Fused heterocycles bearing bridgehead nitrogen as potent HIV-1 NNRTIs. Part 4: Design, synthesis and biological evaluation of novel imidazo[1,2-a]pyrazines

•Novel imidazo[1,2-a]pyrazines were identified as HIV-1 inhibitors.•4a and 5a exhibited anti-HIV-1 (IIIB) activity with EC50 values of 0.26 μM and 0.32 μM respectively.•Some drug-like properties of 4a and 5a were predicted.•Preliminary SARs and molecular simulation of these new analogues were detailed.

Through a structure-guided core-refining approach, a series of novel imidazo[1,2-a]pyrazine derivatives were designed, synthesized and evaluated as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Biological results of antiviral assay in MT-4 cell cultures showed that 12 target compounds displayed moderate activities against wild-type (wt) HIV-1 strain (IIIB) with EC50 values ranging from 0.26 μM to 19 μM. Among them, 4a and 5a were found to be the two most active analogues possessing EC50 values of 0.26 μM and 0.32 μM respectively, comparable to delavirdine (DLV, EC50 = 0.54 μM) and nevirapine (NVP, EC50 = 0.31 μM) in a cell-based assay. Additionally, 9 compounds showed RT inhibitory activity superior to that of NVP. Moreover, some predicted drug-like properties of representative compounds 4a and 5a, as well as the structure-activity relationship (SAR) analysis were discussed in detail. The binding mode of compound 4a was investigated by molecular simulation studies.

Graphical abstractThrough a structure-guided core-refining approach, a series of novel imidazo[1,2-a]pyrazine derivatives were designed, synthesized and identified as inhibitors of wild-type HIV-1 strain in this paper.Figure optionsDownload full-size imageDownload as PowerPoint slide