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

• Published in: European journal of medicinal chemistry 2016-10, Vol.122, p.185-195
• Main Authors: Šimon, Petr, Baszczyňski, Ondřej, Šaman, David, Stepan, George, Hu, Eric, Lansdon, Eric B., Jansa, Petr, Janeba, Zlatko
• Format: Article
• Language: English
• Subjects: Diarylpyrimidine (DAPY); Drug Design; Etravirine; HIV Reverse Transcriptase - antagonists & inhibitors; HIV Reverse Transcriptase - chemistry; HIV Reverse Transcriptase - metabolism; HIV-1 - drug effects; HIV-1 - enzymology; Human immunodeficiency virus (HIV); Molecular Docking Simulation; NNRTIs; Non-nucleoside reverse transcriptase inhibitors; Protein Conformation; Pyrimidines - chemistry; Pyrimidines - metabolism; Pyrimidines - pharmacology; Reverse Transcriptase Inhibitors - chemistry; Reverse Transcriptase Inhibitors - metabolism; Reverse Transcriptase Inhibitors - pharmacology; Rilpivirine
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2016.06.026

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). [Display omitted] •Design and synthesis of novel NNRTIs.•Low nanomolar anti-HIV-1 activity.•Co-crystal structure of HIV-1 reverse transcriptase with the inhibitor.