title: Synthesis and biological evaluation of CTP synthetase inhibitors as potential agents for the treatment of African trypanosomiasis.
abstract: Acivicin analogues with an increased affinity for CTP synthetase (CTPS) were designed as potential new trypanocidal agents. The inhibitory activity against CTPS can be improved by increasing molecular complexity, by inserting groups able to establish additional interactions with the binding pocket of the enzyme. This strategy has been pursued with the synthesis of α-amino-substituted analogues of Acivicin and N1-substituted pyrazoline derivatives. In general, there is direct correlation between the enzymatic activity and the in vitro anti-trypanosomal efficacy of the derivatives studied here. However, this cannot be taken as a general rule, as other important factors may play a role, notably the ability of uptake/diffusion of the molecules into the trypanosomes.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milano, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Tamborini
authors.forename: Andrea
authors.initials: A
authors.lastname: Pinto
authors.forename: Terry K
authors.initials: TK
authors.lastname: Smith
authors.forename: Louise L
authors.initials: LL
authors.lastname: Major
authors.forename: Maria C
authors.initials: MC
authors.lastname: Iannuzzi
authors.forename: Sandro
authors.initials: S
authors.lastname: Cosconati
authors.forename: Luciana
authors.initials: L
authors.lastname: Marinelli
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Leonardo
authors.initials: L
authors.lastname: Lo Presti
authors.forename: Pui E
authors.initials: PE
authors.lastname: Wong
authors.forename: Michael P
authors.initials: MP
authors.lastname: Barrett
authors.forename: Carlo
authors.initials: C
authors.lastname: De Micheli
authors.forename: Paola
authors.initials: P
authors.lastname: Conti
mesh_terms: D019731:Carbon-Nitrogen Ligases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D007555:Isoxazoles / Q000737:chemistry* / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology; D014344:Trypanocidal Agents / Q000737:chemistry* / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000201:enzymology; D014353:Trypanosomiasis, African / Q000188:drug therapy
chemical_list: D004791:Enzyme Inhibitors; D007555:Isoxazoles; D011720:Pyrazoles; D014344:Trypanocidal Agents; D019731:Carbon-Nitrogen Ligases; C019951:CTP synthetase; C006303:acivicin