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 μM) comparable to that of nevirapine (IC50 10.60 μM). The biological testing results are in accordance with the docking.

A synthesis route to get a novel series of hydrid analogues of MKC-442 and pyridinon as inhibitors of HIV-1 reverse transcripts and evaluate results about their potent inhibiting activity against HIV-RT.Figure optionsDownload as PowerPoint slide