Synthesis and SAR study of acridine, 2-methylquinoline and 2-phenylquinazoline analogues as anti-prion agents

Cope, Hannah; Mutter, Roger; Heal, William P.; Pascoe, Cameron A.; Brown, Paul E.; Pratt, Steve D.; Chen, B.

doi:10.1016/j.ejmech.2006.05.002

Cited by 42 publications

(22 citation statements)

References 26 publications

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“…This has been achieved by ligands binding the structured part of PrP C and able to form a stable protein-ligand complex that blocks the confor- Figure 3E) [79][80][81][83][84][85][86][87][88]. The protein-ligand complex might lower the free energy of the native folded state and consequently reduce the rate of misfolding [89].…”

Section: From Bivalent To Mtlsmentioning

confidence: 95%

Multitarget Ligands and Theranostics: Sharpening the Medicinal Chemistry Sword Against Prion Diseases

2014

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Prion diseases (PrDs) are fatal neurodegenerative disorders, for which no effective therapeutic and diagnostic tools exist. The main pathogenic event has been identified as the misfolding of a disease-associated prion protein. Nevertheless, pathogenesis seems to involve an intricate array of concomitant processes. Thus, it may be unlikely that drugs acting on single targets can effectively control PrDs. In addition, diagnosis occurs late in the disease process, by which point it is difficult to determine a successful therapeutic intervention. In this context, multitarget ligands (MTLs) and theranostic ligands (TLs) emerge for their potential to effectively cure and diagnose PrDs. In this review, we discuss the medicinal chemistry challenges of identifying novel MTLs and TLs against PrDs, and envision their impact on prion drug discovery.

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Section: From Bivalent To Mtlsmentioning

confidence: 95%

Multitarget Ligands and Theranostics: Sharpening the Medicinal Chemistry Sword Against Prion Diseases

2014

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“…Thus, stably infected cell lines acting as a host for PrP Sc are routinely employed for in vitro screening of potential antiprion agents. [5] We previously reported the use of a scrapie mouse brain (SMB) cell line, [6,7] cloned from murine brain infected with the Chandler scrapie strain, in the identification of a number of active inhibitors of PrP Sc accumulation across four distinct structural classes: 9-aminoacridines and related compounds, [8] pyridine-3,5-dicarbonitriles, [9] indole-3-glyoxylamides, [10] and 2,4-diphenyl-thiazoles and oxazoles 1 (Figure 1). [11] Within the latter class, six moderately active compounds were identified, with EC 50 values ranging from 1.5-20 mm.…”

Section: Introductionmentioning

confidence: 99%

Improved 2,4‐Diarylthiazole‐Based Antiprion Agents: Switching the Sense of the Amide Group at C5 Leads to an Increase in Potency

et al. 2010

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Amide derivatives of 2,4-diarylthiazole-5-carboxylic acids were synthesised and tested for efficacy in a cell line model of prion disease. A number of compounds demonstrating antiprion activity were thereby identified from the screening libraries, showing improved potency and reproducibility of results relative to amide derivatives of the related 2,4-diphenyl-5-aminothiazole, which have been documented previously. Thus, 'switching' the sense of the amide bond at thiazole C5 revealed a more promising lead series of potential prion disease therapeutics. Furthermore, 3,5-diaryl-1,2,4-thiadiazoles isolated as by-products during library synthesis provided a handful of additional examples possessing an antiprion effect, thereby augmenting the set of newly identified active compounds. Evaluation of binding to cellular prion protein (PrP(C)) showed only weak affinities at best, suggesting that the newly identified antiprion agents do not mediate their biological effect through direct interaction with PrP(C).

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“…8 1,3,4-thiadiazolium-2-thiolates, being isoelectronic with Sydnone, 9 have also been widely reported for their biological activities. [10][11][12] Quinazolinones are important class of fused heterocycles that are of considerable interest on account of diverse range of their biological activities 13 like antihypertensive, 14 CNS depressants, 15 analgesic, 16 anti-histamine, 17,18 biofungicide, diuretic properties protein tyrosine, antihypertens, 19 antifolates inhibitor, 20,21 anticancer, 22 antidepressant, anthelmintic agent, 23 antiprion agent, 24 antibacterial, 25,26 cholecystokinin inhibitor, antimalarial activity, 27 antiallergic, antifungal, 28 antitumor, 29 antiproliferative activity, 30 anticonvulsant, 31 anti-HIV, 32,33 antagonists, [34][35][36] and several other useful and interesting properties. 37 Quinazolinones showed potent cytotoxic activity 38 against Human Gllioblasion Cells.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Antimicrobial Activity of 2-Substituted-3-((3-(6-Nitrobenzo[D]thiazol-2-yl)-4-oxo-3,4-Dihydroquinazolin-2-yl)Methyl)-1,3,4-thiadiazol-3-ium-5-thiolate

Akbari

Savaliya

Patel

2014

Phosphorus, Sulfur, and Silicon and the Related Elements

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Synthesis and SAR study of acridine, 2-methylquinoline and 2-phenylquinazoline analogues as anti-prion agents

Cited by 42 publications

References 26 publications

Multitarget Ligands and Theranostics: Sharpening the Medicinal Chemistry Sword Against Prion Diseases

Multitarget Ligands and Theranostics: Sharpening the Medicinal Chemistry Sword Against Prion Diseases

Improved 2,4‐Diarylthiazole‐Based Antiprion Agents: Switching the Sense of the Amide Group at C5 Leads to an Increase in Potency

Synthesis and Antimicrobial Activity of 2-Substituted-3-((3-(6-Nitrobenzo[D]thiazol-2-yl)-4-oxo-3,4-Dihydroquinazolin-2-yl)Methyl)-1,3,4-thiadiazol-3-ium-5-thiolate

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