title: Novel (2,6-difluorophenyl)(2-(phenylamino)pyrimidin-4-yl)methanones with restricted conformation as potent non-nucleoside reverse transcriptase inhibitors against HIV-1.
abstract: To elucidate the structure-geometry-activity relationship in diarylpyrimidine family (DAPYs) containing carbonyl linker between the central pyrimidine core and phenyl type B-arm, a series of (2,6-difluorophenyl)(2-(phenylamino)pyrimidin-4-yl)methanones was designed, prepared and tested for their anti-HIV-1 activity. The carbonyl linker bearing B phenyl arm was successfully attached at both C-2 and C-4 positions of the central pyrimidine ring using a new synthetic approach. Further modifications of target compounds are present at C-5 position of the pyrimidine ring. In vitro anti-HIV-1 activity study performed on a series of 22 compounds confirmed the crucial importance of both conformational rigidity between phenyl B arm and the pyrimidine core linked through the carbonyl bridge, as well as presence of fluoro substituents in ortho-positions of phenyl B moiety. The most potent derivative of the series, compound 17, having almost perpendicular angle within the two planes made from the B aromatic arm and the pyrimidine ring, exhibited low nanomolar anti-HIV-1 activity (EC50 = 4 nM) with no significant toxicity (CC50 > 57.1 μM).
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo nám. 2, Prague-6 CZ-16610, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Šimon
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo nám. 2, Prague-6 CZ-16610, Czech Republic.
authors.forename: Ondřej
authors.initials: O
authors.lastname: Baszczyňski
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo nám. 2, Prague-6 CZ-16610, Czech Republic.
authors.forename: David
authors.initials: D
authors.lastname: Šaman
authors.affiliation: Gilead Sciences Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.
authors.forename: George
authors.initials: G
authors.lastname: Stepan
authors.affiliation: Gilead Sciences Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Hu
authors.affiliation: Gilead Sciences Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.
authors.forename: Eric B
authors.initials: EB
authors.lastname: Lansdon
authors.affiliation: Gilead Sciences Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.
authors.forename: Petr
authors.initials: P
authors.lastname: Jansa
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo nám. 2, Prague-6 CZ-16610, Czech Republic. Electronic address: janeba@uochb.cas.cz.
authors.forename: Zlatko
authors.initials: Z
authors.lastname: Janeba
mesh_terms: D015195:Drug Design; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D011743:Pyrimidines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase
keywords: Diarylpyrimidine (DAPY); Etravirine; Human immunodeficiency virus (HIV); NNRTIs; Non-nucleoside reverse transcriptase inhibitors; Rilpivirine