Desing and synthesis of potent anti-Trypanosoma cruzi agents new thiazoles derivatives which induce apoptotic parasite death

Abstract

Chagas disease, caused by the kinetoplastid protozoan parasite Trypanosoma cruzi, remains a relevant cause of illness and premature death and it is estimated that 6 million to 7 million people are infected worldwide. Although chemotherapy options are limited presenting serious problems, such as low efficacy and high toxicity. T. cruzi is susceptible to thiazoles, making this class of compounds appealing for drug development. Previously, thiazoles resulted in an increase in anti-T. cruzi activity in comparison to thiosemicarbazones. Here, we report the structural planning, synthesis and anti-T. cruzi evaluation of new thiazoles derivatives (3a-m and 4a-m), designed from molecular hybridization associated with non-classical bioisosterism. By varying substituents attached to the phenyl and thiazole rings, substituents were observed to retain, enhance or greatly increase their anti-T. cruzi activity, in comparison to the corresponding thiosemicarbazones. In most cases, electron-withdrawing substituents, such as bromine, 3,4-dichloro and nitro groups, greatly increased antiparasitic activity. Specifically, new thiazoles were identified that inhibit the epimastigote proliferation and were toxic for trypomastigotes without affecting macrophages viability. These compounds were also evaluated against cruzain. However, inhibition of this enzyme was not observed, suggesting that the compounds work through another mechanism. In addition, examination of T. cruzi cell death showed that these molecules induce apoptosis. In conclusion, except for compounds 3h and 3k, all thiazoles derivatives evaluated exhibited higher cytotoxic activity against the trypomastigote forms than the reference medicament benznidazole, without affecting macrophages viability. Compounds 4d and 4k were highlights, CC50 = 1.2 e 1.6 μM, respectively. Mechanistically, these compounds do not inhibit the cruzain, but induce T. cruzi cell death by an apoptotic process, being considered a good starting point for the development of new anti-Chagas drug candidates.

Thiazole Ring—A Biologically Active Scaffold

“…Da Silva et al [208] synthesized 2-(pyridin-2-yl)-1,3-thiazoles (140a-m and 141a-m, (Figure 56) and studied their antiparasitic and host cell cytotoxicity (Figure 56). Primarily, the ability of compounds to inhibit the epimastigote proliferation of T. cruzi Dm28 strain, as well as their toxicity against Y strain trypomastigotes, was determined.…”

Review on Experimental Treatment Strategies Against Trypanosoma cruzi

“…81 Thiazole compounds showed in vitro activity and promoted reduction of parasitemia and mortality possibly by acting as cruzipain inhibitors (Figure 3). [82][83][84][85] Amidine-containing compounds represent a versatile class of drugs, with potential antiprotozoal treatment, acting through multiple mechanisms against T. cruzi. 86 Many compounds presented in vitro and in vivo activity against T. cruzi (see Table 1).…”

“…[ [82][83][84][85] Ergosterol biosynthesis inhibitors 4-aminopyridyl-based lead compounds Compounds showed anti-T. cruzi effects in acute and chronically infected mice, but without cure.…”

<p>One-Pot Synthesis of Novel Thiazoles as Potential Anti-Cancer Agents</p>

“…6 Recent pharmaceutical advances have allowed the specific targeting of protein-protein interactions in the BCL-2 family. 5,7 Thiosemicarbazones are a large class of compounds, which represent great therapeutic value against parasitic diseases 8,9 and microbial diseases. 10 They were also identified to be among the most interesting antitumor inhibitors due to induction of oxidative stress and ROS-mediated cell injury.…”