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

TABERNA M.; SAYE M; MIRANDA M; PEREIRA CA; MOGLIONI A

Congreso; DRUG DISCOVERY FOR NEGLECTED DISEASES INTERNATIONAL CONGRESS 2018. 4th Scientific Meeting of the Research Network; 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 infection. 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. 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. 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 and it was recently reported that a synthetic proline analogue that inhibits the uptake also possesses trypanocidal effect . 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 themain 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. Thus, PRO coupling wasachieved 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.