In Vitro and In Silico Analysis of New n-Butyl and Isobutyl Quinoxaline-7-carboxylate 1,4-di-N-oxide Derivatives against Trypanosoma cruzi as Trypanothione Reductase Inhibitors

Abstract

American trypanosomiasis is a worldwide health problem that requires attention due to ineffective treatment options. We evaluated n-butyl and isobutyl quinoxaline-7-carboxylate 1,4-di-N-oxide derivatives against trypomastigotes of the Trypanosoma cruzi strains NINOA and INC-5. An in silico analysis of the interactions of 1,4-di-N-oxide on the active site of trypanothione reductase (TR) and an enzyme inhibition study was carried out. The n-butyl series compound identified as T-150 had the best trypanocidal activity against T. cruzi trypomastigotes, with a 13% TR inhibition at 44 μM. The derivative T-147 behaved as a mixed inhibitor with Ki and Ki’ inhibition constants of 11.4 and 60.8 µM, respectively. This finding is comparable to the TR inhibitor mepacrine (Ki = 19 µM).

From Benznidazole to New Drugs: Nanotechnology Contribution in Chagas Disease

“…Lycnofolide (LYC) is a sesquiterpene lactone of natural origin, isolated from Lychnophora trichocarpha, and exhibits anti- T. cruzi activity. Although its mechanism is not well elucidated, it is believed that it acts by covalently binding to the trypanothione enzyme in the parasite, which has a function analogous to glutathione for mammalian cells, inactivating it and leading to increased intracellular oxidative stress and is essential and exclusive in trypanosomatids [ 167 , 168 ]. However, due to its physicochemical characteristics not favoring its oral bioavailability, its potential was studied using two types of nanosystems.…”

Repurposing of rabeprazole as an anti- Trypanosoma cruzi drug that targets cellular triosephosphate isomerase

“…High throughput screening assays have been conducted on thousands of natural and synthetic compounds, and a few have advanced to clinical trials listed in the Clinical Trials database ( https://clinicaltrials.gov ) 15 . Some therapeutic targets studied include sterol-14-α demethylase (CYP51) 16 , the 80 kDa enzyme prolyl oligopeptidase (Tc80) 17 , cysteine peptidase cruzipain 18 , 19 , the proteasome 20 , trypanothione reductase 21 , superoxide dismutase (Fe-SOD) and triosephosphate isomerase (TIM) 22 . TIM catalyses the interconversion of DHAP and GAP, which is a vital mechanism for the complete catabolism of glucose and the generation of net energy in the form of ATP and metabolites such as NADH.…”