Author:

Keywords:

Cell Line, HIV-1 Reverse Transcriptase, Humans, Reverse Transcriptase Inhibitors, Structure-Activity Relationship, Thymine, Uracil, Science & Technology, Life Sciences & Biomedicine, Physical Sciences, Chemistry, Medicinal, Chemistry, Multidisciplinary, Pharmacology & Pharmacy, Chemistry, HIV-1 reverse transcriptase inhibitor, 1-alkoxymethyl-5-alkyl-6-naphthylmethyl uracil, structure-activity relationship, CELL LEUKEMIA-VIRUS, ANTI-HIV-1 ACTIVITY, ACYCLIC NUCLEOSIDES, COUPLING AGENT, CONVENIENT, ACYCLONUCLEOSIDE, ALKYLATION, PYRIMIDINE, RETROVIRUS, ANTIBODIES, HIV Reverse Transcriptase, 0304 Medicinal and Biomolecular Chemistry, 0306 Physical Chemistry (incl. Structural), 1115 Pharmacology and Pharmaceutical Sciences, General Chemistry, 3214 Pharmacology and pharmaceutical sciences

Abstract:

1-alkoxymethyl-5-alkyl-6-naphthylmethyl uracils, which are novel 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) analogues, were synthesized for evaluation as selective and potent nonnucleoside human immunodeficiency virus (HIV)-1 reverse transcriptase inhibitors. The anti-HIV-1 activity of these compounds was assayed in vitro using HIV-1 infected MT-4 and CEM bioassays. The EC50, CC50 and SI were recorded and calculated. The appropriate position, especially in the 1-position of the naphthyl ring, led to dramatic increases in potency, in both MT-4 and CEM cellular assays. The most important compounds in this series, 1-ethoxymethyl-5-isopropyl-6-(1-naphthylmethyl)thymine 8l (IC50=17 nM, CC50=38332 nM, SI=2229) and 1-benzyloxymethyl-5-ethyl-6-(1-naphthylmethyl)thymine 8n (IC50=17 nM, CC50=32560 nM, SI=1889) were significantly more potent than HEPT (EC50=7.0 microM, CD50=740 microM) in the anti-HIV-1 in vitro cellular assay.