, an overreduction of anthranilic acid is completely suppressed by the fungus and gives the target flavor compound in satisfactory preparative yields. It was shown that the activity of Bjerkandera adusta towards anthranilic acid does not apply to its m- and p-isomers.
Assuntos
Benzaldeídos , ortoaminobenzoatos , ortoaminobenzoatos/química , ortoaminobenzoatos/metabolismo , Benzaldeídos/química , Benzaldeídos/metabolismo , Oxirredução , Coriolaceae/metabolismo , Coriolaceae/químicaRESUMO
Despite the high global prevalence, rheumatoid arthritis lacks a satisfactory treatment. Hence, the present study is undertaken to design and synthesize novel anti-inflammatory compounds. For this, quinoline and anthranilic acid, two medicinally-privileged moieties, were linked by pharmacophore hybridization, and following their computational assessments, three hybrids 5a-c were synthesized in good over all yields. The in vitro and in vivo anti-inflammatory potential of these hybrids was determined by anti-denaturation and anti-proteinase, and carrageenan-induced paw edema models. The computational studies of these hybrids revealed their drug-likeness, optimum pharmacokinetics, and less toxicity. Moreover, they demonstrated high binding affinity (-9.4 to -10.6 kcal mol-1) and suitable binding interactions for TNF-α, FLAP, and COX-II. A three-step synthetic route resulted in the hybrids 5a-c with 83-86% yield of final step. At 50 µg mL-1, the antiprotease and anti-denaturation activity of compound 5b was significantly higher than 5a and 5c. Furthermore, 5b significantly reduced the edema in the right paw of the rats that received carrageenan. The results of this study indicate the medicinal worth of the novel hybrids in treating inflammatory disorders such as rheumatoid arthritis.
Assuntos
Desenho de Fármacos , Edema , Simulação de Acoplamento Molecular , Quinolinas , ortoaminobenzoatos , Quinolinas/química , Quinolinas/farmacologia , Quinolinas/síntese química , Animais , Edema/tratamento farmacológico , Edema/induzido quimicamente , ortoaminobenzoatos/química , ortoaminobenzoatos/farmacologia , ortoaminobenzoatos/síntese química , Ratos , Carragenina , Masculino , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/síntese química , Estrutura Molecular , Ratos Wistar , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/síntese química , Relação Dose-Resposta a Droga , Relação Estrutura-Atividade , Ciclo-Oxigenase 2/metabolismo , Ciclo-Oxigenase 2/químicaRESUMO
Crystallization is a widely used purification technique in the manufacture of active pharmaceutical ingredients (APIs) and precursor molecules. However, when impurities and desired compounds have similar molecular structures, separation by crystallization may become challenging. In such cases, some impurities may form crystalline solid solutions with the desired product during recrystallization. Understanding the molecular structure of these recrystallized solid solutions is crucial to devise methods for effective purification. Unfortunately, there are limited analytical techniques that provide insights into the molecular structure or spatial distribution of impurities that are incorporated within recrystallized products. In this study, we investigated model solid solutions formed by recrystallizing salicylic acid (SA) in the presence of anthranilic acid (AA). These two molecules are known to form crystalline solid solutions due to their similar molecular structures. To overcome challenges associated with the long 1H longitudinal relaxation times (T1(1H)) of SA and AA, we employed dynamic nuclear polarization (DNP) and 15N isotope enrichment to enable solid-state NMR experiments. Results of solid-state NMR experiments and DFT calculations revealed that SA and AA are homogeneously alloyed as a solid solution. Heteronuclear correlation (HETCOR) experiments and plane-wave DFT structural models provide further evidence of the molecular-level interactions between SA and AA. This research provides valuable insights into the molecular structure of recrystallized solid solutions, contributing to the development of effective purification strategies and an understanding of the physicochemical properties of solid solutions.
Assuntos
Isótopos de Carbono , Cristalização , Espectroscopia de Ressonância Magnética , Isótopos de Nitrogênio , Ácido Salicílico , ortoaminobenzoatos , Espectroscopia de Ressonância Magnética/métodos , Ácido Salicílico/química , Cristalização/métodos , Isótopos de Nitrogênio/química , ortoaminobenzoatos/química , Isótopos de Carbono/química , Soluções/química , Estrutura MolecularRESUMO
Avenanthramide-C (AVN-C) is the biomarker for oat with a variety of physiological functions, whereas its application is constrained by low stability and bioavailability. Avenanthramide-C is the biomarker for oat with a variety of physiological functions, whereas its application is constrained by low stability and bioavailability. This study evaluated the potential of yeast cell (YC) and yeast cell wall (YCW) capsules as delivery systems for stabilizing AVN-C. It was observed that these yeast capsules possessed the ellipsoidal morphology and intact structure without visual pores. Additionally, the YCW capsules exhibited higher encapsulation and loading capacity due to the large internal space. The interaction of yeast capsules with AVN-C involved the hydrophobic interactions and hydrogen bonding. Moreover, the loading of AVN-C induced high hydrophobicity inside the yeast capsules, which helped to protect AVN-C against degradation and release AVN-C in a slow and sustained manner in the simulated gastrointestinal tract. The YCW capsules have potential as controlled delivery system for AVN-C, which could be further used as a nutraceutical and added to functional foods.
Assuntos
Avena , Cápsulas , Parede Celular , Saccharomyces cerevisiae , ortoaminobenzoatos , Avena/química , ortoaminobenzoatos/química , Cápsulas/química , Parede Celular/química , Saccharomyces cerevisiae/química , Saccharomyces cerevisiae/metabolismo , Biomarcadores , Interações Hidrofóbicas e HidrofílicasRESUMO
To increase the structural diversity of insecticides and meet the needs of effective integrated insect management, the structure of chlorantraniliprole was modified based on a previously established three-dimensional quantitative structure-activity relationship (3D-QSAR) model. The pyridinyl moiety in the structure of chlorantraniliprole was replaced with a 4-fluorophenyl group. Further modifications of this 4-fluorophenyl group by introducing a halogen atom at position 2 and an electron-withdrawing group (e.g., iodine, cyano, and trifluoromethyl) at position 5 led to 34 compounds with good insecticidal efficacy against Mythimna separata, Plutella xylostella, and Spodoptera frugiperda. Among them, compound IV f against M. separata showed potency comparable to that of chlorantraniliprole. IV p against P. xylostella displayed a 4.5 times higher potency than chlorantraniliprole. In addition, IV d and chlorantraniliprole exhibited comparable potencies against S. frugiperda. Transcriptome analysis showed that the molecular target of compound IV f is the ryanodine receptor. Molecular docking was further performed to verify the mode of action and insecticidal activity against resistant P. xylostella.
Assuntos
Inseticidas , Mariposas , Animais , Inseticidas/farmacologia , Inseticidas/química , Diamida/farmacologia , Diamida/química , Simulação de Acoplamento Molecular , Mariposas/metabolismo , ortoaminobenzoatos/farmacologia , ortoaminobenzoatos/química , Relação Quantitativa Estrutura-Atividade , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Larva/metabolismoRESUMO
Diamide insecticides have gained popularity due to their high efficacy and low toxicity to nontarget organisms. However, diamide-associated resistance has emerged recently, causing a significant reduction in their potency, thereby hindering sustainable agricultural development. Here, we explored novel diamide insecticide analogs and, using a structure-based approach, rationally designed and synthesized 28 nitrophenyl substituted anthranilic diamides. Most of the compounds showed moderate to good activity against Mythimna separata, Plutella xylostella, and Spodoptera frugiperda. Among them, compounds Ia and Im showed extraordinarily high activity and their mode of action was verified on isolated neurons. Additionally, Im exhibited over 10-fold greater potency than chlorantraniliprole in a HEK293 cell line stably expressing S. frugiperda ryanodine receptors (SfRyRs) containing the resistance mutations, G4891E and I4734M. The binding modes of Im in the SfRyRs were predicted using in silico molecular docking analysis. Our novel nitrophenyl substituted anthranilic diamide derivatives provide valuable insights for the design of insecticidal RyR-targeting compounds to effectively control both wild type and diamide insecticide-resistant lepidopteran pests.
Assuntos
Inseticidas , Mariposas , Animais , Humanos , Diamida/farmacologia , Simulação de Acoplamento Molecular , Células HEK293 , Mariposas/genética , Spodoptera/metabolismo , Inseticidas/farmacologia , Inseticidas/química , ortoaminobenzoatos/farmacologia , ortoaminobenzoatos/química , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Resistência a Inseticidas/genéticaRESUMO
The research and development of organofluorine chemistry has flourished; in particular, monofluoroalkene has aroused considerable interest from medicinal and organic chemists. It is a significant attempt to introduce monofluoroalkene into agrochemicals. In this study, monofluoroalkene was introduced into diamide molecules and inserted between the aliphatic amide and benzene ring, and 44 compounds have been successfully synthesized. The bioassay results showed that compounds with monofluoro-acrylamide moiety (Z-isomers) had excellent larvicidal activity against lepidopteran pests at 5 mg·L-1. The LC50 values of compounds B16, B18, and B21 against Mythimna separata were 1.02, 1.32, and 0.78 mg·L-1, respectively. 3D-QSAR analysis including the CoMFA model and the CoMSIA model was conducted to illustrate the contributions of steric, electrostatic, hydrophobic, and hydrogen bond fields on the bioactivity. Moreover, typical symptoms caused by chlorantraniliprole including dehydration, shrinkage, and blackening were also observed on the test larvae treated with monofluoro-acrylamide diamide compounds. M. separata central neurons calcium imaging experiment of compound B18 indicated that the monofluoro-acrylamide diamide compounds were potential insect ryanodine receptor activators. The molecular docking was performed in the CHL binding domain of Plutella xylostella RyR and revealed that the predicted binding mode of compound B21 was slightly different from that of CHL. The MM|GBSA dG Bind values of B21 and CHL with P. xylostella RyR were respectively -85.797 and -95.641 kcal·mol-1. The present work explored the insecticidal properties of a new diamide scaffold containing a monofluoro-acrylamide fragment and extended the application of monofluoroalkene in the agrochemical field.
Assuntos
Inseticidas , Mariposas , Animais , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Diamida/farmacologia , Diamida/química , Acrilamidas , Simulação de Acoplamento Molecular , Mariposas/metabolismo , Inseticidas/farmacologia , Inseticidas/química , Acrilamida , ortoaminobenzoatos/químicaRESUMO
Three-dimensional quantitative structure-activity relationship (3D-QSAR) is one of the most important and effective tools to direct molecular design in new pesticide development. Chlorantraniliprole is an anthranilic diamide ryanodine receptor (RyR) agonist with ultrahigh activity, high selectivity, and mammalian safety. To continue our studies on new insecticide development, here, we designed new insecticidal N-phenylpyrazoles by using 3D-QSAR of chlorantraniliprole analogues as a guide. Most of the target compounds synthesized exhibited medium to excellent activity against Mythimna separata, Plutella xylostella, and Spodoptera frugiperda. Compounds III b and III y showed similar activity against M. separata as chlorantraniliprole (LC50 values: 0.21, 0.25, and 0.16 µg mL-1 respectively). Compounds III b exhibited a 3-fold higher potency against P. xylostella than chlorantraniliprole. For S. frugiperda, the potency of III a and III b was 2.9 and 2.0 times higher than that of the positive control, respectively. The mode of action of the title compounds was validated by calcium imaging experiments and molecular docking using their target RyRs. III b can dock well with mutated P. xylostella RyRs, implying a potentially lower cross-resistance risk as compared with commercial RyR agonists. Density functional theory calculations suggested the feasibility of higher potency with the structural modifications. Compound III b was found to be an ultrahigh active insecticidal candidate with a broad spectrum for integrated pest management.
Assuntos
Inseticidas , Mariposas , Animais , Inseticidas/farmacologia , Inseticidas/química , Relação Quantitativa Estrutura-Atividade , Larva , Simulação de Acoplamento Molecular , Mariposas/metabolismo , ortoaminobenzoatos/farmacologia , ortoaminobenzoatos/química , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Resistência a Inseticidas , Diamida/química , Mamíferos/metabolismoRESUMO
The world's hunger is continuously rising due to conflicts, climate change, pandemics (such as the recent COVID-19), and crop pests and diseases. It is widely accepted that zero hunger is impossible without using agrochemicals to control crop pests and diseases. Diamide insecticides are one of the widely used green insecticides developed in recent years and play important roles in controlling lepidopteran pests. Currently, eight diamine insecticides have been commercialized, which target the insect ryanodine receptors. This review summarizes the development and optimization processes of diamide derivatives acting as ryanodine receptor activators. The review also discusses pest resistance to diamide derivatives and possible solutions to overcome the limitations posed by the resistance. Thus, with reference to structural biology, this study provides an impetus for designing and developing diamide insecticides with improved insecticidal activities.
Assuntos
COVID-19 , Inseticidas , Mariposas , Animais , Inseticidas/farmacologia , Inseticidas/química , Canal de Liberação de Cálcio do Receptor de Rianodina/química , Diamida/farmacologia , Diamida/química , ortoaminobenzoatos/químicaRESUMO
In order to develop anthranilic diamides with novel chemotypes, a series of anthranilic diamides with acrylamide linkers were designed and synthesized. The results of preliminary bioassays indicated that compounds with a monofluoroalkene amide linker (Z-isomer) exhibited good larvicidal activity against lepidopteran pests. The LC50 values of compound A23 against Mythimna separata and Plutella xylostella were 1.44 and 3.48 mg·L-1, respectively, while those of chlorantraniliprole were 0.08 and 0.06 mg·L-1, respectively. Compound A23 also exhibited the same level of lethal potency against resistant and susceptible strains of Spodoptera frugiperda at 50 mg·L-1. Compound A23 exhibited similar symptoms as chlorantraniliprole in test larvae. Comparative molecular field analysis was conducted to demonstrate the structure-activity relationship. Central neuron calcium imaging experiments indicated that monofluoroalkene compounds were potential ryanodine receptor (RyR) activators and activated calcium channels in both the endoplasmic reticulum and the cell membrane. Molecular docking suggested that A23 had a better binding potency to P. xylostella RyR than chlorantraniliprole. The MM|GBSA dG bind value of A23 with P. xylostella RyR was 117.611 kcal·mol-1. Monofluoroalkene was introduced into anthranilic diamide insecticides for the first time and brought a novel chemotype for insect RyR activators. The feasibility of fluoroalkenes as insecticide fragments was explored.
Assuntos
Inseticidas , Mariposas , Animais , Amidas , Diamida/farmacologia , Diamida/química , Simulação de Acoplamento Molecular , Mariposas/metabolismo , ortoaminobenzoatos/farmacologia , ortoaminobenzoatos/química , Inseticidas/química , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismoRESUMO
Anthranilate phosphoribosyltransferase catalyses the second reaction in the biosynthesis of tryptophan from chorismate in microorganisms and plants. The enzyme is homodimeric with the active site located in the hinge region between two domains. A range of structures in complex with the substrates, substrate analogues and inhibitors have been determined, and these have provided insights into the catalytic mechanism of this enzyme. Substrate 5-phospho-d-ribose 1-diphosphate (PRPP) binds to the C-terminal domain and coordinates to Mg2+, in a site completed by two flexible loops. Binding of the second substrate anthranilate is more complex, featuring multiple binding sites along an anthranilate channel. This multi-modal binding is consistent with the substrate inhibition observed at high concentrations of anthranilate. A series of structures predict a dissociative mechanism for the reaction, similar to the reaction mechanisms elucidated for other phosphoribosyltransferases. As this enzyme is essential for some pathogens, efforts have been made to develop inhibitors for this enzyme. To date, the best inhibitors exploit the multiple binding sites for anthranilate. This article is part of the theme issue 'Reactivity and mechanism in chemical and synthetic biology'.
Assuntos
Antranilato Fosforribosiltransferase , ortoaminobenzoatos , Antranilato Fosforribosiltransferase/química , Antranilato Fosforribosiltransferase/metabolismo , Sítios de Ligação , Domínio Catalítico , ortoaminobenzoatos/química , ortoaminobenzoatos/metabolismoRESUMO
In this study, a method, based on an ultraperformance liquid chromatography coupled with high-field quadrupole orbitrap high-resolution mass spectrometry (UHPLC-QE-HF-HRMS) platform, was established for the trace determination of three major avenanthramides (AVNs). The MS conditions for determining the AVNs were optimized, and the cracking methods of avenanthramides were analyzed. The linear range of the results and the correlation coefficient were 1−2000 µg/L and >0.996, respectively. Further, the established method was employed for the determination of the AVN contents of oats at different germination times, and the results indicated that the AVN contents of Zaohua and Bayou oats increased 19.26 and 6.09 times, respectively, after germination. The total AVN content of both oat varieties reached a maximum on the fifth day of germination (153.51 ± 4.08 and 126.30 ± 3.33 µg/g for the Zaohua and Bayou oats, respectively). Furthermore, this study investigated the antiallergic and antioxidant activities of the germinated oats via hyaluronidase inhibition and 2,2-diphenyl-1-picrylhydrazyl (DPPH)-scavenging assays. The antiallergic and DPPH-scavenging abilities of the ungerminated forms of both oat varieties were weaker. However, on the fifth day of germination, the inhibition rate of anthranilamide hyaluronidase reached 72.7% and 67.3% for the Zaohua and Bayou oat varieties, respectively. The antiallergic abilities of the oats increased significantly on the fifth day of germination in terms of their antiallergic capacities and DPPH clearance (82.67% and 77.64% for the Zaohua and Bayou oats, respectively), and the two indicators exhibited similar trends. These findings demonstrated that AVNs exhibit good antisensitivity and antioxidation properties, and the antisensitivity effect correlated positively with the AVN content.
Assuntos
Antialérgicos , Avena , Antialérgicos/análise , Antioxidantes/química , Avena/química , Grão Comestível/química , Germinação , Hialuronoglucosaminidase , ortoaminobenzoatos/químicaRESUMO
The diamide insecticides show exceptional activity against Lepidoptera insects via activation of ryanodine receptors (RyRs). In the present study, a series of anthranilic diamides containing a fluoroaniline moiety were designed, synthesized, and evaluated for insecticidal potency. Most titled compounds exerted moderate to remarkably high activity against Mythimna separata, Plutella xylostella, and Spodoptera frugiperda. The insecticidal activity of compound II l and II ac against M. separata was 26.7 and 26.7% at 0.1 mg L-1, respectively, equivalent to that of chlorantraniliprole (0.1 mg L-1, 30.0%). Compounds II l, II y, and II z exhibited 8.0-, 1.8-, and 4.7-fold higher potency than chlorantraniliprole against P. xylostella, respectively, as compared with their LC50s. Compounds II k and II aa showed good insecticidal activity against S. frugiperda with LC50 of 0.56 and 0.46 mg L-1, respectively, comparable to that of the commercial insecticide chlorantraniliprole with LC50 of 0.31 mg L-1. Calcium imaging experiments indicated RyRs as the action target. Molecular docking suggested a higher binding energy of 8.647 kcal/mol between II l and the M. separata RyR than the 7.820 kcal/mol between chlorantraniliprole and the M. separata RyR. Meanwhile, the docking results of II l with mutated P. xylostella RyR at site G4946E showed that II l could have a good inhibition effect on the resistant P. xylostella. The density functional theory calculations suggested the importance of the fluoroaniline moiety in potency. Those novel anthranilic diamides containing a fluorinated aniline moiety are good insecticidal candidates.
Assuntos
Inseticidas , Mariposas , Compostos de Anilina/farmacologia , Animais , Diamida/química , Diamida/farmacologia , Inseticidas/química , Inseticidas/farmacologia , Simulação de Acoplamento Molecular , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Relação Estrutura-Atividade , ortoaminobenzoatos/química , ortoaminobenzoatos/farmacologiaRESUMO
Reconsideration of the spectroscopic data for penipacids A-E, first reported in 2013 as the acyclic amidines 1-5 from the South China deep sea sediment-derived fungus Penicillium paneum SD-44, prompted a total synthesis structure revision as the hydrazones 6-10. This revision strongly supported the proposition that penipacids A-B (6-7) were artifact Schiff base adducts of the cryptic (undetected) natural product N-aminoanthranilic acid (11) with diacetone alcohol, induced by excessive exposure to acetone and methanol under acidic handling conditions. Likewise, the revised structures for penipacids C-D (8-9) and E (10) raise the possibility that they may also be artifact Schiff base adducts of 11 and the media constituents pyruvic acid and furfural, respectively. A review of the natural products literature revealed other Schiff base (hydrazone) natural products that might also be viewed as Schiff base adduct artifacts of 11. Having raised the prospect that 11 is an undetected and reactive cryptic natural product, we went on to establish that 11 is not cytotoxic to a range of bacterial, fungal or mammalian (human) cell types. Instead, when added as a supplement to microbial cultivations, 11 can act as a chemical cue/transcriptional regulator, activating and/or enhancing the yield of biosynthetic gene clusters encoding for other natural product chemical defenses. This study demonstrates the value of challenging the structure and artifact status of natural products, as a window into the hidden world of cryptic and highly reactive natural products.
Assuntos
Produtos Biológicos , ortoaminobenzoatos , Bactérias/genética , Bactérias/metabolismo , Produtos Biológicos/química , Humanos , Família Multigênica , Bases de Schiff , Metabolismo Secundário , ortoaminobenzoatos/químicaRESUMO
BACKGROUND: Diamide insecticides have attracted significant attention due to their high efficacy and low toxicity to non-target organisms since they were introduced to the market. In order to tackle the problems of insecticide resistance and ecological safety, 16 novel nitrobenzene substituted anthranilic diamides with ester, hydroxyl or sulfonyl at the 3-position of the pyrazole ring were designed and synthesized. RESULTS: All of these compounds possessed good activity against the ryanodine receptor (RyR) from Spodoptera frugiperda and relatively lower activity against mammalian RyR1, showing a better insect-selectivity compared to chlorantraniliprole in a cell-based assay. The molecular docking analysis predicted the binding conformations of these compounds, which showed a good correlation between the insecticidal activity and the binding scores. In vitro studies using a calcium imaging method demonstrated that the novel compounds could not only activate the RyR but may also target the dihydropyridine receptor on the plasma membrane of insect neurons, implicating a similar but not same mode of action. CONCLUSION: Substituted anthranilic diamides with an ester at the 3-position of the pyrazole ring exhibited a promising insecticidal activity and better insect-selectivity, which provided insight into the rational design of a new generation of effective diamide insecticides.
Assuntos
Inseticidas , Mariposas , Animais , Diamida/química , Diamida/farmacologia , Ésteres/farmacologia , Inseticidas/química , Mamíferos/metabolismo , Simulação de Acoplamento Molecular , Mariposas/metabolismo , Pirazóis , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , ortoaminobenzoatos/química , ortoaminobenzoatos/farmacologiaRESUMO
Streptomycetes are major producers of bioactive natural products, including the majority of the naturally produced antibiotics. While much of the low-hanging fruit has been discovered, it is predicted that less than 5% of the chemical space of natural products has been mined. Here, we describe the discovery of the novel actinomycins L1 and L2 produced by Streptomyces sp. MBT27, via application of metabolic analysis and molecular networking. Actinomycins L1 and L2 are diastereomers, and the structure of actinomycin L2 was resolved using NMR and single crystal X-ray crystallography. Actinomycin L is formed via spirolinkage of anthranilamide to the 4-oxoproline moiety of actinomycin X2, prior to the condensation of the actinomycin halves. Such a structural feature has not previously been identified in naturally occurring actinomycins. Adding anthranilamide to cultures of the actinomycin X2 producer Streptomyces antibioticus, which has the same biosynthetic gene cluster as Streptomyces sp. MBT27, resulted in the production of actinomycin L. This supports a biosynthetic pathway whereby actinomycin L is produced from two distinct metabolic routes, namely those for actinomycin X2 and for anthranilamide. Actinomycins L1 and L2 showed significant antimicrobial activity against Gram-positive bacteria. Our work shows how new molecules can still be identified even in the oldest of natural product families.
Assuntos
Antibacterianos/uso terapêutico , Produtos Biológicos/uso terapêutico , Dactinomicina/química , Streptomycetaceae/química , Antibacterianos/química , Produtos Biológicos/química , Vias Biossintéticas/efeitos dos fármacos , Dactinomicina/análogos & derivados , Dactinomicina/uso terapêutico , Bactérias Gram-Positivas/efeitos dos fármacos , Bactérias Gram-Positivas/patogenicidade , Humanos , Streptomyces antibioticus/química , Streptomycetaceae/genética , ortoaminobenzoatos/químicaRESUMO
Aromatic cyclic ß2,3-amino acids (cßAAs), such as 2-aminobenzoic acid and 3-aminothiophene-2-carboxylic acid, are building blocks that can induce unique folding propensities of peptides. Although their ribosomal elongation had been a formidable task due to the low nucleophilicity of their amino groups, we have recently overcome this issue by means of an engineered tRNAPro1E2 that enhances their incorporation efficiency into nascent peptide chains. Here we report ribosomal synthesis of a random macrocyclic peptide library containing aromatic and aliphatic cßAAs, and its application to de novo discovery of binders against human IFNGR1 and FXIIa as model targets. The potent binding peptides showed not only high inhibitory activity but also high protease resistance in human serum. Moreover, these cßAAs play a critical role in exhibiting their properties, establishing a discovery platform for de novo foldamer-like macrocycles containing such unique building blocks.
Assuntos
Ácidos Carboxílicos/química , Compostos Macrocíclicos/química , Peptídeos Cíclicos/química , ortoaminobenzoatos/química , Sequência de Aminoácidos , Engenharia Química , Humanos , Compostos Macrocíclicos/metabolismo , Biblioteca de Peptídeos , Peptídeos Cíclicos/metabolismo , Ligação Proteica , Ribossomos , SoroRESUMO
To complement the knowledge on the anti-inflammatory activity of methyl and isopropyl N-methylanthranilates, two natural products with panacea-like properties, we investigated their effects on thioglycolate-elicited macrophages by evaluating macrophage ability to metabolize MTT, macrophage membrane function, and macrophage myeloperoxidase and phagocytic activities. Moreover, two additional aspects of the inflammatory response of these compounds, their inhibitory activity on xanthine oxidase and catalase, were studied. It was found that these two compounds regulate elicited macrophage functions, most probably by interfering with the function of cell membranes and changing the reducing cellular capacity or enzyme activity of macrophages. Nonetheless, no significant inhibitory action either towards xanthine oxidase or catalase was found, suggesting that the inhibition of these enzymes is not involved in the anti-inflammatory mode of action of these two esters.