The synthesis and structure–activity relationship of substituted N-phenyl anthranilic acid analogs as amyloid aggregation inhibitors

Simons, Lloyd J.; Caprathe, Bradley W.; Callahan, Michael J.; Graham, James M.; Kimura, Tomoe; Lai, Yingjie; LeVine, Harry; Lipinski, William J.; Sakkab, Annette T.; Tasaki, Yoshikazu; Walker, Lary C.; Yasunaga, Tomohide; Ye, Yuyang; Zhuang, Nian; Augelli‐Szafran, Corinne E.

doi:10.1016/j.bmcl.2008.12.049

Cited by 45 publications

(31 citation statements)

References 4 publications

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“…It has been well documented that 2-amino benzoic acid derivatives exhibit broad spectrum of activity including antiviral (Selvam et al, 2008), anticancer (Cocco et al, 2004), anti-alzheimer (Simons et al, 2009), antiallergic (Inglis et al, 2007), diuretic (Dambrosio et al, 1965) and insecticidal (Raman et al, 2008) activities.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, antimicrobial evaluation, ot-QSAR and mt-QSAR studies of 2-amino benzoic acid derivatives

2010

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A series of 2-amino benzoic acid derivatives (1-28) were synthesized and evaluated for their in vitro antimicrobial activity against the panel of Gram positive, Gram negative bacterial and fungal strains. The results of antimicrobial studies indicated that, in general, the synthesized compounds were found to be bacteriostatic and fungistatic in action. QSAR studies performed by the development of one target and multi target models indicated that multi-target model was effective in describing the antimicrobial activity as well demonstrated the effect of structural parameters viz. LUMO, 3 v v and W on antimicrobial activity of 2-amino benzoic acid derivatives.

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Section: Introductionmentioning

confidence: 99%

Synthesis, antimicrobial evaluation, ot-QSAR and mt-QSAR studies of 2-amino benzoic acid derivatives

2010

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“…Nevertheless, small inhibitors have been reported to disrupt soluble oligomers and to interfere with formed larger structures. More specifically, small compounds have been tested as inhibitors of a-syn aggregation (e.g., polyphenols, phenothiazines, porphyrins, polyene macrolides, curcumins, and Congo red and its derivatives [145,146] ), polyQ aggregation for HD treatment (e.g., benzothiazole [147] ), tau protein (e.g., anthracyclines such as daunorubicin, aminothienopyridazines, phenothiazines such as methylene blue, Nphenylamines, phenylthiazolyl-hydrazides, polyphenols, porphyrins, quinazolines, rhodanines, cyanine dyes, [148,149] and compound N774 [150,151] ), prion proteins (e.g., porphyrins and phthalocyanines, [152] lysosomotropic antimalarial compounds [153] ), and Ab peptide [154] (e.g., curcumin derivatives, [155] N-phenylanthranilic acid analogues, [156] quinacrine conjugates, [157] bis-styrylpyridine and bis-styrylbenzene derivatives, [158] tricyclic pyrones, [159] julolidine aldehyde [160] ). Detailed discussion of single compounds is beyond the aim of this review, but it must be emphasized that compounds claiming anti-aggregating action have in most cases been evaluated for their overall effect on the aggregation process without any detailed investigation of the specific pre-fibrillar species targeted by the inhibitor.…”

Section: Induction Of Physiological Chaperone Moleculesmentioning

confidence: 99%

Strategies for the Inhibition of Protein Aggregation in Human Diseases

2010

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Protein misfolding and aggregation has been related to several human disorders, generally termed protein aggregation diseases. These diseases include neurodegenerative disorders such as Alzheimer's, Parkinson's, and Huntington's diseases and peripheral disorders such as systemic amyloidosis and type 2 diabetes. The complexity of the aggregation processes and the intertwined events account for the fact that no effective disease-modifying treatments for these disorders are currently available. Nevertheless, in-depth research into the aggregation processes has recently yielded major insights into some key mechanisms of aggregation-mediated cell toxicity, offering new targets for drug development. In addition, recent findings in the field have identified similar features, revealing the possibility of shared mechanisms and hence potential common approaches for intervention. This review aims to give an overview of potential strategies for tackling protein aggregation and its associated toxicity, focusing on protein aggregation in human disease.

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“…However, previous structure activity relationship (SAR) studies for the identification of the main characteristics that are significant for the inhibition ability included only limited data of small sets of similar compounds. These studies included SAR of N-phenyl anthranilic acid analogs, [29] SAR of amyloid aggregation inhibitors based on curcumin scaffold [30] and the study of polyphenols [27]. To the best of our knowledge, a comprehensive computational study for this purpose has not been reported yet.…”

Section: Introductionmentioning

confidence: 97%

Quantitative structure–activity relationship analysis of β-amyloid aggregation inhibitors

Stempler

Levy‐Sakin

Frydman‐Marom

et al. 2010

J Comput Aided Mol Des

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Inhibiting the aggregation process of the β-amyloid peptide is a promising strategy in treating Alzheimer's disease. In this work, we have collected a dataset of 80 small molecules with known inhibition levels and utilized them to develop two comprehensive quantitative structure-activity relationship models: a Bayesian model and a decision tree model. These models have exhibited high predictive accuracy: 87% of the training and test sets using the Bayesian model and 89 and 93% of the training and test sets, respectively, by the decision tree model. Subsequently these models were used to predict the activities of several new potential β-amyloid aggregation inhibitors and these predictions were indeed validated by in vitro experiments. Key chemical features correlated with the inhibition ability were identified. These include the electro-topological state of carbonyl groups, AlogP and the number of hydrogen bond donor groups. The results demonstrate the feasibility of the developed models as tools for rapid screening, which could help in the design of novel potential drug candidates for Alzheimer's disease.

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The synthesis and structure–activity relationship of substituted N-phenyl anthranilic acid analogs as amyloid aggregation inhibitors

Cited by 45 publications

References 4 publications

Synthesis, antimicrobial evaluation, ot-QSAR and mt-QSAR studies of 2-amino benzoic acid derivatives

Synthesis, antimicrobial evaluation, ot-QSAR and mt-QSAR studies of 2-amino benzoic acid derivatives

Strategies for the Inhibition of Protein Aggregation in Human Diseases

Quantitative structure–activity relationship analysis of β-amyloid aggregation inhibitors

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