In This Issue Cite This: ACS Med. Chem. Lett. 2019, 10, 396−397
ACS Med. Chem. Lett. 2019.10:396-397. Downloaded from pubs.acs.org by 5.62.152.96 on 05/20/19. For personal use only.
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SYNTHESIS AND ANTI-HIV PROFILE OF A NOVEL TETRAHYDROINDAZOLYLBENZAMIDE DERIVATIVE OBTAINED BY OXAZOLONE CHEMISTRY Human immunodeficiency virus (HIV) infection remains incurable and results in millions of deaths annually. Current treatments allow management of infection, but they do not provide a cure. Cellular factors involved in HIV replication offer new opportunities to target the virus. In their Featured Letter, Scala and co-workers (DOI: 10.1021/acsmedchemlett.8b00511) report the identification of a tetrahydroindazolylbenzamide derivative with anti-HIV activity. Compounds were prepared by an unexplored synthetic route, leading to a new method to functionalize the pyrazole ring at position 3. An in vitro assay demonstrated remarkable inhibition of HIV replication, low cytotoxicity, and high selectivity of compound 6. Mechanism of action studies revealed that the arrest of viral replication occurs at early steps, thus eliminating it as an integrase inhibitor. Although further studies are needed to identify the exact mechanism of action, the reported data suggest that compound 6 acts as late reverse transcriptase inhibitor. The presented synthetic route offers to medicinal chemists a rapid way to optimize the antiviral activity by functionalization of the side-chain at the C3-pyrazole ring with alkyl and aryl substituents. Furthermore, the introduction of one or more late reverse transcription inhibitors in currently approved therapy regimens could compliment these treatments.
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the main pharmacophoric groups of both GSK-3β and HDAC inhibitors with various linkers. Resulting compounds were tested for their ability to inhibit GSK-3β, HDAC1, and HDAC6, which identified compound 11 as the most potent inhibitor. Cellular assays revealed that compound 11 increases histone acetylation and reduces tau phosphorylation while exhibiting low cytotoxicity and exerting protective effects against oxidative stress. The same compound also induced neurogenesis and demonstrated immunomodulatory effects. Despite the fact that the idea of improving Alzheimer’s therapy outcomes via multitarget inhibitors is widely accepted, the number of highly potent compounds is very limited. This Letter offers promising results that indicate targeting of GSK-3β and HDAC by a single compound with a safe pharmacokinetic profile can be an effective strategy to overcome the many challenges encountered in AD drug discovery research.
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CHALCONES AND CHALCONE-MIMETIC DERIVATIVES AS NOTCH INHIBITORS IN A MODEL OF T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA Notch signaling is an intercellular communication pathway that modulates various biological processes. Aberrant Notch activation is associated with the onset of certain types of cancers, and Notch signaling has been linked to chemotherapy resistance. Hence, the development of Notch inhibitors is an active research area. In this issue, Quaglio and co-workers (DOI: 10.1021/ acsmedchemlett.8b00608) describe a structure−activity relationship study based on a previously identified chalcone in order to identify new Notch inhibitors as antileukemia agents. They designed and synthesized new chalcones and chalconemimetic derivatives by means of hit-likeness and chemical diversity. The resulting compounds were evaluated for their antiproliferative properties and inhibition of Notch1 expression in cellular assays. Compound 18 emerged as the most promising derivative in this series. These results highlight (a) the importance of the 2′- and 4-OH groups for both cell proliferation and Notch inhibition and (b) the efficient replacement of the double bond by a six-membered saturated ring.
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DISCOVERY OF THE FIRST-IN-CLASS GSK-3β/HDAC DUAL INHIBITOR AS DISEASE-MODIFYING AGENT TO COMBAT ALZHEIMER’S DISEASE Drug discovery for Alzheimer’s disease (AD) remains a challenging research area due to the complex nature of this disease. Newer therapeutic approaches involve the use of ligands that modulate multiple AD-relevant targets simultaneously. In this regard, the connection between glycogen synthase kinase (GSK-3β) and histone deacetylases has emerged as an attractive opportunity. Herein, Millelli and co-workers (DOI: 10.1021/acsmedchemlett.8b00507) report the identification of the first GSK-3β/ HDCA dual inhibitor endowed with very promising antiAlzheimer’s activity. The authors designed and synthesized a small group of potential dual inhibitors by combining © 2019 American Chemical Society
Special Issue: Highlighting Medicinal Chemistry in Italy Published: April 11, 2019 396
DOI: 10.1021/acsmedchemlett.9b00136 ACS Med. Chem. Lett. 2019, 10, 396−397
ACS Medicinal Chemistry Letters
In This Issue
The authors provide an interesting example of how chemical manipulation of a previously reported hit compound can rapidly lead to the identification of a new chemical scaffold. Even though further in-depth investigations are needed, tetrahydronaphthalene derivatives appear as a promising starting point to develop more effective antiproliferative agents by blocking Notch activity.
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DOI: 10.1021/acsmedchemlett.9b00136 ACS Med. Chem. Lett. 2019, 10, 396−397
