Discovery and Characterization of Fluorine-Substituted Diarylpyrimidines Derivatives as Novel HIV-1 NNRTIs with Highly Improved Resistance Profiles and Low Activity for the hERG Ion Channel.

07:00 EST 14th January 2020 | BioPortfolio

Summary of "Discovery and Characterization of Fluorine-Substituted Diarylpyrimidines Derivatives as Novel HIV-1 NNRTIs with Highly Improved Resistance Profiles and Low Activity for the hERG Ion Channel."

Our previous efforts have led to the development of two potent NNRTIs K-5a2 and 25a, exhibiting effective anti-HIV-1 potency and resistance profiles compared with etravirine. However, both inhibitors suffered from potent hERG inhibition and short half-life. In this article, with K-5a2 and etravirine as leads, series of novel fluorine-substituted diarylpyrimidine derivatives were designed via molecular hybridization and bioisosterism strategies. The results indicated 24b was the most active inhibitor, exhibiting broad-spectrum activity (EC50 = 3.60 - 21.5 nM) against resistant strains, significantly lower cytotoxicity (CC50 = 155 μM) and reduced hERG inhibition (IC50 > 30 μM). Crystallographic studies confirmed the binding of 24b and the role of the fluorine atom, as well as optimal contacts of a nitrile group with the main-chain carbonyl group of H235. Furthermore, 24b showed longer half-life and favorable safety properties. All the results demonstrated that 24b has significant promise in circumventing drug resistance as an anti-HIV-1 candidate.


Journal Details

This article was published in the following journal.

Name: Journal of medicinal chemistry
ISSN: 1520-4804


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Medical and Biotech [MESH] Definitions

Unstable isotopes of fluorine that decay or disintegrate emitting radiation. F atoms with atomic weights 17, 18, and 20-22 are radioactive fluorine isotopes.

A subclass of organophosphates that have a FLUORINE atom substituted for one of the OXYGEN atoms.

Derivatives of BENZENE that contain FLUORINE.

Steroids which are substituted with one or more fluorine atoms in any position.

Inorganic compounds that contain fluorine as an integral part of the molecule.

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