Daclatasvir, a well-known HCV NS5A protein inhibitor reported by Bristol-Myers Squibb (BMS) in 2010, shows high antiviral activities against HCV. In spite of its extremely high inhibitory activity, attenuation of its inhibition towards mutated NS5A proteins such as the ones with L31V and Y93H is of a great concern. Upon prolonged exposure, the proteins become resistant to daclatasvir, causing the antiviral activities to drop by 15,000 times. Many pharmaceutical companies have introduced new NS5A inhibitors containing proline-valine-carbamate motif adopted from daclatasvir to solve the resistance problems. From our continuing effort in the development of efficient HCV NS5A inhibitors, we discovered that fluorene or carbazole can be employed as a core structure of highly effective NS5A inhibitors. They are connected through amide bonds to the proline-valine-carbamate motif. Both 2,7-diaminofluorene and 2,7-diaminocarbazole appeared to be proper core structures, allowing for straightforward amide bond formation with a proline linker. However, amide bond can possibly be cleaved via metabolic pathways in our body system. Then the metabolites containing aminoarene moieties have been known as a mutagen. Adduct between DNA bases and electrophilic aniline metabolite has been known to be one cause of mutations.<br/>To avoid the mutagenesis issue, we introduced various functional groups at the C9 or N9 position of 2,7-diaminofluorene or 2,7-diaminocarbazole, respectively. We have found that the fluorene derivatives equipped with long chain 9,9-dialkyl groups can be free from mutation problems. Likewise in carbazole cases compounds having long alkyl groups at the <i>N</i>9 position were found to be non-mutagenic. We discovered that 2,7-diaminofluorene and 2,7-diaminocarbazole moieties can be employed in drug discovery without necessarily causing mutation problems through proper modification at the C9 or N9 position.<br/>

Mutagenicity evaluation of 2,7-diaminofluorene and 2,7-diaminocarbazole derivatives for use in drug discovery

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.