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Fused heterocycles bearing bridgehead nitrogen as potent HIV-1 NNRTIs. Part 4: design, synthesis and biological evaluation of novel imidazo[1,2-a]pyrazines.
- Source :
-
European journal of medicinal chemistry [Eur J Med Chem] 2015 Mar 26; Vol. 93, pp. 330-7. Date of Electronic Publication: 2015 Feb 16. - Publication Year :
- 2015
-
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.<br /> (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)
- Subjects :
- Anti-HIV Agents chemical synthesis
Anti-HIV Agents chemistry
Anti-HIV Agents metabolism
Anti-HIV Agents pharmacology
Chemistry Techniques, Synthetic
Computational Biology
HIV Reverse Transcriptase chemistry
HIV Reverse Transcriptase metabolism
HIV-1 drug effects
Molecular Docking Simulation
Protein Conformation
Pyrazines chemical synthesis
Pyrazines metabolism
Reverse Transcriptase Inhibitors chemical synthesis
Reverse Transcriptase Inhibitors chemistry
Reverse Transcriptase Inhibitors metabolism
Reverse Transcriptase Inhibitors pharmacology
Structure-Activity Relationship
Drug Design
HIV Reverse Transcriptase antagonists & inhibitors
HIV-1 enzymology
Imidazoles chemistry
Pyrazines chemistry
Pyrazines pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1768-3254
- Volume :
- 93
- Database :
- MEDLINE
- Journal :
- European journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 25707013
- Full Text :
- https://doi.org/10.1016/j.ejmech.2015.02.022