Synthesis and fungicidal activity of tubulin polymerisation promoters. Part 1: pyrido[2,3‐<i>b</i>]pyrazines

Crowley, Patrick; Lamberth, Clemens; Müller, Urs; Wendeborn, Sebastian; Nebel, K.; Williams, John C.; Sageot, Olivia‐A.; Carter, Neil; Mathie, Tanya; Kempf, Hans‐Joachim; Godwin, Jeremy; Peter, S; Dobler, M.

doi:10.1002/ps.1852

Cited by 27 publications

(18 citation statements)

References 28 publications

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“…Furthermore, screening programs directed at the discovery of antifungal agents identified multiple series of synthetic mono- and di-heterocyclic compounds with MT-stabilizing properties, including certain triazolopyrimidines, typified by cevipabulin 227 (also known as TTI-237, 62 , Figure 16A), as well as some structurally related phenylpyrimidines 228 (Figure 16B), pyridopyridazines, 229 pyridotriazines 230 (Figure 16C) and pyridazines 231 ( e.g. , 63 , Figure 16D).…”

Section: Mt-stabilizing Natural Products and Analogues Thereofmentioning

confidence: 99%

Microtubule Stabilizing Agents as Potential Treatment for Alzheimer’s Disease and Related Neurodegenerative Tauopathies

et al. 2012

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The microtubule (MT)-associated protein tau, which is highly expressed in the axons of neurons, is an endogenous MT-stabilizing agent that plays an important role in the axonal transport. Loss of MT-stabilizing tau function, caused by misfolding, hyperphosphorylation and sequestration of tau into insoluble aggregates, leads to axonal transport deficits with neuropathological consequences. Several in vitro and preclinical in vivo studies have shown that MT-stabilizing drugs can be utilized to compensate for the loss of tau function and to maintain/restore an effective axonal transport. These findings indicate that MT-stabilizing compounds hold considerable promise for the treatment of Alzheimer disease and related tauopathies. The present article provides a synopsis of the key findings demonstrating the therapeutic potential of MT-stabilizing drugs in the context of neurodegenerative tauopathies, as well as an overview of the different classes of MT-stabilizing compounds.

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Section: Mt-stabilizing Natural Products and Analogues Thereofmentioning

confidence: 99%

Microtubule Stabilizing Agents as Potential Treatment for Alzheimer’s Disease and Related Neurodegenerative Tauopathies

et al. 2012

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“…S1). The triazolopyrimidine bicycle of the former developmental compound BAS600F ( 16 ) could be successfully replaced by a 6,6‐bicyclic pyridopyrazine ( 17 ) or pyridotriazine ( 18 ), a ring‐opened pyrazolyl‐pyrazinone ( 19 ), or a monocyclic pyridazine ( 20 ), imidazole ( 21 ) or pyrazole ( 22 ) . All of these ring‐isosteric analogs share a similar substitution pattern with their lead compound 16 .…”

Section: Scaffold Hopping Via Isosteric Ring Replacementmentioning

confidence: 99%

Agrochemical lead optimization by scaffold hopping

Lamberth

2017

Pest Management Science

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Scaffold hopping, the exchange of a specific portion of a potential active ingredient with another substructure with the aim of finding isofunctional molecular structures with significantly different molecular backbones, often offers the chance in lead discovery or optimization to mitigate problems related to toxicity, intellectual property, and insufficient potency or stability. Scaffold hopping tools such as isosteric ring replacement including 1,3 nitrogen shift and cyclic imine-amide isosterism, but also ring opening and ring closure approaches, functional group isosterism, reversion of functional groups, chain shortening, chain lengthening, and scaffolds delivered by natural products, have become a permanent fixture of the innovation and optimization process in crop protection research. Their appropriate use will be explained through examples of success stories in the field of agrochemistry. Analogies to, but also differences from, the main categories of scaffold hopping in medicinal drug discovery are discussed. © 2017 Society of Chemical Industry.

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“…Originally reported as anti-fungal agents, microtubule (MT)-active [1,2,4]triazolo[1,5-a]pyrimidines and related heterocyclic molecules 1–5 have since attracted attention as potential candidates for a variety of applications including cancer chemotherapy, 6 as well as neurodegenerative disease treatment. 7–10 The mechanism of action of this class of compounds has been the focus of several studies and appears to be distinct from that of other MT-targeting agents.…”

mentioning

confidence: 99%

Design, synthesis and evaluation of photoactivatable derivatives of microtubule (MT)-active [1,2,4]triazolo[1,5-a]pyrimidines

Oukoloff

Kovalevich

Cornec

et al. 2018

Bioorganic & Medicinal Chemistry Letters

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The [1,2,4]triazolo[1,5-a]pyrimidines comprise a promising class of non-naturally occurring microtubule (MT)-active compounds. Prior studies revealed that different triazolopyrimidine substitutions can yield molecules that either promote MT stabilization or disrupt MT integrity. These differences can have important ramifications in the therapeutic applications of triazolopyrimidines and suggest that different analogues may exhibit different binding modes within the same site or possibly interact with tubulin/MTs at alternative binding sites. To help discern these possibilities, a series of photoactivatable triazolopyrimidine congeners was designed, synthesized and evaluated in cellular assays with the goal of identifying candidate probes for photoaffinity labeling experiments. These studies led to the identification of different derivatives that incorporate a diazirine ring in the amine substituent at position 7 of the triazolopyrimidine heterocycle, resulting in molecules that either promote stabilization of MTs or disrupt MT integrity. These photoactivatable candidate probes hold promise to investigate the mode of action of MT-active triazolopyrimidines.

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Synthesis and fungicidal activity of tubulin polymerisation promoters. Part 1: pyrido[2,3‐b]pyrazines

Cited by 27 publications

References 28 publications

Microtubule Stabilizing Agents as Potential Treatment for Alzheimer’s Disease and Related Neurodegenerative Tauopathies

Microtubule Stabilizing Agents as Potential Treatment for Alzheimer’s Disease and Related Neurodegenerative Tauopathies

Agrochemical lead optimization by scaffold hopping

Design, synthesis and evaluation of photoactivatable derivatives of microtubule (MT)-active [1,2,4]triazolo[1,5-a]pyrimidines

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