Synthesis and in vitro anti-HIV evaluation of a new series of 6-arylmethyl-substituted S-DABOs as potential non-nucleoside HIV-1 reverse transcriptase inhibitors.
A series of new 5-alkyl-2-benzylsulfanylpyrimidin-4(3H)-ones (5a-y) bearing different substituted arylmethyl moieties at the C-6 position of the pyrimidine core have been synthesized and evaluated for their in vitro activities against HIV-1 and HIV-2 in MT-4 cell cultures. The majority of the title compounds showed moderate to good activities against HIV-1 with an IC(50) range from 6.67 microM to 0.12 microM. Among them, 6-(3,5-dimethylbenzyl) analogue 5q exhibited the most potent anti-HIV-1 activity (IC(50)=0.12 microM, SI>2642), which was about 40-fold more active than the reference compounds 1-[(2-hydroxyethoxy)methyl]-6-(phenylsulfanyl)thymine (HEPT) and 2',3'-dideoxyinosine (DDI). The structure-activity relationships (SARs) of these new congeners were further discussed.
Wang
Yue-Ping
YP
Department of Chemistry, Fudan University, Shanghai 200433, PR China.
Chen
Fen-Er
FE
De Clercq
Erik
E
Balzarini
Jan
J
Pannecouque
Christophe
C
D002460:Cell Line; D018360:Crystallography, X-Ray; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization; D017550:Spectroscopy, Fourier Transform Infrared; D013329:Structure-Activity Relationship
D011744:Pyrimidinones; D018894:Reverse Transcriptase Inhibitors; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase