Efficient identification of novel anti-glioma lead compounds by machine learning models.

Glioblastoma multiforme (GBM) is the most devastating and widespread primary central nervous system tumor. Pharmacological treatment of this malignance is limited by the selective permeability of the blood-brain barrier (BBB) and relies on a single drug, temozolomide (TMZ), thus making the discovery of new compounds challenging and urgent. Therefore, aiming to discover new anti-glioma drugs, we developed robust machine learning models for predicting anti-glioma activity and BBB penetration ability of new compounds. Using these models, we prioritized 41 compounds from our in-house library of compounds, for further in vitro testing against three glioma cell lines and astrocytes. Subsequently, the most potent and selective compounds were resynthesized and tested in vivo using an orthotopic glioma model. This approach revealed two lead candidates, 4m and 4n, which efficiently decreased malignant glioma development in mice, probably by inhibiting thioredoxin reductase activity, as shown by our enzymological assays. Moreover, these two compounds did not promote body weight reduction, death of animals, or altered hematological and toxicological markers, making then good candidates for lead optimization as anti-glioma drug candidates.

4-Nerolidylcatechol and its synthetic analogues: antioxidant activity and toxicity evaluation.

4-Nerolidylcatechol (1) is a secondary metabolite of plants and is described as a promising anti-inflammatory, antimalarial, antiulcerogenic, analgesic and cytotoxic compound possibly due to its antioxidant profile. In this study, we evaluated the pharmacologic activity and the antioxidant and toxicological profiles of compound (1) and its synthetic analogues (2-6). The synthetic analogues were designed from the lead compound, (1), using a molecular-simplification strategy. Compound 5 showed, by 1,1-diphenyl-2-picrylhydrazyl (DPPH) and ß-carotene systems, similar antioxidant activity when compared to compound (1). The oxidative stress in erythrocyte membrane demonstrated the highly protective effect of compounds (4), (5) and (6) and high antioxidant/pro-oxidant activity in relation to the concentrations of compounds (1) and (3). Compounds (2), (4), (5) and (6) were haemobiocompatible. All compounds (1-6) showed cytotoxic effects in 3T3 cells, but compounds (2) and (6) were highly cytotoxic in this lineage when compared to compound (1). Compound (5) had a lower myelosuppressive effect in haematopoietic progenitor cells compared to (1). Both compounds, (1) and (5), showed low genotoxic effects in vitro, on human lymphocyte cells. In addition, these compounds also showed low-toxicity in vivo as defined a LD50 > 2000 mg/kg. In this assay, we did not observe death in the animals exposed to treatment with (1) and (5) compound. In conclusion, the structural design of the analogues as validated once compound (5) was found to have an antioxidant profile that was as potent as the lead compound (1). In addition, considering the safety profile, these compounds are promising as preventive and/or therapeutic agents against oxidative damage.