Pharmaceutical Chemistry

Biography

Biography: Satoshi Mizuta

Abstract

  Trifluoromethyl heterocycles have been an important motif of pharmaceutical drugs and agrochemicals because the presence of a CF₃ group can cause the improved metabolic stability, lipophilicity and bioavailability. Nowadays, numerous CF₃ substituted heterocycle-containing pharmaceuticals on the market can be witnessed, with examples such as trifluridine, efavirenz, celecoxib and mefloquin. Over the past decades, there has been an increasing interest in the development of method for the efficient synthesis of such fluorinated heterocyclic molecules as potential biological targets. Nevertheless, synthetic method accessing an array of CF₃-containing heterocycles remains underdeveloped, in particular for nonaromatic heterocycles. Considering the difficulty of introducing CF₃ moiety in nonaromatic ring systems, divergent synthesis using a simple and readily available CF₃-containing precursor to convert into the diverse set of trifluoromethyl heterocyclic compounds may be one of the versatile and straightforward strategies for drug discovery. In this study, a series of α-trifluoromethyl α,β-unsaturated lactones and trifluoromethyl pyrazolinones were designed and synthesized. These two structural motifs of trifluoromethyl heterocycles were synthesized based on the synthetic pathway including a tandem stereoselective functionalization of the key precursor 3,3-dibromo-2-trifluoromethyl acrylic acid ethyl ester and intramolecular cyclization reaction. Further modification by Suzuki-Miyaura cross-coupling reaction provided a set of multi-functionalized α,β-unsaturated lactones and pyrazolinones. All synthesized compounds were bioassayed in vitro to determine their inhibitory activity against influenza A virus. We further modified a few potent hits in a viral inhibition assay and cunducted SAR studies on these scaffolds. The results showed that CF₃-containing spirolactones possessed promising inhibitory activity being nearly active as oseltamivir.