5-Alkyl-2-[(methylthiomethyl)thio]-6-(benzyl)-pyrimidin-4-(1H)-ones as potent non-nucleoside reverse transcriptase inhibitors of S-DABO series.
Novel dihydroalkoxybenzyloxopyrimidine (S-DABO) derivatives targeting the non-nucleoside inhibitor (NNI) binding site of human immunodeficiency virus (HIV) reverse transcriptase (RT) have been synthesized using a novel computer model for the NNI binding pocket and tested for their RT inhibitory activity in cell-free assays using purified recombinant HIV RT as well as for their anti-HIV activity in HTL VIIIB-infected peripheral blood mononuclear cells. Our computational approach allowed the identification of several ligand derivatization sites for the generation of more potent S-DABO derivatives. Our lead S-DABO derivative, 5-isopropyl-2-[(methylthiomethyl)thio]-6-(benzyl)-pyrimidin-4-(1H)-one (compound 3), elicited potent anti-HIV activity with an IC50 value of less than 1nM for inhibition of HIV replication without any evidence of cytotoxicity and an unprecedented selectivity index of > 100,000.
Vig
R
R
Department of Chemistry, Wayne Hughes Institute, St. Paul, MN 55113, USA.
Mao
C
C
Venkatachalam
T K
TK
Tuel-Ahlgren
L
L
Sudbeck
E A
EA
Uckun
F M
FM
D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D002474:Cell-Free System; D015195:Drug Design; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D009000:Monocytes / Q000187:drug effects / Q000821:virology; D011744:Pyrimidinones / Q000737:chemistry / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013440:Sulfides / Q000737:chemistry / Q000494:pharmacology*
C116724:5-isopropyl-2-((methylthiomethyl)thio)-6-(benzyl)pyrimidin-4(1H)-one; D019380:Anti-HIV Agents; D011744:Pyrimidinones; D018894:Reverse Transcriptase Inhibitors; D013440:Sulfides