2-Alkylamino-6-[1-(2,6-difluorophenyl)alkyl]-3,4-dihydro-5-alkylpyrimidin- 4(3H)-ones (F2-NH-DABOs) 4, 5 belonging to the dihydro-alkoxy-benzyl- oxopyrimidine (DABO) family and bearing different alkyl- and arylamino side chains at the C2-position of the pyrimidine ring were designed as active against wild type (wt) human immunodeficiency virus type 1 (HIV-1) and some relevant HIV-1 mutants. Biological evaluation indicated the importance of the further anchor point of compounds 4, 5 into the non-nucleoside binding site (NNBS): newly synthesized compounds were highly active against both wild type and the Y181C HIV-1 strains. In anti-wt HIV-1 assay the potency of amino derivatives did not depend on the size or shape of the C2-amino side chain, but it associated with the presence of one or two methyl groups (one at the pyrimidine C5-position and the other at the benzylic carbon), being thymine, α-methyluracil or α-methylthymine derivatives almost equally active in reducing wt HIV-1-induced cytopathogenicity in MT-4 cells. Against the Y181C mutant strain, 2,6-difluorobenzyl-α-methylthymine derivatives 4d, 5h′-n′ showed the highest potency and selectivity among tested compounds, both a properly sized C2-NH side chain and the presence of two methyl groups (at C5 and benzylic positions) being crucial for high antiviral action. © 2005 Elsevier Ltd. All rights reserved.