Anti-parasitic effect of novel amidines against Trypanosoma cruzi: phenotypic and in silico absorption, distribution, metabolism, excretion and toxicity analysis

Abstract

S U M M A R YNew more selective and potent drugs are urgently need to treat Chagas disease (CD). Among the many synthetic compounds evaluated against Trypanosoma cruzi, aromatic amidines (AAs) and especially arylimidamides (AIAs) have potent activity against this parasite. Presently, the effect of four mono-amidines (DB2228, DB2229, DB2292 and DB2294), four diamidines (DB2232, DB2235, DB2251 and DB2253) and one AIA (DB2255) was screened in vitro against different forms (bloodstream trypomastigotes -BT and intracellular forms) and strains from discrete typing unit (DTU) I and VI of T. cruzi and their cytotoxic profile on mammalian host cells. Except for DB2253, all molecules were as active as benznidazole (Bz), resulting in 50% of reduction in the number of alive BT, with EC 50 ranging from 2·7 to 10·1 µM after 24 h of incubation. DB2255 was also the most potent against amastigotes (Tulahuen strain) showing similar activity to that of Bz (3 µM). In silico absorption, distribution, metabolism, excretion and toxicity analysis demonstrated probability of human intestinal adsorption, while mutagenicity and inhibition of hERG1 were not predicted, besides giving acceptable predicted volumes of distribution. Our findings contribute for better knowledge regarding the biological effect of this class of aromatic molecules against T. cruzi aiming to identify novel promising agent for CD therapy.

In Vitro and In Vivo Studies of the Trypanocidal Effect of Novel Quinolines

“…We conducted different analyses that included computational and cell-based screening as well as mouse models of trypanosome infections. As reported previously, in silico analyses have the advantages of low cost, fast processing, and the fact that compounds can be evaluated without synthesizing them, allowing large libraries to be explored (22). However, computational screens often fail to simulate the full complexity of biological systems and need to be complemented with experimental studies (19).…”

“…In fact, plasma biochemical analyses of quinoline-treated mice confirmed the low-cardiotoxicity profile determined by CK measurements. Thus, in vitro whole-cell-based screening associated with theoretical analyses of the ADMET properties and mouse models of acute toxicity were used to select potential drug candidates to proceed to in vivo efficacy evaluations (22). The in silico properties of the novel quinolines were evaluated by using the pKCSM tool, and the overall findings predicted good oral absorption, a high probability of permeability in Caco2 cells, good human intestinal absorption, and low probabilities of mutagenicity and inhibition of hERG1.…”

“…Computational assessment of drug-like properties. Absorption, distribution, metabolism, excretion, and toxicity (ADMET and Lipinski's rule of five) properties of the studied quinolines were evaluated by using the pKCSM approach, which uses graph-based signatures to develop predictive ADMET (22,24).…”

“…For T. cruzi assays, BT of the Y strain (DTU II) (30) (5 ϫ 10 6 BT per ml) were incubated for 2 and 24 h at 37°C in RPMI in the presence or absence of serial dilutions of the compounds (up to 32 M). After compound incubation, the death rates of parasites were determined by light microscopy through the direct quantification of the number of live parasites by using a Neubauer chamber, and the EC 50 (the compound concentration that reduces the number of parasites by 50%) was calculated (22). For assaying intracellular forms of the Y strain (DTU II), the most promising compound was further evaluated with infection of primary cultures of CC (using a ratio of 10 BT to 1 host cell).…”

In Vitro Phenotypic Activity and In Silico Analysis of Natural Products from Brazilian Biodiversity on Trypanosoma cruzi

“…Absorption, distribution, metabolism, excretion, and toxicity (ADMET) and Lipinski’s rule of five properties of compounds 1 , 2 and 8 and BZ were accessed using the Predicting Small-Molecule Pharmacokinetic and Toxicity Properties (pKCSM) approach, which uses graph-based signatures to develop predictive ADMET [ 44 , 45 ].…”