Synthesis and in Vitro Evaluation of Potential Antichagasic Dipeptide Prodrugs of Primaquine

Abstract

American trypanosomiasis (Chagas' disease) is an endemic parasitic disease afflicting more than 20 million people in Latin America. Currently, therapy is unsatisfactory and only two drugs are available. Primaquine, an antimalarial drug, has trypanocidal activity. Dipeptide derivatives of primaquine, Phe-Arg-PQ, Lys-Arg-PQ, and Phe-Ala-PQ, were synthesized. The choice of the peptides was based on the primary specificity of cruzipain, the major cysteine proteinase from T cruzi. The prodrugs obtained were tested on the LLC-MK2 cell culture infected with trypomastigotes forms of T. cruzi. Phe-Arg-PQ, Lys-Arg-PQ, and Phe-Ala-PQ were active in all stages.

Primaquine revisited six decades after its discovery

“…PQ-Arg-Lys was seen to be active against T. cruzi development inside host cells, probably by interfering with the initial steps of trypomastigote-amastigote transformation. This derivative was more active than the other two, so it seems that specific cleavage has an important role in PQ release [186].…”

Primaquine dipeptide derivatives bearing an imidazolidin-4-one moiety at the N-terminus as potential antimalarial prodrugs

“…Peptide and amino acid derivatives of primaquine have been prepared to reduce toxicity of the parent drug as well as to suppress the metabolic pathway leading to 2 [15][16][17][18]. Despite the improved activity/toxicity ratio, most of these derivatives are rapidly hydrolyzed to primaquine by aminopeptidases and endopeptidases [16,18], suggesting that they might undergo extensive hydrolysis to the parent drug in the intestinal lumen when given orally.…”

Synthesis, crystal structure and biological activity screening of novel N-(α-bromoacyl)-α-amino esters containing valyl moiety

“…The structures of 1-3 were confirmed by IR, 1 H and 13 C NMR spectral data. The formation of the amide bond in 1-3 gives rise of several characteristic IR bands in the solid state IR spectrum: broad bands for the N-H stretching vibration of the hydrogen bonded amide groups in the region 3340-3290 cm -1 ; very intense bands for the corresponding amide C=O stretching vibration (Amide I) at 1653-1655 cm -1 ; and strong bands for the N-H deformation vibration (Amide II) between 1554 and 1527 cm -1 .…”

“…The 1 H and 13 C spectra indicated the presence of a mixture of two diastereoisomers for all compounds. Having in mind the starting (R,S) stereoconfiguration of 2-bromo-3-methylbutanoyl chloride, C6 in the N-(α-bromoacyl)-α-amino esters is also expected to be (R,S).…”

“…[6][7][8][9] Dipeptides represent attractive pro-moieties for generating dipeptide prodrugs also of other drugs containing hydroxyl-, [10][11][12] thiol- 4 and amino groups. [13][14][15] Variation of the dipeptide carrier structure allows fine adjustment of the lipophilicity, prodrug stability and pharmacological activity.…”