Abstract
A novel series of 2-arylalkylthio-5-iodine-6-substitutedbenzyl-pyrimidine-4(3H)-ones (S-DABOs) 8a–x had been synthesized via an efficient method. Their biological activity against HIV virus and RT assay were evaluated. Some compounds, especially 8h, 8l and 8n, displayed promising activity against HIV-1 RT with IC50 values in a range of 0.41 μM to 0.71 μM, which were much better than that of nevirapine. Molecular modeling studies revealed that the binding mode would be affected via forming an additional hydrogen bond by incorporating an oxygen atom on the C-2 side chain. The biological activity was in accordance with the docking results.
Highlights
The reverse transcriptase (RT) of HIV-1, being an essential enzyme in the replication of the virus, is recognized as a great potential target for designing antiretroviral drugs [1]
The high mutation rate of HIV-1 RT and the rapid emergence of drug resistance has limited the therapeutic efficacy of nucleoside reverse transcriptase inhibitors (NNRTIs) and this necessitates the continued discovery and development of drugs with novel mechanisms of action [5]
By studying the crystal structures of different kinds of NNRTIs, it’s found that S-DABOs share the same binding mode as that of TNK-651. They interact with the binding site composed by Tyr181, Tyr188 and Trp229 residues, which is near the catalytic site of the RT
Summary
The reverse transcriptase (RT) of HIV-1, being an essential enzyme in the replication of the virus, is recognized as a great potential target for designing antiretroviral drugs [1]. The non-nucleoside reverse transcriptase inhibitors (NNRTIs), a class of components of HAART, have received special attention due to their unique antiviral potency with generally low toxicity and favorable pharmacokinetic properties [2,3]. The high mutation rate of HIV-1 RT and the rapid emergence of drug resistance has limited the therapeutic efficacy of NNRTIs and this necessitates the continued discovery and development of drugs with novel mechanisms of action [5]. By studying the crystal structures of different kinds of NNRTIs, it’s found that S-DABOs share the same binding mode as that of TNK-651. They interact with the binding site composed by Tyr181, Tyr188 and Trp229 residues, which is near the catalytic site of the RT. The N-3-H of S-DABOs forms a crucial hydrogen bond with
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