Identification In Silico and In Vitro of Novel Trypanosomicidal Drug‐Like Compounds

Abstract

Atom-based bilinear indices and linear discriminant analysis are used to discover novel trypanosomicidal compounds. The obtained linear discriminant analysis-based quantitative structure-activity relationship models, using non-stochastic and stochastic indices, provide accuracies of 89.02% (85.11%) and 89.60% (88.30%) of the chemicals in the training (test) sets, respectively. Later, both models were applied to the virtual screening of 18 in-house synthesized compounds to find new pro-lead antitrypanosomal agents. The in vitro antitrypanosomal activity of this set against epimastigote forms of Trypanosoma cruzi is assayed. Predictions agree with experimental results to a great extent (16 ⁄ 18) of the chemicals. Sixteen compounds show more than 70% of epimastigote inhibition at a concentration 100 lg ⁄ mL. In addition, three compounds (CRIS 112, CRIS 140 and CRIS 147) present more than 70% of epimastigote inhibition at a concentration of 10 lg ⁄ mL (79.95%, 73.97% and 78.13%, respectively) with low values of cytotoxicity (19.7%, 7.44% and 20.63%, correspondingly).Taking into account all these results, we could say that these three compounds could be optimized in forthcoming works. Even though none of them resulted more active than nifurtimox, the current results constitute a step forward in the search for efficient ways to discover new lead antitrypanosomals.

Exploring the potential activity spectrum of two 5-nitroindazolinone prototypes on different Trypanosoma cruzi strains

“…According to these facts, we evaluated the effectiveness of derivatives 22 and 24 upon the three main forms of T. cruzi Y strain, which is routinely used in our laboratories for in vitro and in vivo drug screening models (Castillo-Garit, et al 2012; da Silva et al 2012; Araújo et al 2014; Fonseca-Berzal et al 2015). The trypanocidal profile both prototypes accomplished on this strain was quite similar to that of over CL-B5 parasites (Vega et al 2012; Fonseca-Berzal et al 2014).…”

“…trypomastigotes and amastigotes) must be carried out in vitro before advancing compounds to in vivo assays (Romanha et al 2010), since different drug susceptibility can be registered among different stages from the same T. cruzi stock (Moraes et al 2014). According to these facts, we evaluated the effectiveness of derivatives 22 and 24 upon the three main forms of T. cruzi Y strain, which is routinely used in our laboratories for in vitro and in vivo drug screening models (Castillo-Garit, et al 2012;da Silva et al 2012;Araújo et al 2014;Fonseca-Berzal et al 2015). The trypanocidal profile both prototypes accomplished on this strain was quite similar to that of over CL-B5 parasites (Vega et al 2012;Fonseca-Berzal et al 2014).…”

Deletion of Ubiquitin Fold Modifier Protein Ufm1 Processing Peptidase Ufsp in L. donovani Abolishes Ufm1 Processing and Alters Pathogenesis

“…To test whether this in vitro Ufm1 processing activity of the recombinant Ufsp can be inhibited by the anti-parasitic drugs that are commonly in use, and thus to verify if Ufsp activity is amenable to inhibition we tested a limited set of the anti-parasitic drugs in our assay. We tested Nifurtimox, Amphotericin B, Melarprosol, and Geramin following the doses most commonly used in in vitro studies [23]–[26]. Results showed that Nifurtimox, Melarprosol, and Geramin did not inhibit Ufm1 processing activity at the concentrations tested (low, medium and high, Fig.…”

<strong>An approach toward the identification of new antileishmaniasic compounds.</strong>

“…"In silico" methods are useful tools for screening chemicals, especially in early stages of the drug discovery process [5][6][7][8]. In the last two decades these studies have played a fundamental role in the development of a number of drugs that are currently on the market [9].…”