title: Catechol pyrazolinones as trypanocidals: fragment-based design, synthesis, and pharmacological evaluation of nanomolar inhibitors of trypanosomal phosphodiesterase B1.
abstract: Trypanosomal phosphodiesterases B1 and B2 (TbrPDEB1 and TbrPDEB2) play an important role in the life cycle of Trypanosoma brucei, the causative parasite of human African trypanosomiasis (HAT), also known as African sleeping sickness. We used homology modeling and docking studies to guide fragment growing into the parasite-specific P-pocket in the enzyme binding site. The resulting catechol pyrazolinones act as potent TbrPDEB1 inhibitors with IC₅₀ values down to 49 nM. The compounds also block parasite proliferation (e.g., VUF13525 (20b): T. brucei rhodesiense IC₅₀ = 60 nM, T. brucei brucei IC₅₀ = 520 nM, T. cruzi = 7.6 μM), inducing a typical multiple nuclei and kinetoplast phenotype without being generally cytotoxic. The mode of action of 20b was investigated with recombinantly engineered trypanosomes expressing a cAMP-sensitive FRET sensor, confirming a dose-response related increase of intracellular cAMP levels in trypanosomes. Our findings further validate the TbrPDEB family as antitrypanosomal target.
authors.affiliation: Leiden/Amsterdam Centre of Drug Research-LACDR, Amsterdam Institute of Molecules, Medicines and Systems- AIMMS, Division of Medicinal Chemistry, VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
authors.forename: Kristina M
authors.initials: KM
authors.lastname: Orrling
authors.forename: Chimed
authors.initials: C
authors.lastname: Jansen
authors.forename: Xuan Lan
authors.initials: XL
authors.lastname: Vu
authors.forename: Vreni
authors.initials: V
authors.lastname: Balmer
authors.forename: Patrick
authors.initials: P
authors.lastname: Bregy
authors.forename: Anitha
authors.initials: A
authors.lastname: Shanmugham
authors.forename: Paul
authors.initials: P
authors.lastname: England
authors.forename: David
authors.initials: D
authors.lastname: Bailey
authors.forename: Paul
authors.initials: P
authors.lastname: Cos
authors.forename: Louis
authors.initials: L
authors.lastname: Maes
authors.forename: Emily
authors.initials: E
authors.lastname: Adams
authors.forename: Erika
authors.initials: E
authors.lastname: van den Bogaart
authors.forename: Eric
authors.initials: E
authors.lastname: Chatelain
authors.forename: Jean-Robert
authors.initials: JR
authors.lastname: Ioset
authors.forename: Andrea
authors.initials: A
authors.lastname: van de Stolpe
authors.forename: Stèphanie
authors.initials: S
authors.lastname: Zorg
authors.forename: Johan
authors.initials: J
authors.lastname: Veerman
authors.forename: Thomas
authors.initials: T
authors.lastname: Seebeck
authors.forename: Geert Jan
authors.initials: GJ
authors.lastname: Sterk
authors.forename: Iwan J P
authors.initials: IJ
authors.lastname: de Esch
authors.forename: Rob
authors.initials: R
authors.lastname: Leurs
mesh_terms: D001665:Binding Sites; D002396:Catechols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015195:Drug Design; D062105:Molecular Docking Simulation; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D047069:Pyrazolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000201:enzymology; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects / Q000201:enzymology
chemical_list: C577927:3-(3-(4-(4-(2H-tetrazole-5-yl)phenoxy)butoxy)-4-methoxyphenyl)-1-cycloheptyl-4,4-dimethyl-1H-pyrazol-5(4H)-one; D002396:Catechols; D011720:Pyrazoles; D047069:Pyrazolones; D013777:Tetrazoles; D014344:Trypanocidal Agents; D000242:Cyclic AMP; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1