Crystal structure of Fatty Acid Thioesterase A bound by 129 fragments provides diverse development opportunities DOI Open Access
Eva Kot, Matteo P. Ferla,

Patricia H. Hollinshead

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 25, 2024

Abstract To alleviate the growing issue of herbicide resistance, diversification portfolio is necessary. A promising yet underutilised mode action (MoA) are Fatty Acid Thioesterases (Fat), which terminate de novo fatty acid (FA) biosynthesis by releasing acids from acyl carrier protein (ACP) cofactors. These enzymes impact plant growth and sterility determining amount length FAs present. find novel chemical matter targeting this MoA we have solved crystal structure Arabidopsis thaliana FatA to 1.5Å conducted a crystallographic fragment screen identified 141 hits. Our fragments recapitulated interactions made current herbicides, but also targeted regions, namely active site dimer interface. Ten demonstrated on-scale potency, two those exploiting different known herbicides. The revealed large conformational changes exploited some fragments, including stabilisation loop shifts in ACP-binding lid domain. alter accessibility substrate binding reducing size apparent access channel. Finally, readily lend themselves designing compounds that both merge motifs allow catalogue-based SAR exploration. Elaboration one resulted an improvement affinity ∼20 μM ∼90nM KD. Thus our data may facilitate accelerated early discovery alternative inhibitors scaffolds modes interaction.

Language: Английский

Synthesis and biological profile of 2,3-dihydro[1,3]thiazolo[4,5-b]pyridines, a novel class of acyl-ACP thioesterase inhibitors DOI Creative Commons
Jens Frackenpohl, David M. Barber,

Guido Bojack

et al.

Beilstein Journal of Organic Chemistry, Journal Year: 2024, Volume and Issue: 20, P. 540 - 551

Published: March 1, 2024

The present work covers novel herbicidal lead structures that contain a 2,3-dihydro[1,3]thiazolo[4,5- b ]pyridine scaffold as structural key feature carrying substituted phenyl side chain. These new compounds show good acyl-ACP thioesterase inhibition in line with strong activity against commercially important weeds broadacre crops, e.g., wheat and corn. desired ]pyridines were prepared via an optimized BH 3 -mediated reduction involving tris(pentafluorophenyl)borane Lewis acid. Remarkably, greenhouse trials showed some of the target outlined herein display promising control grass weed species preemergence application, combined dose response window enables partial selectivity certain crops.

Language: Английский

Citations

6
Discovery and optimization of spirocyclic lactams that inhibit acyl‐ACP thioesterase DOI

Elisabeth Asmus,

David M. Barber,

Guido Bojack

et al.

Pest Management Science, Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 9, 2024

There are various methods to control weeds, that represent considerable challenges for farmers around the globe, although applying small molecular compounds is still most effective and versatile technology date. In search novel chemical entities with new modes-of-action can weeds displaying resistance, we have investigated two spirocyclic classes of acyl-ACP thioesterase inhibitors based on X-ray co-crystal structures subsequent modelling studies.

Language: Английский

Citations

5
Design, synthesis, crystal structure, fungicidal activity, and mechanism of action of novel thiazole-based hydrazide derivatives containing the 4-aminoquinazoline moiety DOI

Mingyan Yi,

Hong Li, Sha Li

et al.

Bioorganic Chemistry, Journal Year: 2025, Volume and Issue: 156, P. 108237 - 108237

Published: Feb. 2, 2025

Language: Английский

Citations

0
Aminoisothiazolamides, a new class of potent inhibitors of lysyl‐tRNA synthetase DOI Creative Commons
David Bernier, David M. Barber,

Guido Bojack

et al.

Pest Management Science, Journal Year: 2025, Volume and Issue: unknown

Published: March 14, 2025

Abstract Background Owing to the economic relevance of resistance evolution against herbicides, new chemical entities addressing unprecedented molecular targets are urgently needed develop future sustainable weed control solutions. As part our discovery research, class aminoisothiazolamides was investigated. Results Aminoisothiazolamide 3‐amino‐4‐chloro‐N‐(cyclohexylmethyl)isothiazole‐5‐carboxamide 1a and several its derivatives displayed potent herbicidal fungicidal in vivo activity initial glasshouse tests. Lysyl‐tRNA synthetase 1 (KRS1) identified as putative target for validated a key contributor biochemical mode‐of‐action aminoisothiazolamides. Thermal stability shift analysis with KRS1 from Arabidopsis thaliana ( At KRS1) revealed that specifically increased thermostability this enzyme, proving enzyme aminoisothiazolamide target. It turned out inhibition Hs KRS strongly correlated, Hence, acute toxicity tests were initiated at very early project stage complementing Conclusion The observed toxicological effects paired anticipated likelihood overcome problem, owing highly conserved active sites different species, finally resulted conclusion stop further exploration otherwise promising Thus, we opted discard lead structures before start in‐depth investigations when sequence analyses suggested similar levels conservation between respective binding pockets plants mammalians. © 2025 Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf Society Chemical Industry.

Language: Английский

Citations

0
Synthesis and biological profile of substituted hexahydrofuro[3,4‐b]furans, a novel class of bicyclic acyl‐acyl carrier protein (ACP) thioesterase inhibitors DOI Creative Commons

Hartmut Ahrens,

David M. Barber,

Guido Bojack

et al.

Pest Management Science, Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 6, 2024

Abstract BACKGROUND Weed control is a significant challenge for farmers around the globe. Of various methods available combatting weeds, small molecules remain most effective and versatile technology to date. In search novel chemical entities with new modes of action toward herbicide‐resistant we have investigated hexahydrofuro[3,4‐ b ]furan‐based acyl‐acyl carrier protein (ACP) thioesterase inhibitors inspired by X‐ray co‐crystal structure‐based modeling studies. RESULTS By exploiting scaffold hopping concepts molecular studies were able identify lead structures showing promising activity in vivo against commercially important grass weeds line strong target affinity. CONCLUSION The present work covers series herbicidal that possess ]furan as structural key feature, carrying ortho‐substituted aryloxy side chains. Based on an optimized synthetic approach broad structure–activity relationship (SAR) study was carried out. compounds emerging from our modeling‐inspired variations show good acyl‐ACP inhibition initial activity. Glasshouse trials showed ]furans outlined herein display cold warm season grass‐weed species pre‐emergence application. Remarkably, some thioesterase‐inhibitors also efficacy are difficult control. © 2024 Author(s). Pest Management Science published John Wiley & Sons Ltd behalf Society Chemical Industry.

Language: Английский

Citations

2
Scaffold hopping approaches for the exploration of herbicidally active compounds inhibiting Acyl‐ACP Thioesterase DOI Creative Commons
Tyler Fahrenhorst‐Jones, Stephanie Lee,

Birgit Bollenbach‐Wahl

et al.

Pest Management Science, Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 19, 2024

Abstract BACKGROUND The sustainable control of weed populations is a significant challenge facing farmers around the world. Although various methods for weeds exist, use small molecule herbicides remains most effective and versatile approach. Striving to find novel that combat resistant via targeting plant specific modes action (MoAs), we further investigated bicyclic class acyl‐acyl carrier protein (ACP) thioesterase (FAT) inhibitors in an effort safe efficacious lead candidates. RESULTS Utilizing scaffold hopping bioisosteric replacements strategies, explored new FAT. Amongst compounds identified structural motifs showed promising target affinity coupled with good vivo efficacy against commercially important species. We studied structure–activity relationship (SAR) dihydropyranopyridine which promise as type FAT inhibiting herbicides. CONCLUSION current work presents how approaches can be implemented successfully herbicidal structures optimized potential agricultural practices. were demonstrated have vitro inhibitory activity MoA well showing variety species, particularly grass greenhouse trials on levels competitive commercial standards. © 2024 Author(s). Pest Management Science published by John Wiley & Sons Ltd behalf Society Chemical Industry.

Language: Английский

Citations

2
Investigation of acetyl‐CoA carboxylase‐inhibiting herbicides that exhibit soybean crop selectivity DOI Creative Commons
Stephanie J. Lee, China M. Payne, Shaun Rees

et al.

Pest Management Science, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 12, 2024

Abstract The sustainable control of weed populations, particularly resistant species, is a significant challenge in agriculture around the world. α‐aryl‐keto‐enol (aryl‐KTE) class acetyl‐CoA carboxylase (ACCase)‐inhibiting herbicides represent possible solution for grasses even though achieving crop selectivity remains challenge. Herein, we present some our investigations into identifying most promising structural features within aryl‐KTE that give highest chance soybean selectivity, whilst also maintaining strong and broad efficacy against problematic species. We further examined results by preparing new molecules which were evaluated glasshouse screening assays their herbicidal as well selectivity. consider uniting this approach with other optimization criteria, such toxicological environmental safety profiles, will enable streamlining protection optimizations programmes, ultimately delivering safer more solutions to farmers consumers. © 2024 Author(s). Pest Management Science published John Wiley & Sons Ltd on behalf Society Chemical Industry.

Language: Английский

Citations

2
Recent advances in the synthesis of thiazolo[4,5-b]pyridines. Part 1: Focus on pyridine annulation to thiazole ring (microreview) DOI
Taras Chaban, O.V. Klenina,

Ihor H. Chaban

et al.

Chemistry of Heterocyclic Compounds, Journal Year: 2024, Volume and Issue: 60(1-2), P. 35 - 37

Published: Feb. 1, 2024

Language: Английский

Citations

1
Thiazole and Isothiazole Chemistry in Crop Protection DOI
Jiaxin Wang,

Anjing Liao,

R. Guo

et al.

Journal of Agricultural and Food Chemistry, Journal Year: 2024, Volume and Issue: 73(1), P. 30 - 46

Published: Dec. 27, 2024

Thiazole and isothiazole are types of five-membered heterocycles that contain both sulfur nitrogen atoms. They have gained attention in the field green pesticide research due to their low toxicity, strong biological activity, ability undergo diverse structural modifications. By incorporating thiazole groups into various compounds, researchers been able create a wide range pesticides with broad-spectrum effectiveness. Understanding relationship between structure these compounds activities is crucial for development new highly potent pesticides. This review highlights derivatives aims inspire innovative based on structures.

Language: Английский

Citations

1
Recent advances in the synthesis of thiazolo[4,5-b]pyridines. Part 2: Focus on thiazole annulation to pyridine ring (microreview) DOI
Taras Chaban, O.V. Klenina,

Ihor H. Chaban

et al.

Chemistry of Heterocyclic Compounds, Journal Year: 2024, Volume and Issue: 60(3-4), P. 130 - 132

Published: April 1, 2024

Language: Английский

Citations

0