Inhibitory activity of 9-phenylcyclohepta[d]pyrimidinedione derivatives against different strains of HIV-1 as non-nucleoside reverse transcriptase inhibitors

Xiaoling Yu,Lin Yuan,Ying Guo,Tiejun Liu,Weisi Xu,Yang Huang,Yiming Shao,Xiaowei Wang,Liying Ma,Junyi Liu

doi:10.1186/1743-422x-8-230

Abstract

BackgroundThe non-nucleoside reverse transcriptase inhibitor (NNRTI), as a major component of the highly active antiretroviral therapy (HAART) to HIV-1 (human immunodeficiency virus type 1) infected patients, required the development of new NNRTIs with improved resistance profile and decreased toxicity. Therefore, a series of novel compounds, 9-phenylcyclohepta[d]pyrimidinedione derivatives (PCPs), were designed based on the chemical structure of TNK-651, to detect anti-HIV-1 activity.Results1-[(benzyloxy)methyl]-9-phenyl-cyclohepta[d] pyrimidinedione (BmPCP) among four PCPs has antiviral activity on laboratory-adapted HIV strains (HIV-1 SF33). The results showed 50% inhibition concentrations (IC50s) of BmPCP were 0.34 μM, 1.72 μM and 1.96 μM on TZM-bl, peripheral blood mononuclear cells (PBMCs) and MT4, respectively. It was also effective against infection by the predominant HIV-1 isolates in China, with IC50s at low μM levels. Its selectivity index (SI) ranged from 67 to 266 in different cells. The results of time-of-addition assay demonstrated that BmPCP inhibited HIV-1 infection by targeting the post entry of the HIV-1 replication cycle. For inhibition of HIV-1 reverse transcriptase activity, the IC50 values of BmPCP and NVP were 1.51 and 3.67 μM, respectively.ConclusionsBmPCP with a novel structure acts as a NNRTI to inhibit HIV-1 replication and can serve as a lead compound for further development of new anti-HIV-1 drugs.

Highlights

The non-nucleoside reverse transcriptase inhibitor (NNRTI), as a major component of the highly active antiretroviral therapy (HAART) to Human immunodeficiency virus type 1 (HIV-1) infected patients, required the development of new NNRTIs with improved resistance profile and decreased toxicity
We found that BmPCP, which has a characteristic seven-alicyclic benzene ring conformation (Figure 1b), exhibited the highest inhibitory potency and lowest toxicity among all four compounds. 50% cytoxicity concentrations (CC50s) of BmPCP are 90.26 μM and 129.29 μM respectively while 50% inhibition concentrations (IC50s) are 1.96 μM and 0.34 μM on MT4 and TZM-bl cells
Selectivity index (SI = CC50/IC50) is 84 and 266 on above both cells. (Table 1) BmPCP was selected for further testing antiviral activity to different clinical HIV isolates and target in this study

Summary

Introduction

The non-nucleoside reverse transcriptase inhibitor (NNRTI), as a major component of the highly active antiretroviral therapy (HAART) to HIV-1 (human immunodeficiency virus type 1) infected patients, required the development of new NNRTIs with improved resistance profile and decreased toxicity. The inhibition of reverse transcriptase (RT) has been one of important targets in inhibiting the replication of HIV-1 and RT inhibitors have been the primary therapeutic strategies in AIDS patient treatment [2,3]. NNRTIs, a major component of the highly active antiretroviral therapy (HAART) are included [5]. Application of such NNRTIs in combination with nucleoside analogues is highly effective in inhibiting HIV-1 replication

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