Potent and Selective Inhibitors of Trypanosoma cruzi Triosephosphate Isomerase with Concomitant Inhibition of Cruzipain: Inhibition of Parasite Growth through Multitarget Activity

Abstract

Triosephosphate isomerase (TIM) is an essential Trypanosoma cruzi enzyme and one of the few validated drug targets for Chagas disease. The known inhibitors of this enzyme behave poorly or have low activity in the parasite. In this work, we used symmetrical diarylideneketones derived from structures with trypanosomicidal activity. We obtained an enzymatic inhibitor with an IC50 value of 86 nm without inhibition effects on the mammalian enzyme. These molecules also affected cruzipain, another essential proteolytic enzyme of the parasite. This dual activity is important to avoid resistance problems. The compounds were studied in vitro against the epimastigote form of the parasite, and nonspecific toxicity to mammalian cells was also evaluated. As a proof of concept, three of the best derivatives were also assayed in vivo. Some of these derivatives showed higher in vitro trypanosomicidal activity than the reference drugs and were effective in protecting infected mice. In addition, these molecules could be obtained by a simple and economic green synthetic route, which is an important feature in the research and development of future drugs for neglected diseases.

Novel and selective inactivators of Triosephosphate isomerase with anti-trematode activity

“…Screening FhTIM. We hypothesized that a TIM dimer interface inactivator would be a successful strategy to identify molecules with selective antiparasitic activity [18][19][20] . Therefore, we selected 340 compounds from our in-house chemical collection and screened them against the isolated recombinant FhTIM.…”

“…www.nature.com/scientificreports www.nature.com/scientificreports/ Cell culture. J774.1 murine macrophage cells (ATCC, USA) were grown in DMEM culture milieu containing 4 mM glutamine and supplemented with 10% FCS 20 . The cells were seeded in a 96-well plate (5×10 4 cells in 200 µL culture medium) and incubated at 37 °C in a 5% CO 2 atmosphere for 48 h, to allow cell adhesion prior to drug testing.…”

Triosephosphate Isomerase Inhibitors as Potential Drugs against Clostridium perfringens

“…In this study, we can relate the importance of loop 6 and loop 7 in the development of drugs against TcTIM and GlTIM, and we propose than, our important amino acids are in the loop 3 region, which alter the region of the interface and C4 has a greater effect with the loop 7, resulting in the alteration of the conformational structure of the active site or that some conformation interacts with Lys14 or His97 that decreases glycolytic activity.…”

Drug discovery and computational strategies in the multitarget drugs era

“…One of the enzymes validated in the study of promising targets for the treatment of Chagas disease is the triosephosphate isomerase (TIM), of which its existing inhibitors have low interactions. For this reason, Aguilera et al (2016) reported the study of derivatives diarylideneketones ( Figure 6) in antitrypanosomal activity, with in vitro and IC 50 in the range of 86 nM, without having negative effects on the mammalian enzyme. In addition to this activity, inhibition of 31% for the cruzain enzyme was also reported.…”