Improving Antitrypanosomal Activity, Selectivity and Drug-Likeness of LINS03 Amide Series by Modulation of Physicochemical Properties

Antitrypanosomal treatment is scarce and unsatisfactory to fight Chagas’ disease. LINS03 compounds have been developed to find novel and safer alternatives against Trypanosoma cruzi. The amide analogue LINS03018 showed high potency and good selectivity towards amastigotes, although its excessive lipophilicity compromises water solubility, cytotoxicity and drug-likeness.1 Molecular modifications on the aromatic ring and side chain of the amide group were performed to improve water solubility along with lipophilicity. Modifications in the aromatic ring and insertion of vinylic spacer between the aromatic and amide groups resulted in improved physicochemical properties and reduced cytotoxicity. However, most compounds lacked activity towards the parasite. Insertion of the piperazine moiety in the side chain was the most promising modification, yielding compounds active against both forms of T. cruzi, with improved selectivity and physicochemical properties. Metric analysis from lipophilic ligand efficiency (LLE) and drug-likeness indexes denotes the progresses made from LINS03018.2