Evaluation of novel compounds as anti-bacterial or anti-virulence agents.

Antimicrobial resistance is a global threat, leading to an alarming increase in the prevalence of bacterial infections that can no longer be treated with available antibiotics. The World Health Organization estimates that by 2050 up to 10 million deaths per year could be associated with antimicrobial resistance, which would equal the annual number of cancer deaths worldwide. To overcome this emerging crisis, novel anti-bacterial compounds are urgently needed. There are two possible approaches in the fight against bacterial infections: a) targeting structures within bacterial cells, similar to existing antibiotics; and/or b) targeting virulence factors rather than bacterial growth. Here, for the first time, we provide a comprehensive overview of the key steps in the evaluation of potential new anti-bacterial and/or anti-virulence compounds. The methods described in this review include: a) in silico methods for the evaluation of novel compounds; b) anti-bacterial assays (MIC, MBC, Time-kill); b) anti-virulence assays (anti-biofilm, anti-quorum sensing, anti-adhesion); and c) evaluation of safety aspects (cytotoxicity assay and Ames test). Overall, we provide a detailed description of the methods that are an essential tool for chemists, computational chemists, microbiologists, and toxicologists in the evaluation of potential novel antimicrobial compounds. These methods are cost-effective and have high predictive value. They are widely used in preclinical studies to identify new molecular candidates, for further investigation in animal and human trials.

Targeting Histone Deacetylases 6 in Dual-Target Therapy of Cancer.

Histone deacetylases (HDACs) are the major regulators of the balance of acetylation of histone and non-histone proteins. In contrast to other HDAC isoforms, HDAC6 is mainly involved in maintaining the acetylation balance of many non-histone proteins. Therefore, the overexpression of HDAC6 is associated with tumorigenesis, invasion, migration, survival, apoptosis and growth of various malignancies. As a result, HDAC6 is considered a promising target for cancer treatment. However, none of selective HDAC6 inhibitors are in clinical use, mainly because of the low efficacy and high concentrations used to show anticancer properties, which may lead to off-target effects. Therefore, HDAC6 inhibitors with dual-target capabilities represent a new trend in cancer treatment, aiming to overcome the above problems. In this review, we summarize the advances in tumor treatment with dual-target HDAC6 inhibitors.

Quantitative structure-activity relationships of xanthen-3-one and xanthen-1,8-dione derivatives and design of new compounds with enhanced antiproliferative activity on HeLa cervical cancer cells.

Xanthene derivatives have become a group of molecules of great importance in discovering of new anticancer drugs. Recent studies of our group performed on xanthen-3-one and xanthen-1,8-dione derivatives have shown their antiproliferative activity on HeLa cervical cell lines. Obtained IC50 values together with calculated molecular descriptors were subjected to Quantitative Structure-Activity Relationship (QSAR) study in order to identify the most relevant molecular features responsible for the observed antiproliferative activity of compounds. Partial least square statistical method and the same training and test set were used to obtain statistical parameters for internal and external validation in 2D- and 3D-QSAR study. The obtained QSAR models have shown next results: 2D-QSAR: R2 = 0.741, Q2 = 0.792, R2pred = 0.875 and 3D-QSAR: R2 = 0.951, Q2 = 0.830, R2pred = 0.769. Based on the performed QSAR analysis and calculated ADMET properties, novel xanthene derivatives with enhanced antiproliferative activity were designed. Communicated by Ramaswamy H. Sarma.