Synthesis of conjugates of benznidazol and proline for evaluation as trypanocidal compounds for Trypanosoma cruzi

SAYE, MELISA; MIRANDA, MARIANA; MOGLIONI, ALBERTINA; TAVERNA, MARISA; PEREIRA, CA

CABA

Congreso; Drug Discovery for Neglected Diseases International Congress 2018; 2018

Instituto de la Química y Metabolismo del Fármaco

Chagas disease is caused by the protozoan parasite Trypanosoma cruzi and currently affects 7 million people in Latin America, with almost 70 million more at risk of infection [1]. Nowadays only benznidazole (BZL) and nifurtimox areused to treat this disease, but both present several side effects and are only effective during the chronic stage of the disease [2]. T. cruzi has a metabolism largely based on amino acid consumption, mainly proline (PRO), which can beused as an alternative carbon and energy source to glucose [3]. PRO is also involved in differentiation processes, cellular invasion and resistance to oxidative, nutritional and osmotic stress [4-7]. The parasite T. cruzi presents different transport systems than mammalian cells to uptake amino acids and derivatives from the extracellular medium. For example, the transporter TcAAAP069 is specific for the amino acid L-PRO [7] and it was recently reported that a synthetic proline analogue that inhibits the uptake also possesses trypanocidal effect [8]. The aim of this work is to take advantage of the specificity of TcAAAP069 to direct the entry of BZL into the parasite and to diminish BZL toxicity. In order to do that, we synthesized conjugates of BZL and PRO and we are testing their potential as TcAAAP069 inhibitors with trypanocidal action. To generate the coupled derivative we modified the BZL molecule (1) in a region remote from the main pharmacophore, the 2-nitroimidazolyl moiety. The nitro group is believed to be responsible for the toxic effects, as is thought to be reduced to various reactive and damaging electrophilic metabolites [9]. Thus, PRO coupling was achieved by means of a sulfonylation reaction to give 2, followed by direct substitution with the aminoacid, giving the final conjugate BZL-PRO (3) via a sulfonamide type connector.Conjugate 3 and derivative 4 were assayed for their trypanocidal action and no inhibition was observed. Moreover, conjugate 3 seems to favor parasite growth (mechanism in evaluation). The electrochemical behavior of the derivatives was studied by cyclic voltammetry to assess if a change in the nitro reduction mechanism was responsible for the loss in trypanocidal activity. The absence of the anodic peak in compounds 3 and 4, which is observed in the voltagram of BZL, indicates a different nitro reduction mechanism. This difference could lead to the conjugate activity inactivation. We are developing new methodologies for the conjugation of PRO to BZL and will assess the correlation between the differences in electrochemical reduction and antiparasitic activity.