Discovery of a novel highly potent broad-spectrum heterocyclic chemical series of arenavirus cell entry inhibitors
| Autor: | Birte Kalveram, Alexander N. Freiberg, Eric Brown, Nadezda V. Sokolova, Greg Henkel, Shibani Naik, Ken McCormack, Alexandra Fetsko, Young-Jun Shin, Vidyasagar Reddy Gantla, Lihong Zhang, Plewe Michael Bruno |
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| Rok vydání: | 2021 |
| Předmět: |
New World Arenavirus
Clinical Biochemistry hERG Pharmaceutical Science Microbial Sensitivity Tests Antiviral Agents 01 natural sciences Biochemistry Article Structure-Activity Relationship Broad spectrum Viral Envelope Proteins Heterocyclic Compounds Drug Discovery medicine Humans Molecular Biology Liver microsomes Cell entry Arenavirus Dose-Response Relationship Drug Molecular Structure biology 010405 organic chemistry Chemistry Organic Chemistry Metabolic stability biology.organism_classification 0104 chemical sciences Entry inhibitor 010404 medicinal & biomolecular chemistry biology.protein Molecular Medicine medicine.drug |
| Zdroj: | Bioorg Med Chem Lett |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2021.127983 |
| Popis: | We identified and explored the structure–activity relationship (SAR) of a novel heterocyclic chemical series of arenavirus cell entry inhibitors. Optimized lead compounds, including diphenyl-substituted imidazo[1,2-a]pyridines, benzimidazoles, and benzotriazoles exhibited low to sub-nanomolar potency against both pseudotyped and infectious Old and New World arenaviruses, attractive metabolic stability in human and most nonhuman liver microsomes as well as a lack of hERG K + channel or CYP enzyme inhibition. Moreover, the straightforward synthesis of several lead compounds (e.g., the simple high yield 3-step synthesis of imidazo[1,2-a]pyridine 37) could provide a cost-effective broad-spectrum arenavirus therapeutic that may help to minimize the cost-prohibitive burdens associated with treatments for emerging viruses in economically challenged geographical settings. |
| Databáze: | OpenAIRE |
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