Optimization of 1,4-Naphthoquinone Hit Compound: A Computational, Phenotypic, and In Vivo Screening against Trypanosoma cruzi

Abstract

Chagas disease (CD) still represents a serious public health problem in Latin America, even after more than 100 years of its discovery. Clinical treatments (nifurtimox and benznidazole) are considered inadequate, especially because of undesirable side effects and low efficacy in the chronic stages of the disease, highlighting the urgency for discovering new effective and safe drugs. A small library of compounds (1a–i and 2a–j) was designed based on the structural optimization of a Hit compound derived from 1,4-naphthoquinones (C2) previously identified. The biological activity, structure-activity relationship (SAR), and the in silico physicochemical profiles of the naphthoquinone derivatives were analyzed. Most modifications resulted in increased trypanocidal activity but some substitutions also increased toxicity. The data reinforce the importance of the chlorine atom in the thiophenol benzene ring for trypanocidal activity, highlighting 1g, which exhibit a drug-likeness profile, as a promising compound against Trypanosoma cruzi. SAR analysis also revealed 1g as cliff generator in the structure-activity similarity map (SAS maps). However, compounds C2 and 1g were unable to reduce parasite load, and did not prevent mouse mortality in T. cruzi acute infection. Phenotypic screening and computational analysis have provided relevant information to advance the optimization and design of new 1,4-naphthoquinone derivatives with a better pharmacological profile.

1,4-Naphthoquinone (CNN1) Induces Apoptosis through DNA Damage and Promotes Upregulation of H2AFX in Leukemia Multidrug Resistant Cell Line

“…The naphthoquinones present different pharmacological properties, among them anticancer action, antifungal, antibacterial and antiviral activities, as well as allelopathic activities [ 30 , 31 , 32 , 33 ]. There are many studies that describe the effect of naphthoquinones, or its analogs, in several type of tumors and demonstrate an in vitro and in vivo chemotherapeutic potential of these compounds [ 34 , 35 , 36 ].…”

Bioactivity of Novel Pyrazole-Thiazolines Scaffolds against Trypanosoma cruzi: Computational Approaches and 3D Spheroid Model on Drug Discovery for Chagas Disease

“…Trypomastigotes were isolated from T. cruzi -infected Vero cell monolayers (10:1 parasites/host cell ratio). On the 4th day post-infection (dpi), free trypomastigotes in the culture supernatant were harvested, and the number of parasites/mL was quantified in a Neubauer chamber [ 36 ].…”

“…Thereafter, the cell monolayers were washed with phosphate-buffered saline (PBS) and 200 μL of fresh medium with a serial dilution of the pyrazole-thiazoline derivatives and Bz (1.9–500 µM) added. The cell viability was determined by luminescent assay using the CellTiter-Glo Kit (Promega Corporation, Madison, WI, USA) based on the ATP level [ 31 , 36 ]. After 72 h of treatment, 20 μL of CellTiter-Glo solution was added per well, and cultures were kept for 2 min under agitation.…”

“…Tissue-derived trypomastigotes (1 × 10 6 parasites/well) were incubated with pyrazole-thiazoline derivatives and Bz in different concentrations (0.41–100 µM) for 24 h at 37 °C in a humidified atmosphere and 5% CO 2 . The parasite viability was determined by the addition of luciferin (300 µg/mL), followed by luminescence detection on the GloMax microplate reader (Promega Corporation, Madison, WI, USA) [ 31 , 36 ].…”

Complexos imínicos de cobre com atividade antiparasitária frente à doença de chagas

“…A maioria das modificações levaram a uma melhoria da atividade tripanocida, embora algumas tenham levado a maior toxicidade. 22 Investigações sobre a atividade tripanocida de derivados de pirazol-imidazolina e pirazol-tetrahidropirimidine contra formas clinicamente relevantes de Apesar dessa ampla diversidade de compostos investigados, é grande a necessidade de desenvolvimento de novos fármacos, com menos efeitos colaterais e com alta eficiência. 10…”