title: Repurposing human PDE4 inhibitors for neglected tropical diseases: design, synthesis and evaluation of cilomilast analogues as Trypanosoma brucei PDEB1 inhibitors.
abstract: A medicinal chemistry exploration of the human phosphodiesterase 4 (hPDE4) inhibitor cilomilast (1) was undertaken in order to identify inhibitors of phosphodiesterase B1 of Trypanosoma brucei (TbrPDEB1). T. brucei is the parasite which causes African sleeping sickness, a neglected tropical disease that affects thousands each year, and TbrPDEB1 has been shown to be an essential target of therapeutic relevance. Noting that 1 is a weak inhibitor of TbrPDEB1, we report the design and synthesis of analogs of this compound, culminating in 12b, a sub-micromolar inhibitor of TbrPDEB1 that shows modest inhibition of T. brucei proliferation.
authors.affiliation: Northeastern University, Department of Chemistry and Chemical Biology, 417 Egan Research Center, 360 Huntington Avenue, Boston, MA 02115, USA.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Amata
authors.affiliation: Marine Biological Laboratory, Josephine Bay Paul Center for Comparative Molecular Biology and Evolution, 7 MBL Street, Woods Hole, MA 02543, USA.
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Bland
authors.affiliation: Northeastern University, Department of Chemistry and Chemical Biology, 417 Egan Research Center, 360 Huntington Avenue, Boston, MA 02115, USA.
authors.forename: Charles T
authors.initials: CT
authors.lastname: Hoyt
authors.affiliation: Northeastern University, Department of Chemistry and Chemical Biology, 417 Egan Research Center, 360 Huntington Avenue, Boston, MA 02115, USA.
authors.forename: Luca
authors.initials: L
authors.lastname: Settimo
authors.affiliation: Marine Biological Laboratory, Josephine Bay Paul Center for Comparative Molecular Biology and Evolution, 7 MBL Street, Woods Hole, MA 02543, USA.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Campbell
authors.affiliation: Northeastern University, Department of Chemistry and Chemical Biology, 417 Egan Research Center, 360 Huntington Avenue, Boston, MA 02115, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Pollastri
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism*; D003509:Cyclohexanecarboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D058492:Drug Repositioning; D006801:Humans; D015394:Molecular Structure; D058069:Neglected Diseases / Q000188:drug therapy / Q000201:enzymology; D009570:Nitriles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014346:Trypanosoma brucei brucei / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D014352:Trypanosomiasis / Q000188:drug therapy / Q000201:enzymology
chemical_list: D003509:Cyclohexanecarboxylic Acids; D009570:Nitriles; D010726:Phosphodiesterase Inhibitors; D015800:Protozoan Proteins; C433247:Cilomilast; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C581006:PDEB1 protein, Trypanosoma brucei
keywords: Antiprotozoal agents; Cilomilast; Phosphodiesterase inhibitors; TbrPDEB1 Trypanosoma brucei