title: Repurposing human PDE4 inhibitors for neglected tropical diseases. Evaluation of analogs of the human PDE4 inhibitor GSK-256066 as inhibitors of PDEB1 of Trypanosoma brucei.
abstract: Cyclic nucleotide phosphodiesterases (PDEs) have been identified as important enzyme targets for drug development in both humans and Trypanosoma brucei, the causative agent of human African trypanosomiasis. With this in mind, we recently reported the profiling of a range of human phosphodiesterase inhibitors, showing that human PDE4 inhibitors tend to display the best potency against the trypanosomal phosphodiesterase TbrPDEB1. Among these was GSK-256066, a potent inhibitor of human PDE4 and a weak inhibitor of TbrPDEB1. In this report, we describe the results of a structure-activity relationship study of this chemotype, leading to the discovery of analogs with improved potency against TbrPDEB1 and micromolar inhibition of T. brucei cellular growth. We rationalize the potency trends via molecular docking of the new inhibitors into a recently reported apo structure of TbrPDEB1. The studies in this article will inform future efforts in repurposing human PDE inhibitors as antitrypanosomal agents.
authors.affiliation: Department of Chemistry and Chemical Biology, Northeastern University, 417 Egan Research Center, 360 Huntington Avenue, Boston, MA, 02115, USA.
authors.forename: Stefan O
authors.initials: SO
authors.lastname: Ochiana
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Bland
authors.forename: Luca
authors.initials: L
authors.lastname: Settimo
authors.forename: Robert K
authors.initials: RK
authors.lastname: Campbell
authors.forename: Michael P
authors.initials: MP
authors.lastname: Pollastri
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000634:Aminoquinolines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D001665:Binding Sites; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000737:chemistry / Q000378:metabolism; D058492:Drug Repositioning; D006801:Humans; D062105:Molecular Docking Simulation; D058069:Neglected Diseases / Q000188:drug therapy; D058988:Phosphodiesterase 4 Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D017434:Protein Structure, Tertiary; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011804:Quinolines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000201:enzymology; D014353:Trypanosomiasis, African / Q000188:drug therapy
chemical_list: C549469:6-((3-((dimethylamino)carbonyl)phenyl)sulfonyl)-8-methyl-4-((3-methyloxyphenyl)amino)-3-quinolinecarboxamide; D000634:Aminoquinolines; D058988:Phosphodiesterase 4 Inhibitors; D015800:Protozoan Proteins; D011804:Quinolines; D013450:Sulfones; C037219:quinoline; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C581006:PDEB1 protein, Trypanosoma brucei
keywords: GSK-256066; TbrPDEB1; TbrPDEB2; Trypanosoma brucei; phosphodiesterase inhibitors