Novel metabolic enzyme inhibitors designed through the molecular hybridization of thiazole and pyrazoline scaffolds

AbstractHerbicide-resistant Echinochloa species are among the most problematic weeds in agricultural crops globally. Recurring herbicide selection pressure in the absence of diverse management practices has resulted in greater than 20% of sampled Echinochloa populations from rice (Oryza sativa L.) fields demonstrating multiple resistance to herbicides in Arkansas, USA. We assessed the resistance profile and potential mechanisms of resistance in a multiple herbicide–resistant junglerice [Echinochloa colona (L.) Link] (ECO-R) population. Whole-plant and laboratory bioassays were conducted to identify the potential mechanisms of non–target site resistance in this population. ECO-R was highly resistant to propanil (>37,800 g ha−1) and quinclorac (>17,920 g ha−1) and had elevated tolerance to cyhalofop (R/S = 1.9) and glufosinate (R/S = 1.2) compared to the susceptible standard. The addition of glufosinate (590 g ha−1) to cyhalofop (314 g ha−1), propanil (4,500 g ha−1), or quinclorac (560 g ha−1) controlled ECO-R 100%. However, cyhalofop applied with propanil (48% control) or quinclorac (15% control) was antagonistic. The application of the known metabolic enzyme inhibitors malathion, carbaryl, and piperonyl butoxide increased control of ECO-R with propanil (>75%) but not with other herbicides. Neither absorption nor translocation of [14C]cyhalofop or propanil was different between ECO-R and ECO-S. [14C]Quinclorac absorption was also similar between ECO-R and ECO-S; however, translocation of quinclorac into tissues above the treated leaf of ECO-R was >20% higher than that in ECO-S. The abundance of metabolites was higher (∼10%) in the treated leaves of ECO-R than in ECO-S beginning 48 h after treatment. The activity of β-cyanoalanine synthase, which detoxifies hydrogen cyanide, was not different between ECO-R and ECO-S following quinclorac treatment. Resistance to propanil was due to herbicide detoxification by metabolic enzymes. Resistance to quinclorac was due to a detoxification mechanism yet to be understood. The reduction in sensitivity to cyhalofop and glufosinate might be a secondary effect of the mechanisms conferring high resistance to propanil and quinclorac.

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Simulating serial-target antibacterial drug synergies using flux balance analysis

10.1101/030791 ◽

2015 ◽

Author(s):

Andrew S Krueger ◽

Christian Munck ◽

Gautam Dantas ◽

George M Church ◽

James Galagan ◽

...

Keyword(s):

Flux Balance Analysis ◽

Enzyme Inhibitors ◽

Metabolic Inhibitors ◽

Metabolic Enzyme ◽

Antibacterial Drug ◽

Flux Balance ◽

Single Target ◽

Metabolic Systems ◽

Balance Analysis ◽

Genome Scale

Flux balance analysis (FBA) is an increasingly useful approach for modeling the behavior of metabolic systems. However, standard FBA modeling of genetic knockouts can not predict drug combination synergies observed between serial metabolic targets, even though such synergies give rise to some of the most widely used antibiotic treatments. Here we extend FBA modeling to simulate responses to chemical inhibitors at varying concentrations, by diverting enzymatic flux to a waste reaction. This flux diversion yields very similar qualitative predictions to prior methods for single target activity. However, we find very different predictions for combinations, where flux diversion, which mimics the kinetics of competitive metabolic inhibitors, can explain serial target synergies between metabolic enzyme inhibitors that we confirmed in Escherichia coli cultures. FBA flux diversion opens the possibility for more accurate genome-scale predictions of drug synergies, which can be used to suggest treatments for infections and other diseases.

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Quinoline‐based promising anticancer and antibacterial agents, and some metabolic enzyme inhibitors

Archiv der Pharmazie ◽

10.1002/ardp.202000086 ◽

2020 ◽

Vol 353 (9) ◽

pp. 2000086 ◽

Cited By ~ 4

Author(s):

Salih Ökten ◽

Ali Aydın ◽

Ümit M. Koçyiğit ◽

Osman Çakmak ◽

Sultan Erkan ◽

...

Keyword(s):

Antibacterial Agents ◽

Enzyme Inhibitors ◽

Metabolic Enzyme

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Enzymatic detoxification strategies for neurotoxic insecticides in adults of three tortricid pests

Bulletin of Entomological Research ◽

10.1017/s0007485319000415 ◽

2019 ◽

Vol 110 (1) ◽

pp. 144-154 ◽

Cited By ~ 2

Author(s):

M.A. Navarro-Roldán ◽

D. Bosch ◽

C. Gemeno ◽

M. Siegwart

Keyword(s):

Enzyme Inhibitors ◽

Cydia Pomonella ◽

Lobesia Botrana ◽

Metabolic Enzyme ◽

Adult Males ◽

Insect Mortality ◽

Neurotoxic Insecticides ◽

Enzyme Families ◽

Susceptible Populations

AbstractWe examined the role of the most important metabolic enzyme families in the detoxification of neurotoxic insecticides on adult males and females from susceptible populations of Cydia pomonella (L.), Grapholita molesta (Busck), and Lobesia botrana (Denis & Schiffermüller). The interaction between the enzyme families – carboxylesterases (EST), glutathione-S-transferases (GST), and polysubstrate monooxygenases (PSMO) – with the insecticides – chlorpyrifos, λ-cyhalothrin, and thiacloprid – was studied. Insect mortality arising from the insecticides, with the application of enzyme inhibitors – S,S,S-tributyl phosphorotrithioate (DEF), diethyl maleate (DEM), and piperonyl butoxide (PBO) – was first determined. The inhibitors' influence on EST, GST, and PSMO activity was quantified. EST and PSMO (the phase-I enzymatic activities) were involved in the insecticide detoxification in the three species for both sexes, highlighting the role of EST, whereas GST (phase-II enzymes) was involved only in G. molesta insecticide detoxification. L. botrana exhibited, in general, the highest level of enzymatic activity, with a significantly higher EST activity compared with the other species. It was the only species with differences in the response between sexes, with higher GST and PSMO activity in females than in males, which can be explained as the lower susceptibility of the females to the tested insecticides. A positive correlation between PSMO activity and the thiacloprid LD50s in the different species-sex groups was observed explaining the species-specific differences in susceptibility to the product reported in a previous study.

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Key Metabolic Enzymes Involved in Remdesivir Activation in Human Lung Cells

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00602-21 ◽

2021 ◽

Author(s):

Ruidong Li ◽

Albert Liclican ◽

Yili Xu ◽

Jared Pitts ◽

Congrong Niu ◽

...

Keyword(s):

Enzyme Inhibitors ◽

Human Lung ◽

Bioinformatic Analysis ◽

Metabolic Enzyme ◽

Nucleoside Triphosphate ◽

Target Cells ◽

Lung Cells ◽

Human Lung Tissue ◽

Key Enzymes ◽

Human Lung Cells

Remdesivir (RDV; GS-5734; Veklury®), the first FDA-approved antiviral to treat COVID-19, is a single diastereomer monophosphoramidate prodrug of an adenosine analogue. RDV is taken up in the target cells and metabolized in multiple steps to form the active nucleoside triphosphate (TP) (GS-443902), which in turn acts as a potent and selective inhibitor of multiple viral RNA polymerases. In this report, we profiled the key enzymes involved in the RDV metabolic pathway with multiple parallel approaches: (1) bioinformatic analysis of nucleoside/tide metabolic enzyme mRNA expression using public human tissue and lung single-cell RNAseq datasets; (2) protein and mRNA quantification of enzymes in human lung tissue and primary lung cells; (3) biochemical studies on the catalytic rate of key enzymes; (4) effects of specific enzyme inhibitors on the GS-443902 formation; and (5) the effects of these inhibitors on RDV antiviral activity against SARS-CoV-2 in cell culture. Our data collectively demonstrated that carboxylesterase 1 (CES1) and cathepsin A (CatA) are enzymes involved in hydrolyzing RDV to its alanine intermediate Met X, which is further hydrolyzed to the monophosphate form by histidine triad nucleotide-binding protein 1 (HINT1). The monophosphate is then consecutively phosphorylated to diphosphate and triphosphate by cellular phosphotransferases. Our data support the hypothesis that the unique properties of RDV prodrug not only allow lung-specific accumulation critical for the treatment of respiratory viral infection such as COVID-19, they also enable efficient intracellular metabolism of RDV and its Met X to monophosphate and successive phosphorylation to form the active TP in disease-relevant cells.

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