- Pharmacological investigation of quinoxaline-bisthiazoles as multitarget-directed ligands for the treatment of Alzheimer's disease
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Alzheimer's disease (AD) is the most prevalent disease of old age leading to dementia. Complex AD pathogenesis involves multiple factors viz. amyloid plaque formation, neurofibrillary tangles and inflammation. Herein we report of a new series of quinoxaline-bisthiazoles as multitarget-directed ligands (MTDLs) targeting BACE-1 and inflammation concurrently. Virtual screening of a library of novel quinoxaline-bisthiazoles was performed by docking studies. The most active molecules from the docking library were taken up for synthesis and characterized by spectral data. Compounds 8a-8n showed BACE-1 inhibition in micro molar range. One of the compounds, 8n showed BACE-1 inhibition at IC50 of 3 ± 0.07 μM. Rat paw edema inhibition in acute and chronic models of inflammation were obtained at 69 ± 0.45% and 55 ± 0.7%, respectively. Compound 8n also showed noteworthy results in AlCl3 induced AD model. The treated rats exhibited excellent antiamnesic, antiamyloid, antioxidant, and neuroprotective properties. Behavioural parameters suggested improved cognitive functions which further validates the testimony of present study. Moreover, compound 8n was found to have inherent gastrointestinal safety. This new string of quinoxaline-bisthiazoles were identified as effective lead for the generation of potent MTDLs and compound 8n was found to showcase qualities to tackle AD pathogenesis.
- Sagar, Sneha R.,Singh, Devendra Pratap,Das, Rajesh D.,Panchal, Nirupa B.,Sudarsanam, Vasudevan,Nivsarkar, Manish,Vasu, Kamala K.
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- 5-ARYL-THIAZOL-2-YL-AMINE COMPOUNDS AND THEIR THERAPEUTIC USE
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The present invention pertains generally to the field of therapeutic compounds, and more specifically to certain 5-aryl-thiazol-2-yl-amine compounds of the following formula (I) (for convenience, collectively referred to herein as "5AT2A compounds"), which, inter alia, inhibit LIM kinase (LIMK) activity. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit LIMK activity, and in the treatment of diseases and conditions that are mediated by LIMK, that are ameliorated by the inhibition of LIMK activity, etc., including proliferative conditions such as cancer (e.g., breast cancer, prostate cancer, melanoma, glioma, etc.), as well as vasodilation (including, e.g., hypertension, angina, cerebral vasospasm, and ischemia following subarachnoid hemorrhage), neurodegenerative disorders, atherosclerosis, fibrosis, and inflammatory diseases (including, e.g., Crohn's disease and chronic obstructive pulmonary disease (COPD)), and glaucoma (also known as ocular hypertension). (Formula (I))
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Page/Page column 89
(2015/03/13)
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- Discovery, Development, and SAR of Aminothiazoles as LIMK Inhibitors with Cellular Anti-Invasive Properties
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As part of a program to develop a small molecule inhibitor of LIMK, a series of aminothiazole inhibitors were discovered by high throughput screening. Scaffold hopping and subsequent SAR directed development led to a series of low nanomolar inhibitors of LIMK1 and LIMK2 that also inhibited the direct biomarker p-cofilin in cells and inhibited the invasion of MDA MB-231-luc cells in a matrigel inverse invasion assay.
- Charles, Mark D.,Brookfield, Joanna L.,Ekwuru, Tennyson C.,Stockley, Martin,Dunn, John,Riddick, Michelle,Hammonds, Tim,Trivier, Elisabeth,Greenland, Gavin,Wong, Ai Ching,Cheasty, Anne,Boyd, Susan,Crighton, Diane,Olson, Michael F.
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supporting information
p. 8309 - 8313
(2015/11/09)
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- Synthesis of nitrogen bicyclic scaffolds: Pyrimido[1,2-a]pyrimidine-2,6- diones
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The multi-step synthesis of 1,3,7-trisubstituted pyrimido[1,2-a] pyrimidinediones starting from isothiocyanates is described. These nitrogen bicycles were prepared by an iterative sequence of functionalization/ cyclocondensation reactions. [4+2] Cycloaddition reactions took place between diazadienic chains and various acyl chlorides providing sophisticated heterobicycles.
- Grosjean, Sylvain,Triki, Smail,Meslin, Jean-Claude,Julienne, Karine,Deniaud, David
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scheme or table
p. 9912 - 9924
(2011/02/22)
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- 2,4-Diamino-1-thia-3-azabutadienes, intermediates in heterocyclic synthesis
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2,4-Diamino-1-thia-3-azabutadienes 1 were studied. Methylation occured at sulfur and acylation at nitrogen hound to the 2 position. Alkylation by α-bromoketones gave rise to 2-amino-5-acylthiazoles. Upon treatment with acrylic dienophiles compounds 1 reac
- Friot,Reliquet,Reliquet,Meslin
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p. 135 - 149
(2007/10/03)
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- New Synthesis of 1,2,4-Thiadiazoles
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A new synthesis of 1,2,4-thiadiazoles has been developed.N'-(Thioaroyl)- (and N'-arylthiocarbamoyl-) N,N-dimethylamidines, which were prepared in excellent yields by reactions of thioamides (and thioureas) with N,N-dimethylalkanamide dimethyl acetals, rea
- Lin, Yang-i,Lang, S. A.,Petty, Sharon R.
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p. 3750 - 3753
(2007/10/02)
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- N,N-Dimethyl-N'-phenylthiocarbamyl formamidine hydrochloride and its use as an anti-inflammatory agent
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N,N-dimethyl-N'-phenylthiocarbamyl formamidine hydrochloride and its use as an anti-inflammatory agent.
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- N,N-dimethyl-N'-phenylthiocarbamyl formamidine and its use as an anti-inflammatory agent
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N,N-dimethyl-N'-phenylthiocarbamyl formamidine and its use as an anti-inflammatory agent.
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