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Novel (2,6-difluorophenyl)(2-(phenylamino)pyrimidin-4-yl)methanones with restricted conformation as potent non-nucleoside reverse transcriptase inhibitors against HIV-1.

Novel (2,6-difluorophenyl)(2-(phenylamino)pyrimidin-4-yl)methanones with restricted conformation as potent non-nucleoside reverse transcriptase inhibitors against HIV-1.
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Šimon P, Baszczyňski O, Šaman D, Stepan G, Hu E, Lansdon EB, Jansa P, Janeba Z,


Šimon P, Baszczyňski O, Šaman D, Stepan G, Hu E, Lansdon EB, Jansa P, Janeba Z, (click to view)

Šimon P, Baszczyňski O, Šaman D, Stepan G, Hu E, Lansdon EB, Jansa P, Janeba Z,

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European journal of medicinal chemistry 2016 Jun 17122() 185-95 doi 10.1016/j.ejmech.2016.06.026

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).

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