The design and synthesis of N-1-alkylated-5-aminoaryalkylsubstituted-6-methyluracils as potential non-nucleoside HIV-1 RT inhibitors

Novel compounds 1a-u, which can be considered as hybrid analogues of MKC-442 and pyridinon, have been synthesized and evaluated as inhibitors of HIV-1 reverse transcriptase (HIV-1 RT). Starting from 6-methyuracil 2, 1-alkylated-5-bromomethyl-6-methyluracils 8 was prepared in four steps by hydroxylmethylation, etherification, N-1 alkylation, and bromination. Finally, compounds 1a-u were achieved in the displacement of 5-bromomethyl group by nucleophiles with amino compounds. Some of compounds 1a-u showed potent inhibitory activity against HIV-1 RT. The most active compounds showed activity in the low micromolecular range with IC50 values (IC50 0.82-5.09 mu M) comparable to that of nevirapine (IC50 10.60 mu M). The biological testing results are in accordance with the docking. (C) 2007 Elsevier Ltd. All rights reserved.