Synthesis of Hybrid Molecules with Imidazole-1,3,4-thiadiazole Core and Evaluation of Biological Activity on Trypanosoma cruzi and Leishmania donovani

Abstract

The aim of this work was to obtain and evaluate, as antiprotozoals, new derivatives of benzoate imidazo-1,3,4-thiadiazole 18-23 based on the concepts of molecular repositioning and hybridization. In the design of these compounds, two important pharmacophoric subunits of the fexnidazole prototype were used: metronidazole was used as a repositioning molecule, p-aminobenzoic acid was incorporated as a bridge group, and 1,3,4-thiadiazole group was incorporated as a second pharmacophore, which at position 5 has an aromatic group with different substituents incorporated. The final six compounds were obtained through a five-step linear route with moderate to good yields. The biological results demonstrated the potential of this new class of compounds, since three of them 19-21 showed inhibitory activity on proliferation, in the order of 50%, in the in vitro assay against epimastigotes of T. cruzi (Strain Y sensitive to nifurtimox and benznidazole) and promastigotes of L. donovani, at a single concentration of 50 μM.

Keywords: L. donovani; T. cruzi; hybridization; nitroimidazole; thiadiazole.

Figure 1

Structures for benznidazole (Bnz), nifurtimox (Nfx), and fexinidazole (Fx).

Figure 2

Structures for glucantime, amphotericin B, and miltefosine.

Figure 3

General structures for the benzoates imidazo-1,3,4-thiadiazole 18–23.

Figure 4

Some active substances placed on the market containing 1,3,4-thiadiazole.

Scheme 1

Synthesis of derivatives 18–23. i. Et₃N, CS₂, 72 h, rt ii. ClCO₂Et, Et₃N, CHCl₃, rt iii. 4a–f, EtOH, 78 °C, 4 h iv. a. H₂SO₄, 0 °C ‣ rt, 24 h b. LiOH 2N, THF, H₂O, 80 °C, 24 h v. EDCI, DMAP, DMF, Mtz 17, rt, 48 h.

Figure 5

Proliferation of T. cruzi epimastigotes and L. donovani promastigotes at a concentration of 50 μM for compounds 18–23. Metronidazole, Benznidazole, Amphotericin B and Nifurtimox as treatment control, U.C, untreated control of the parasites.