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

MARISA L. TAVERNA PORRO; MELISA SAYE; CAMPODALLL'ORTO V.; MIRANDA M.R; CLAUDIO PEREIRA; MOGLIONI, ALBERTINA

Congreso; DDNDIC 2018 ? 4° Reunión Científica de la Red de Investigación de Productos Naturales contra Enfermedades Olvidadas; 2018

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 infection1. Nowadays only benznidazole (BZL) and nifurtimox are used to treat this disease, but both present several side effects and are only effective during the chronic stage of the disease2. T. cruzi has a metabolism largely based on amino acid consumption, mainly proline (PRO), which can be used as an alternative carbon and energy source to glucose3. PRO is also involved in differentiation processes, cellular invasion and resistance to oxidative, nutritional and osmotic stress4-7. 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-PRO7 and it was recently reported that a synthetic proline analogue that inhibits the uptake also possesses trypanocidal effect8. 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 synthetized 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 metabolites9. Thus, PRO coupling was achieved by means of a sulfonylation reaction to give 2, followed by direct substitution with the amino acid, 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 lost in trypanocidal activity. The absence of the anodic peak in compounds 3 and 4, which is observed in the voltagramm of BZL, indicates a different nitro reduction mechanism. This difference could lead to conjugate 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 antiparisitic activity. References1. World Health Organization. 2015. PMID 256718462. Urbina. 2010. PMID 199003953. Sylvester & Krasner. 1976. PMID 7890074. Martins et al. 2009. PMID 194335475. Tonelli et al. 2004. PMID 152366406. Magdaleno et al. 2009. PMID 192293477. Sayé et al. 2014. PMID 246377448. Sayé et al. 2017. PMID 288449789. Hall et al. 2012. PMID 22037852