Synthesis of novel nitroimidazole analogs via click chemistry with potential activity against Leishmaniasis

Classical medicinal chemistry strategies include bioisosterism and molecular hybridization along with the copper-catalyzed azide-alkyne reaction were used for structural design and synthesis of benznidazole structural analogs. 25 compounds in 40% to 97% yield were synthesized and structurally characterized by spectrometric and spectroscopic techniques. A total of 25 nitroimidazole triazole analogs with different substitution patterns were synthesized, and the three compounds with the highest biological activity against the promastigote Leishmania amazonensis strain were summarized in Table 1. It was verified that the electronic density in the triazole ring is determinant for the biological activity of the analogs due to hydrogen bonding interactions with the L. infantum Thr51 residue (PDB 2jk6).

Table 1. Yield, IC50 and Dock Score of the three most active compounds against the promastigote strain of L amazonensis.
Analog Structure Yield IC50 (µM) Edock
48e 97% 6.1 -152.77
48u 83% 10.5 -134.20
48y 85% 13.7 -135.23