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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.
This article was published in the following journal.
Name: Journal of medicinal chemistry
Proguanil, a member of biguanide family, has excellent anti-proliferative activities. Fluorine-containing compounds have been demonstrated to have super biological activities including enhanced bindin...
Herein, we report the synthesis and characterization of new amphiphilic phthalocyanines (Pcs), the study of their singlet oxygen generation capabilities, and biological assays to determine their poten...
For more in-depth exploration of the chemical space around the entrance channel of HIV-1 reverse transcriptase (RT), a series of novel indolylarylsulfones (IASs) bearing different chiral N-substituted...
The discovery of novel potent neuraminidase (NA) inhibitors remains an attractive approach for treating infectious diseases caused by influenza. In this study, we describe the design and synthesis of ...
A practical synthetic approach to the difluoro-substituted bicyclo[1.1.1]pentanes was developed. The key step was an addition of difluorocarbene (:CF2) to electron-rich bicyclo[1.1.0]butanes by CF3TMS...
This pilot trial studies how well fluorine F 18 clofarabine positron emission tomography (PET)/computed tomography (CT) works in imaging patients with autoimmune or inflammatory diseases. ...
RATIONALE: Fluorine F 18 FEQA may be an effective radioactive drug to use with positron emission tomography (PET) scans. PURPOSE: This clinical trial is studying the use of fluorine F 18 ...
This trial studies how well fluorine F 18 fluorthanatrace positron emission tomography (PET)/computed tomography (CT) works in treating participants ovarian, fallopian tube, or primary per...
Fluorine-18 Fluorodeoxyglucose (F-18 FDG) PET/CT is established as a powerful imaging tool for cancer detection and monitoring response to therapy. However, not all cancers are identified ...
RATIONALE: Diagnostic procedures using fluorine F 18 EF5 and positron emission tomography to detect tumor hypoxia may help in planning cancer treatment. PURPOSE: This phase I trial is stu...
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.
Standard antiretroviral therapy (ART) consists of the combination of at least three antiretroviral (ARV) drugs to maximally suppress the HIV virus and stop the progression of HIV disease. Huge reductions have been seen in rates of death and suffering whe...