Anti-influenza virus activity of benzo[d]thiazoles that target heat shock protein 90

Lamut, Andraž; Gjorgjieva, Marina; Naesens, Lieve; Liekens, Sandra; Lillsunde, Katja-Emilia; Tammela, Päivi; Kikelj, D.; Tomašič, Tihomir

doi:10.1016/j.bioorg.2020.103733

Cited by 21 publications

(15 citation statements)

References 61 publications

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“…The benzothiazole moiety was selected as a suitable central scaffold that offers the possibility for the attachment of aromatic substituents and basic amines to positions 2 and 6, which are characteristic for Hsp90 CTD inhibitors ( Figure 1 ). In contrast to the already known benzothiazoles A and B ( Figure 2 ) [ 34 , 35 ], we decided to introduce aromatic groups at position 6 of the benzothiazole moiety and to replace the amide bond at position 2 with an amine directly linked to the benzothiazole ring ( Figure 2 ). This amine would serve as an attachment point for the various linkers to the basic center.…”

Section: Resultsmentioning

confidence: 99%

“…This amine would serve as an attachment point for the various linkers to the basic center. Furthermore, a different orientation of the amide bond was introduced at position 6, in contrast to the already known inhibitors [ 34 , 35 ].…”

Section: Resultsmentioning

confidence: 99%

“…First, the importance of the cationic center in the compounds was evaluated. This was because the previously developed benzothiazole-based Hsp90 CTD inhibitors did not contain a cationic center in their structure [ 34 , 35 ]. For this purpose, variously substituted piperidines were introduced at position 2 of the benzothiazole ring.…”

Section: Resultsmentioning

confidence: 99%

“…Nevertheless, a structure-based study using the cryo-electron microscopy structure of Hsp90β confirmed the importance of the basic center and the aromatic ring at the appropriate distance [ 32 ]. On the other hand, the benzothiazole has been shown to be a useful structural feature for Hsp90 inhibitors [ 34 ] that target the CTD [ 35 ]. However, no connections between the CTD SARs and the benzothiazole ring as a central scaffold have been established to date.…”

Section: Introductionmentioning

confidence: 99%

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Structure-Activity Relationships of Benzothiazole-Based Hsp90 C-Terminal-Domain Inhibitors

et al. 2021

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Heat shock protein 90 (Hsp90) is a chaperone responsible for the maturation of many cancer-related proteins, and is therefore an important target for the design of new anticancer agents. Several Hsp90 N-terminal domain inhibitors have been evaluated in clinical trials, but none have been approved as cancer therapies. This is partly due to induction of the heat shock response, which can be avoided using Hsp90 C-terminal-domain (CTD) inhibition. Several structural features have been shown to be useful in the design of Hsp90 CTD inhibitors, including an aromatic ring, a cationic center and the benzothiazole moiety. This study established a previously unknown link between these structural motifs. Using ligand-based design methodologies and structure-based pharmacophore models, a library of 29 benzothiazole-based Hsp90 CTD inhibitors was prepared, and their antiproliferative activities were evaluated in MCF-7 breast cancer cells. Several showed low-micromolar IC50, with the most potent being compounds 5g and 9i (IC50, 2.8 ± 0.1, 3.9 ± 0.1 μM, respectively). Based on these results, a ligand-based structure–activity relationship model was built, and molecular dynamics simulation was performed to elaborate the binding mode of compound 9i. Moreover, compound 9i showed degradation of Hsp90 client proteins and no induction of the heat shock response.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Structure-Activity Relationships of Benzothiazole-Based Hsp90 C-Terminal-Domain Inhibitors

et al. 2021

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“…On the other hand, expression of another heat shock protein Hsp90, may be downregulated by T4 and M13 phages [ 17 ]. Hsp90 is relevant for the life cycle of viruses and its inhibitors may have antiviral properties [ 18 , 19 ].…”

Section: Phages May Penetrate Epithelial Cells Protect Those Epithelmentioning

confidence: 99%

Phages in the Fight Against COVID-19?

et al. 2020

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Synthesis and Virtual Screening of Pyrazolothiazole Conjugates as Promising SARS‐CoV‐2 Inhibitors

Seliem

2023

ChemistrySelect

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The current coronavirus outbreak has highlighted the significance of continuing to develop novel antiviral agents. The SARS‐CoV‐2 main protease (Mpro), essential for virus replication, has been recognized as a potential target for developing novel COVID‐19 therapeutics. Herein, we report synthesizing a series of pyrazolothiazole conjugates and in silico molecular docking screening of their interactions with the COVID‐19 protease 6LU7 protein. The new hybrids were obtained by condensing substituted pyrazole‐4‐carbaldehyde with N‐phenyl‐hydrazinecarbothioamide and subsequent refluxing with selected α‐haloketones in a basic medium. The structures of the novel pyrazolothiazoles were fully verified by FTIR, 1H NMR, 13C NMR, and elemental analyses. Molecular docking and free energy analyses using the MM/GBSA approach revealed that 5 a–c and 7 a–c formed stable interactions within the protease 6LU7 pocket, thus, could be potential inhibitors of SARS‐CoV‐2.

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Anti-influenza virus activity of benzo[d]thiazoles that target heat shock protein 90

Cited by 21 publications

References 61 publications

Structure-Activity Relationships of Benzothiazole-Based Hsp90 C-Terminal-Domain Inhibitors

Structure-Activity Relationships of Benzothiazole-Based Hsp90 C-Terminal-Domain Inhibitors

Phages in the Fight Against COVID-19?

Synthesis and Virtual Screening of Pyrazolothiazole Conjugates as Promising SARS‐CoV‐2 Inhibitors

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