Development of novel amide–derivatized 2,4-bispyridyl thiophenes as highly potent and selective Dyrk1A inhibitors. Part II: Identification of the cyclopropylamide moiety as a key modification

Darwish, Sarah S.; Abdel‐Halim, Mohammad; ElHady, Ahmed K.; Salah, Mohamed; Abadi, Ashraf H.; Becker, Walter; Engel, Matthias

doi:10.1016/j.ejmech.2018.08.097

Cited by 19 publications

(4 citation statements)

References 56 publications

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“…Next, we evaluated the capacity of 3b , 16b , and 24b to inhibit Dyrk1A in intact cells. In HeLa cells, the phosphorylation of Thr434 in the splicing factor 3B1 (SF3B1) solely depends on the activity of endogenously expressed Dyrk1A; hence, the reduction of SF3B1 phosphorylation levels can be used as a measure for the efficacy of Dyrk1A inhibitors in intact cells. − As can be seen in Figure , the phosphorylation of SF3B1 in the HeLa cells was reduced by 16b and 24b depending on the concentration. IC 50 values of 1.44 and 0.625 μM were determined for 16b and 24b , respectively.…”

Section: Resultsmentioning

confidence: 99%

Discovery of Hydroxybenzothiazole Urea Compounds as Multitargeted Agents Suppressing Major Cytotoxic Mechanisms in Neurodegenerative Diseases

Aboushady

Gabr

ElHady

et al. 2021

ACS Chem. Neurosci.

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Multiple factors are causally responsible and/or contribute to the progression of Alzheimer's and Parkinson's diseases. The protein kinase Dyrk1A was identified as a promising target as it phosphorylates tau protein, α-synuclein, and parkin. The first goal of our study was to optimize our previously identified Dyrk1A inhibitors of the 6-hydroxy benzothiazole urea chemotype in terms of potency and selectivity. Our efforts led to the development of the 3-fluorobenzyl amide derivative 16b, which displayed the highest potency against Dyrk1A (IC 50 = 9.4 nM). In general, the diversification of the benzylamide moiety led to an enhanced selectivity over the most homologous isoform, Dyrk1B, which was a meaningful indicator, as the high selectivity could be confirmed in an extended selectivity profiling of 3b and 16b. Eventually, we identified the novel phenethyl amide derivative 24b as a triple inhibitor of Dyrk1A kinase activity (IC 50 = 119 nM) and the aggregation of tau and α-syn oligomers. We provide evidence that the novel combination of selective Dyrk1A inhibition and suppression of tau and α-syn aggregations of our new lead compound confers efficacy in several established cellular models of neurotoxic mechanisms relevant to neurodegenerative diseases, including α-synand 6-hydroxydopamine-induced cytotoxicities.

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Section: Resultsmentioning

confidence: 99%

Discovery of Hydroxybenzothiazole Urea Compounds as Multitargeted Agents Suppressing Major Cytotoxic Mechanisms in Neurodegenerative Diseases

Aboushady

Gabr

ElHady

et al. 2021

ACS Chem. Neurosci.

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“…Phase I and phase II metabolic stability were measured for our most potent compound 10a to further evaluate its applicability to go into in vivo studies. This was done using human liver S9 fractions, following the previously reported protocol [ 41 , 42 ]. A number of samples were taken at defined time points, and using LC-MS/MS, the remaining percentage of the parent compound was determined.…”

Section: Resultsmentioning

confidence: 99%

Design and Synthesis of Novel Bis-Imidazolyl Phenyl Butadiyne Derivatives as HCV NS5A Inhibitors

et al. 2022

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In today’s global plan to completely eradicate hepatitis C virus (HCV), the essential list of medications used for HCV treatment are direct-acting antivirals (DAAs), as interferon-sparing regimens have become the standard-of-care (SOC) treatment. HCV nonstructural protein 5A (NS5A) inhibitors are a very common component of these regimens. Food and Drug Administration (FDA)-approved NS5A inhibitors, although very potent, do not have the same potency against all eight genotypes of HCV. Therefore, this study aims to synthesize NS5A inhibitor analogues with high potency pan-genotypic activity and high metabolic stability. Starting from an NS5A inhibitor scaffold previously identified by our research group, we made several modifications. Two series of compounds were created to test the effect of changing the length and spatial conformation (para-para vs. meta-meta-positioned bis-imidazole-proline-carbamate), replacing amide groups in the linker with imidazole groups, as well as different end-cap compositions and sizes. The frontrunner inhibits genotype 1b (Con1) replicon, with an EC50 value in the picomolar range, and showed high genotypic coverage with nanomolar range EC50 values against four more genotypes. This together with its high metabolic stability (t½ > 120 min) makes it a potential preclinical candidate.

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“…Our goal was to reduce the binding affinity of the benzylthiourea quinazoline derivatives to the ATP binding pocket of EGFR kinase while retaining the best NF-κB inhibitory activities of the dual inhibitors in the IC50 range from 0.3 to 0.7 µM [37]. Although the introduction of a bulky substituent in the 4-position of the aminophenyl group in the published compounds B and C had reduced the inhibition of EGFR kinase compared with A, further modifications at this position did not seem promising because the potency against NF-κB did not increase in parallel but rather dropped with the bulkiness of the substituent in C. Therefore, we decided to explore whether modification at the opposite molecule end could also lead to reduced affinity against EGFR kinase, hopefully without impairing the NF-κB inhibition.…”

Section: Compound Designmentioning

confidence: 99%

“… Design concept to abolish the EGFR inhibitory activity based on the predicted binding modes of compounds A ( A ) and 20 ( B ) in the ATP pocket of EGFR kinase. Molecular docking was performed to the coordinates of the gefitinib–EGFR cocrystal structure (PDB code: 4WKQ) as previously described using MOE [ 36 , 37 ]. The ATP binding pocket is shown as a transparent Connolly surface with color-encoded lipophilic (brown) and hydrophilic areas (cyan), and the ligands are drawn as orange sticks.…”

Section: Figures Scheme and Tablesmentioning

confidence: 99%

Development of (4-Phenylamino)quinazoline Alkylthiourea Derivatives as Novel NF-κB Inhibitors

et al. 2022

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For many inflammatory diseases, new effective drugs with fewer side effects are needed. While it appears promising to target the activation of the central pro-inflammatory transcription factor NF-κB, many previously discovered agents suffered from cytotoxicity. In this study, new alkylthiourea quinazoline derivatives were developed that selectively inhibit the activation of NF-κB in macrophage-like THP−1 cells while showing low general cytotoxicity. One of the best compounds, 19, strongly inhibited the production of IL-6 (IC50 = 0.84 µM) and, less potently, of TNFα (IC50 = 4.0 µM); in comparison, the reference compound, caffeic acid phenethyl ester (CAPE), showed IC50s of 1.1 and 11.4 µM, respectively. Interestingly, 19 was found to block the translocation of the NF-κB dimer to the nucleus, although its release from the IκB complex was unaffected. Furthermore, 19 suppressed the phosphorylation of NF-κB-p65 at Ser468 but not at Ser536; however, 19 did not inhibit any kinase involved in NF-κB activation. The only partial suppression of p65 phosphorylation might be associated with fewer side effects. Since several compounds selectively induced cell death in activated macrophage-like THP−1 cells, they might be particularly effective in various inflammatory diseases that are exacerbated by excess activated macrophages, such as arteriosclerosis and autoimmune diseases.

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Development of novel amide–derivatized 2,4-bispyridyl thiophenes as highly potent and selective Dyrk1A inhibitors. Part II: Identification of the cyclopropylamide moiety as a key modification

Cited by 19 publications

References 56 publications

Discovery of Hydroxybenzothiazole Urea Compounds as Multitargeted Agents Suppressing Major Cytotoxic Mechanisms in Neurodegenerative Diseases

Discovery of Hydroxybenzothiazole Urea Compounds as Multitargeted Agents Suppressing Major Cytotoxic Mechanisms in Neurodegenerative Diseases

Design and Synthesis of Novel Bis-Imidazolyl Phenyl Butadiyne Derivatives as HCV NS5A Inhibitors

Development of (4-Phenylamino)quinazoline Alkylthiourea Derivatives as Novel NF-κB Inhibitors

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