Targeted cancer therapies are used to inhibit the growth, progression, and metastasis of the tumor by interfering with specific molecular targets and are currently the focus of anticancer drug development. Protein kinase B, also known as Akt, plays a central role in many types of cancer and has been validated as a therapeutic target nearly two decades ago. This review summarizes the intracellular functions of Akt as a pivotal point of converging signaling pathways involved in cell growth, proliferation, apoptotis and neo-angiogenesis, and focuses on the drug design strategies to develop potent anticancer agents targeting Akt. The discovery process of Akt inhibitors has evolved from adenosine triphosphate (ATP)-competitive agents to alternative approaches employing allosteric sites in order to overcome the high degree of structural similarity between Akt isoforms in the catalytic domain, and considerable structural analogy to the AGC kinase family. This process has led to the discovery of inhibitors with greater specificity, reduced side-effects and lower toxicity. A second generation of Akt has inhibitors emerged by incorporating a chemically reactive Michael acceptor template to target the nucleophile cysteines in the catalytic activation loop. The review outlines the development of several promising drug candidates emphasizing the importance of each chemical scaffold. We explore the pipeline of Akt inhibitors and their preclinical and clinical examination status, presenting the potential clinical application of these agents as a monotherapy or in combination with ionizing radiation, other targeted therapies, or chemotherapy.

Protein kinase B (Akt), similar to many other protein kinases, is at the crossroads of cell death and survival, playing a pivotal role in multiple interconnected cell signaling mechanisms implicated in cell metabolism, growth and division, apoptosis suppression and angiogenesis. Akt protein kinase displays important metabolic effects, among which are glucose uptake in muscle and fat cells or the suppression of neuronal cell death. Disruptions in the Akt-regulated pathways are associated with cancer, diabetes, cardiovascular and neurological diseases. The regulation of the Akt signaling pathway renders Akt a valuable therapeutic target. The discovery process of Akt inhibitors using various strategies has led to the identification of inhibitors with great selectivity, low side-effects and toxicity. The usefulness of Akt emerges beyond cancer therapy and extends to other major diseases, such as diabetes, heart diseases, or neurodegeneration. This review presents key features of Akt structure and functions, and presents the progress of Akt inhibitors in regards to drug development, and their preclinical and clinical activity in regards to therapeutic efficacy and safety for patients.

To date, multi-drug resistant bacteria represent an increasing health threat, with a high impact on mortality, morbidity, and health costs on a global scale. The ability of bacteria to rapidly and permanently acquire new virulence factors and drug-resistance elements requires the development of new antimicrobial agents and selection of new proper targets, such as sortase A. This specific bacterial target plays an important role in the virulence of many Gram-positive pathogens, and its inhibition should produce a mild evolutionary pressure which will not favor the development of resistance. A primary screening using a fluorescence resonance energy transfer assay was used to experimentally evaluate the inhibitory activity of several compounds on sortase A. Using molecular docking and structure-activity relationship analyses, several lead inhibitors were identified, which were further tested for antimicrobial activity using the well diffusion test and minimum inhibitory concentration. The toxicity was assessed using the Daphnia magna test and used as a future screening filter. Three natural compounds were identified in this study as promising candidates for further development into therapeutically useful anti-infective agents that could be used to treat infections caused by multi-drug resistant bacterial pathogens which include sortase A in their enzymatic set.

Pyrrolizidine alkaloids (PAs) are a widespread class of hepatotoxic heterocyclic organic compounds found in approximately 3% of world flora. Some PAs have been shown to have genotoxic and carcinogenic effects. The present study focuses on the toxicity effects of four dry extracts obtained from medicinal plants (Senecio vernalis, Symphytum officinale, Petasites hybridus and Tussilago farfara), on two aquatic organisms, Artemia salina and Daphnia magna, and the correlation with their PAs content. A new GC-MS method, using a retention time (TR)-5MS type capillary column was developed. PAs Kovats retention indices, for this type of column were computed for the first time. The lethal dose 50% (LC50) values for the two invertebrate models were correlated (Pearson's coefficient, >0.9) and the toxicity was PA concentration-dependent, for three of the four extracts. All tested extracts were found to be toxic in both aquatic organism models. The results can be used to develop a GC-MS validated method for the assay of PAs in medicinal plants with a further potential application in the risk assessment study of PAs toxicity in humans.

Hydrazone complexes of Cu(II), Co(II), Zn(II), Ni(II) and Pt(II) with N-isonicotinoyl-N′-(3-metoxy-2 hydroxybenzaldehyde)-hydrazone (HL) were synthesized and characterized by different physico-chemical techniques including elemental and thermal analysis, magnetic susceptibility measurements, molar electric conductivity, as well as IR (infrared), 1H-NMR and 13C-NMR (hydrogen and carbon nuclear magnetic resonance, UV-Vis (ultraviolet-visible), FAB (fast atom bombardment), EPR (electron paramagnetic resonance), and mass spectroscopies. The crystal structure of ligand was determined by single crystal X-ray diffraction studies. Spectral data showed that hydrazone behaves as an ONO tridentate ligand through the azomethine nitrogen, phenolate and keto oxygen atoms. For the copper(II) complexes, metal–ligand bonding parameters were evaluated from the EPR spectra. These parameters indicate the presence of in-plane π bonding. In addition, the f values of complexes 1–4 indicate small distortion from planarity. The effect of these complexes on proliferation of human breast cancer (MCF-7 and SKBR-3), human melanoma (A375), lung adenocarcinoma cells (NCI-H1573) and their antibacterial activity against Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus and Candida albicans strains were studied and compared with those of free ligand. The ligand and complexes 1–3 showed significant antimicrobial activity against the Gram-positive bacteria Staphylococcus aureus and Candida albicans in comparison to the control drugs. The complexes 2–4 could be potential antitumor agents, leading to a significant improvement of the cytotoxic activity when compared with HL.

New pyrazole derivatives were designed and synthesized as potential protein kinase inhibitors in the view to develop specific antitumor therapies. The structures of the compounds were elucidated using spectral and elemental analyses. The antitumor potential was estimated using wheat seeds and the general toxicity was evaluated by alternative methods, using invertebrate animals. One 3-aminopyrazole derivative emerged as a potential candidate for the development of future cytotoxic compounds.

Bacterial sortases are cysteine transpeptidases that regulate the covalent linkage of several surface protein virulence factors in Gram-positive bacteria. Virulence factors play significant roles in adhesion, invasion of host tissues, biofilm formation and immune evasion, mediating the bacterial pathogenesis and infectivity. Therefore, sortases are emerging as important targets for the design of new anti-infective agents. We employed a computational study, based on structure derived descriptors and molecular fingerprints, in order to develop simple classification methods which could allow predicting low active or high active SrtA inhibitors. Our results indicate that a highly active SrtA inhibitor has a molecular weight ranging between 180 and 600, contains one up to four nitrogen atoms, up to three oxygen atoms and under 18 hydrogen atoms. Also the hydrogen acceptor number and the molecular flexibility, as assessed by the number of rotatable bounds, have emerged as the most relevant descriptors for SrtA affinity. The Bemis-Murcko scaffolding revealed favoured scaffolds as containing at least two ring structures bonded directly or merged in a condensed cycle. This data represent a valuable tool for identifying new potent SrtA inhibitors, potential anti-virulence agents targeted against Gram-positive bacteria, including multiresistant strains.

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