Discovery of 4,4-Disubstituted Quinazolin-2-ones as T-Type Calcium Channel Antagonists

BACE1 (β-secretase, memapsin 2, Asp2) has emerged as a promising target for the treatment of Alzheimer's Disease. BACE1 is an aspartic protease which functions in the first step of the pathway leading to the production and deposition of amyloid-β peptide (Aβ). Its gene deletion showed only mild phenotypes. BACE1 inhibition has direct implications in the Alzheimer's Disease pathology without largely affecting viability. However, inhibiting BACE1 selectively in vivo has presented many challenges to medicinal chemists. Since its identification in 2000, inhibitors covering many different structural classes have been designed and developed. These inhibitors can be largely classified as either peptidomimetic or non-peptidic inhibitors. Progress in these fields resulted in inhibitors that contain many targeted drug-like characteristics. In this review, we describe structure-based design strategies and evolution of a wide range of BACE1 inhibitors including compounds that have been shown to reduce brain Aβ, rescue the cognitive decline in transgenic AD mice and inhibitor drug candidates that are currently in clinical trials.

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“…Many other examples of similarly constrained hydroxyethylamine inhibitors have been reported in patent literatures. 204-210 …”

Section: Design Of Peptidomimetic Bace1 Inhibitorsmentioning

confidence: 99%

BACE1 (β-secretase) inhibitors for the treatment of Alzheimer's disease

2014

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“…Addition of ethylmagnesium bromide and phenylmagnesium bromide to the nitrile 26 followed by acidic quenching provided the corresponding ketones 42a and 42b , respectively. [53] Subsequent cleavage of the methoxy protecting group afforded the final compounds 43a and 43b .…”

Section: Resultsmentioning

confidence: 99%

“…[53] The crude material was purified by flash chromatography on silica gel (hexanes, then hexanes–EtOAc 3:1 to 3:2) to provide the pure product as a pale-yellow oil (254 mg, 68% on a 1.0 mmolar scale).…”

Section: General Proceduresmentioning

confidence: 99%

Modification of Triclosan Scaffold in Search of Improved Inhibitors for Enoyl‐Acyl Carrier Protein (ACP) Reductase in Toxoplasma gondii

et al. 2013

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Through our focused effort to discover new and effective agents against toxoplasmosis, a structure-based drug design approach was utilized to develop a series of potent inhibitors of the enoyl-acyl carrier protein (ACP) reductase (ENR) enzyme in Toxoplasma gondii (TgENR). Modifications to positions 5 and 4′ of the well-known ENR inhibitor triclosan afforded a series of 29 new analogs. Among the resulting compounds, many showed high potency and improved physicochemical properties in comparison with the lead. The most potent compounds 16a and 16c have IC50 values of 250 nM against Toxoplasma gondii tachyzoites without apparent toxicity to the host cells. Their IC50 values against the recombinant TgENR were 43 and 26 nM, respectively. Additionally, 11 other analogs in this series had IC50 values ranging from 17 to 130 nM in the enzyme-based assay. With respect to their excellent in vitro activity as well as improved drug-like properties, the lead compounds 16a and 16c are deemed to be an excellent starting point for the development of new medicines to effectively treat Toxoplasma gondii infections.

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“…Several methodologies for the 4-phenylquinazolin-2(1H)-one scaffold have been described in the literature; however, they require prolonged reaction times [16,17] or expensive reagents [18][19][20][21]. Most of the time heating using microwave radiation allows one to drastically reduce times and increase the yield of reactions.…”

Section: Chemistrymentioning

confidence: 99%

Microwave Assisted Synthesis of 4-Phenylquinazolin-2(1H)-one Derivatives that Inhibit Vasopressor Tonus in Rat Thoracic Aorta

et al. 2020

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Quinazolinones have pharmacological effects on vascular reactivity through different mechanisms. We synthesized 4-phenylquinazolin-2(1H)-one derivatives under microwave irradiation and tested them on the rat thoracic aorta. The prepared compounds 2a–2f were obtained in about 1 h with suitable yields (31–92%). All derivatives produced vasorelaxant effects with IC50 values ranging from 3.41 ± 0.65 µM to 39.72 ± 6.77 µM. Compounds 2c, 2e and 2f demonstrated the highest potency in endothelium-intact aorta rings (IC50 4.31 ± 0.90 µM, 4.94 ± 1.21 µM and 3.41 ± 0.65 µM respectively), and they achieved around 90% relaxation (30 μM). In aorta rings without an endothelium, the effect of compound 2f was abolished. Using the MTT assay to test for cell viability, only compound 2b induced cytotoxicity at the maximum concentration employed (30 µM). The results show that vasorelaxation by 4-phenylquinazolin-2(1H)-one derivatives might depend on the activation of a signalling pathway triggered by endothelium-derived factors.

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Discovery of 4,4-Disubstituted Quinazolin-2-ones as T-Type Calcium Channel Antagonists

Cited by 36 publications

References 31 publications

BACE1 (β-secretase) inhibitors for the treatment of Alzheimer's disease

BACE1 (β-secretase) inhibitors for the treatment of Alzheimer's disease

Modification of Triclosan Scaffold in Search of Improved Inhibitors for Enoyl‐Acyl Carrier Protein (ACP) Reductase in Toxoplasma gondii

Microwave Assisted Synthesis of 4-Phenylquinazolin-2(1H)-one Derivatives that Inhibit Vasopressor Tonus in Rat Thoracic Aorta

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