Synthesis and anti-human immunodeficiency virus activity of substituted ( o,o-difluorophenyl)-linked-pyrimidines as potent non-nucleoside reverse transcriptase inhibitors

Antiviral Chemistry & Chemotherapy
Lucie ČechováPetr Šimon

Abstract

With the worldwide number of human immunodeficiency virus positive patients stagnant and the increasing emergence of viral strains resistant to current treatment, the development of novel anti-human immunodeficiency virus drug candidates is a perpetual quest of medicinal chemists. Herein, we report a novel group of diarylpyrimidines, non-nucleoside reverse transcriptase inhibitors, which represents an important class of current anti-human immunodeficiency virus therapy. Series of diarylpyrimidines containing o, o-difluorophenyl (A-arm), 4-cyanophenylamino (B-arm), and a small substituent (e.g. NH2, OMe) at positions 2, 4, and 6 of the pyrimidine ring were prepared. The A-arm was modified in the para position (F or OMe) and linked to the central pyrimidine core with a variable spacer (CO, O, NH). Antiviral activities of 20 compounds were measured against wild type human immunodeficiency virus-1 and mutant reverse transcriptase strains (K103N, Y181C) using a cytoprotection assay. To the most promising structural motives belong the o, o-difluoro- p-methoxy A-arm in position 4, and the amino group in position 6 of pyrimidine. Single digit nanomolar activities with no significant toxicity (CC50 > 17,000 nM) were found for compounds ...Continue Reading

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Citations

Jan 25, 2020·Current Topics in Medicinal Chemistry·Luiz Claudio Ferreira PimentelMonica Macedo Bastos

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Methods Mentioned

BETA
nuclear magnetic resonance
X-Ray
NMR
reverse phase chromatography
reverse

Software Mentioned

Glide XP

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