title: Synthesis and evaluation of human phosphodiesterases (PDE) 5 inhibitor analogs as trypanosomal PDE inhibitors. Part 1. Sildenafil analogs.
abstract: Parasitic diseases, such as African sleeping sickness, have a significant impact on the health and well-being in the poorest regions of the world. Pragmatic drug discovery efforts are needed to find new therapeutic agents. In this Letter we describe target repurposing efforts focused on trypanosomal phosphodiesterases. We outline the synthesis and biological evaluation of analogs of sildenafil (1), a human PDE5 inhibitor, for activities against trypanosomal PDEB1 (TbrPDEB1). We find that, while low potency analogs can be prepared, this chemical class is a sub-optimal starting point for further development of TbrPDE inhibitors.
authors.affiliation: Northeastern University Department of Chemistry & Chemical Biology, 417 Egan Research Center, 360 Huntington Avenue, Boston, MA 02115, USA.
authors.forename: Cuihua
authors.initials: C
authors.lastname: Wang
authors.forename: Trent D
authors.initials: TD
authors.lastname: Ashton
authors.forename: Alden
authors.initials: A
authors.lastname: Gustafson
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Bland
authors.forename: Stefan O
authors.initials: SO
authors.lastname: Ochiana
authors.forename: Robert K
authors.initials: RK
authors.lastname: Campbell
authors.forename: Michael P
authors.initials: MP
authors.lastname: Pollastri
mesh_terms: D000818:Animals; D001681:Biological Assay; D006801:Humans; D058986:Phosphodiesterase 5 Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry*; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011687:Purines / Q000138:chemical synthesis / Q000737:chemistry; D000068677:Sildenafil Citrate; D012996:Solutions; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000737:chemistry; D014346:Trypanosoma brucei brucei / Q000201:enzymology*
chemical_list: D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D015800:Protozoan Proteins; D011687:Purines; D012996:Solutions; D013450:Sulfones; D014344:Trypanocidal Agents; D000068677:Sildenafil Citrate; D010727:Phosphoric Diester Hydrolases