Nejvíce citovaný článek - PubMed ID 27371922
Novel (2,6-difluorophenyl)(2-(phenylamino)pyrimidin-4-yl)methanones with restricted conformation as potent non-nucleoside reverse transcriptase inhibitors against HIV-1
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 35 (EC50 = 2 nM), 37 (EC50 = 3 nM), and 13 (EC50 = 4 nM) having O, NH, and CO linkers, respectively.
- Klíčová slova
- Diarylpyrimidine, etravirine, human immunodeficiency virus, non-nucleoside reverse transcriptase inhibitor, rilpivirine,
- MeSH
- buněčné linie MeSH
- HIV reverzní transkriptasa antagonisté a inhibitory MeSH
- HIV-1 účinky léků enzymologie MeSH
- inhibitory reverzní transkriptasy chemická syntéza chemie farmakologie MeSH
- krystalografie rentgenová MeSH
- látky proti HIV chemická syntéza chemie farmakologie MeSH
- lidé MeSH
- magnetická rezonanční spektroskopie s uhlíkem 13C MeSH
- mikrobiální testy citlivosti MeSH
- molekulární modely MeSH
- molekulární struktura MeSH
- protonová magnetická rezonanční spektroskopie MeSH
- pyrimidiny chemická syntéza chemie farmakologie MeSH
- vyvíjení léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- HIV reverzní transkriptasa MeSH
- inhibitory reverzní transkriptasy MeSH
- látky proti HIV MeSH
- pyrimidiny MeSH
- reverse transcriptase, Human immunodeficiency virus 1 MeSH Prohlížeč
