Synthesis and Biological Evaluation of CTP Synthetase Inhibitors as Potential Agents for the Treatment of African Trypanosomiasis

• DOI: 10.1002/cmdc.201200304
• Publication Date: 2012-08-03T17:53:34Z
• Authors: Lucia Tamborini; Andrea Pinto; Terry K. Smith; Louise L. Major; Maria C. Iannuzzi; Sandro Cosconati; Luciana Marinelli; Ettore Novellino; Leonardo Lo Presti; Pui E. Wong; Michael P. Barrett; Carlo De Micheli; Paola Conti
• Keywords: Trypanosoma brucei brucei; Amino acids; CTP synthetase; Isoxazolines; Pyrazolines; Trypanosoma;; Isoxazoles; Trypanocidal Agents; 01 natural sciences; 0104 chemical sciences; Molecular Docking Simulation; Trypanosomiasis, African; Amino acids; CTP synthetase; Isoxazolines; Pyrazolines; Trypanosoma; Humans; Pyrazoles; Carbon-Nitrogen Ligases; Enzyme Inhibitors; HeLa Cells

AbstractAcivicin 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.