| Autor: |
Prener L; Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo nám. 2, Prague 6 160 00, Czech Republic., Baszczyňski O; Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo nám. 2, Prague 6 160 00, Czech Republic.; Department of Organic Chemistry, Faculty of Science, Charles University, Hlavova 8, Prague 2 128 43, Czech Republic., Kaiser MM; Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo nám. 2, Prague 6 160 00, Czech Republic., Dračínský M; Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo nám. 2, Prague 6 160 00, Czech Republic., Stepan G; Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States., Lee YJ; Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States., Brumshtein B; Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States., Yu H; Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States., Jansa P; Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States., Lansdon EB; Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States., Janeba Z; Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo nám. 2, Prague 6 160 00, Czech Republic. |
| Abstrakt: |
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) represent cornerstones of current regimens for treatment of human immunodeficiency virus type 1 (HIV-1) infections. However, NNRTIs usually suffer from low aqueous solubility and the emergence of resistant viral strains. In the present work, novel bicyclic NNRTIs derived from etravirine (ETV) and rilpivirine (RPV), bearing modified purine, tetrahydropteridine, and pyrimidodiazepine cores, were designed and prepared. Compounds 2 , 4 , and 6 carrying the acrylonitrile moiety displayed single-digit nanomolar activities against the wild-type (WT) virus (EC 50 = 2.5, 2.7, and 3.0 nM, respectively), where the low nanomolar activity was retained against HXB2 (EC 50 = 2.2-2.8 nM) and the K103N and Y181C mutated strains (fold change, 1.2-6.7×). Most importantly, compound 2 exhibited significantly improved phosphate-buffered saline solubility (10.4 μM) compared to ETV and RPV (≪1 μM). Additionally, the binding modes of compounds 2 , 4 , and 6 to the reverse transcriptase were studied by X-ray crystallography. |
