New thymol-derived triazole exhibits promising activity against Trichophyton rubrum.

Fungal infections have emerged worldwide, and azole antifungals are widely used to control these infections. However, the emergence of antifungal resistance has been compromising the effectiveness of these drugs. Therefore, the objective of this study was to evaluate the antifungal and cytotoxic activities of the nine new 1,2,3 triazole compounds derived from thymol that were synthesized through Click chemistry. The binding mode prediction was carried out by docking studies using the crystallographic structure of Lanosterol 14α-demethylase G73E mutant from Saccharomyces cerevisiae. The new compounds showed potent antifungal activity against Trichophyton rubrum but did not show relevant action against Aspergillus fumigatus and Candida albicans. For T. rubrum, molecules nº 5 and 8 showed promising results, emphasizing nº 8, whose fungicidal and fungistatic effects were similar to fluconazole. In addition, molecule nº 8 showed low toxicity for keratinocytes and fibroblasts, concluding that this compound demonstrates promising characteristics for developing a new drug for dermatophytosis caused by T. rubrum, or serves as a structural basis for further research.

Anti-Candida, docking studies, and in vitro metabolism-mediated cytotoxicity evaluation of Eugenol derivatives.

The high morbidity and mortality rates of Candida infections, especially among immunocompromised patients, are related to the increased resistance rate of these species and the limited therapeutic arsenal. In this context, we evaluated the anti-Candida potential and the cytotoxic profile of eugenol derivatives. Anti-Candida activity was evaluated on C. albicans and C. parapsilosis strains by minimum inhibitory concentration (MIC), scanning electron microscopy (SEM), and molecular docking calculations at the site of the enzyme lanosterol-14-α-demethylase active site, responsible for ergosterol formation. The cytotoxic profile was evaluated in HepG2 cells, in the presence and absence of the metabolizing system (S9 system). The results indicated compounds 1b and 1d as the most active ones. The compounds have anti-Candida activity against both strains with MIC ranging from 50 to 100 µg ml-1 . SEM analyses of 1b and 1d indicated changes in the envelope architecture of both C. albicans and C. parapsilosis like the ones of eugenol and fluconazole, respectively. Docking results of the evaluated compounds indicated a similar binding pattern of fluconazole and posaconazole at the lanosterol-14-α-demethylase binding site. In the presence of the S9 system, compound 1b showed the same cytotoxicity profile as fluconazole (1.08 times) and compound 1d had 1.23 times increase in cytotoxicity. Eugenol and other evaluated compounds showed a significant increase in cytotoxicity. Our results suggest compound 1b as a promising starting point candidate to be used in the design of new anti-Candida agent prototypes.

Bioactivity of Meliaceae, Amaryllidaceae, Solanaceae and Amaranthaceae plant aqueous extracts against the cattle tick Rhipicephalus microplus.

Commercial synthetic acaricides have selected resistant populations of Rhipicephalus microplus, and generate residues in the environment or in milk/cattle products. In this study, aqueous extracts (AE) from Melia azedarach (Maz), Allium sativum, Capsicum chinense, Nicotiana tabacum (Nta) and Dysphania ambrosioides were evaluated for the bioactivity against the cattle tick. The treatment using Nta or Maz AE resulted in the lowest egg hatching rate (34.0 ± 11% and 25.0 ± 19%), and in the values of reproduction inhibition ranging from 89.0% to 85.3%. Phytochemical screening associated to RP-HPLC/DAD analysis suggested the presence of alkaloids for Nta and gallic acid derivatives and catechins, for Maz. Such results highlighted that the use of Nta and Maz AE can be a promising source of bioactive compounds for the control of infections caused by the cattle tick.

Novel [6]-gingerol Triazole Derivatives and their Antiproliferative Potential against Tumor Cells.

BACKGROUND: Effective cancer treatment is a major public health challenge. The limitations of current therapies and their adverse effects reduce the efficacy of treatment, leading to significant mortality rates worldwide. Moreover, natural product chemistry occupies a prominent role in the search for new treatment alternatives, by contributing a spectrum of chemical structures that may potentially yield new bioactive compounds. The compound [6]-gingerol (1) is the main active substance in ginger (Zingiber officinale) and several studies have shown it to produce beneficial effects, including antitumor activity. OBJECTIVE: This work aims to obtain new gingerol derivatives with cytotoxic activity. METHODS: [6]-gingerol was isolated and its derivatives were produced using click chemistry, obtaining eight new compounds. All chemical structures were determined by means of IR, NMR and HRMS data, and cytotoxicity was evaluated in the HCT 116 (colon carcinoma) and MCF-7 (breast carcinoma) cell lines at concentrations of 5 µmol L-1 and 50 µmol L-1. RESULTS: At 50 µmol L-1, more than 70% inhibition of cell growth was achieved with compounds 2e, 2g against HCT 116, and 2b, 2d, 2e, 2f and 2g against MCF-7. CONCLUSION: The obtained compounds showed only moderate cytotoxic activity. However, the products with substituents occupying the meta position in relation to the triazole ring showed increased cytotoxic properties. The brominated compound (2g) showed the strongest activity, inhibiting cell proliferation by 87%.

In silico design and search for acetylcholinesterase inhibitors in Alzheimer's disease with a suitable pharmacokinetic profile and low toxicity.

Alzheimer's disease is a complex neurodegenerative disorder of the central nervous system, characterized by amyloid-ß deposits, τ-protein aggregation, oxidative stress and reduced levels of acetylcholine in the brain. One pharmacological approach is to restore acetylcholine level by inhibiting acetylcholinesterase (AChE) with reversible inhibitors, such as galanthamine, thus helping to improve the cognitive symptoms of the disease. In order to design new galanthamine derivatives and search for novel, potential inhibitors with improved interactions, as well as a suitable pharmacokinetic profile and low toxicity, several molecular modeling techniques were applied. These techniques included the investigation of AChE-drug complexes (1QT1 and 1ACJ Protein Data Bank codes), ligand-binding sites calculation within the active site of the enzyme, pharmacophore perception of galanthamine derivatives, virtual screening, toxicophorical analysis and estimation of pharmacokinetics properties. A total of four galanthamine derivatives having a N-alkyl-phenyl chain were designed, since the tertiary amine substituents could reach the peripheral anionic site that is not occupied by galanthamine. In addition, 12 drug-like compounds from the Ilibdiverse database were selected by virtual screening as novel, hypothetical AChE inhibitors. The toxicophorical analysis revealed that only four proposed inhibitors have chemical groups able to develop mutagenicity and chromosome damage. The remaining compounds showed only mild or none toxicophorical alerts. At least three screened compounds presented theoric parameters consistent with good oral bioavailability. The designed molecules have the potential to become new lead compounds that might guide the design of drugs with optimized pharmacodynamic and pharmacokinetic properties in order to improve the treatment of Alzheimer's disease by creating new pharmacotherapeutic options.