Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Chemistry, Medicinal, Pharmacology & Pharmacy, HIV-1 RT, Imidazo[1,2-a]pyrazines, Core-refining, NNRTIs, Biological activity, Molecular simulation, CORE-REFINING APPROACH, REVERSE-TRANSCRIPTASE, COLORIMETRIC ASSAY, DISCOVERY, INHIBITORS, DERIVATIVES, STRATEGIES, Anti-HIV Agents, Chemistry Techniques, Synthetic, Computational Biology, Drug Design, HIV Reverse Transcriptase, HIV-1, Imidazoles, Molecular Docking Simulation, Protein Conformation, Pyrazines, Reverse Transcriptase Inhibitors, Structure-Activity Relationship, 0304 Medicinal and Biomolecular Chemistry, 0305 Organic Chemistry, 1115 Pharmacology and Pharmaceutical Sciences, Medicinal & Biomolecular Chemistry, 3214 Pharmacology and pharmaceutical sciences, 3404 Medicinal and biomolecular chemistry, 3405 Organic chemistry

Abstract:

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.