Dementia is characterized by the impairment of cognition and behavior of people over 65 years. Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder in the world, as approximately 47 million people are affected by this disease and the tendency is that this number will increase to 62% by 2030. Two microscopic features assist in the characterization of the disease, the amyloid plaques and neurofibrillary agglomerates. All these factors are responsible for the slow and gradual deterioration of memory that affect language, personality or cognitive control. For the AD diagnosis, neuropsychological tests are performed in different spheres of cognitive functions but since not all cognitive functions may be affected, cerebrospinal fluid biomarkers are used along with these tests. To date, cholinesterase inhibitors are used as treatment, they are the only drugs that have shown significant improvements in the cognitive functions of AD patients. Despite the proven effectiveness of cholinesterase inhibitors, an AD carrier, even while being treated, is continually subjected to progressive degeneration of the neuronal tissue. For this reason, other biochemical pathways associated with the pathophysiology of AD have been explored as alternatives to the treatment of this condition such as inhibition of β-secretase and glycogen synthase kinase-3β. The present study aims to conduct a review of the epidemiology, pathophysiology, symptoms, diagnosis and treatment of Alzheimer's disease, emphasizing the research and development of new therapeutic approaches.

: Parkinson's Disease (PD) is the second most common neurodegenerative disease in the elderly population, with a higher prevalence in men, independent of race and social class; it affects approximately 1.5 to 2.0% of the elderly population over 60 years and 4% for those over 80 years of age. PD is caused by the necrosis of dopaminergic neurons in the substantia nigra, which is the brain region responsible for the synthesis of the neurotransmitter dopamine (DA), resulting in its decrease in the synaptic cleft. The monoamine oxidase B (MAO-B) degrades dopamine, promoting the glutamate accumulation and oxidative stress with the release of free radicals, causing excitotoxicity. The PD symptoms are progressive physical limitations such as rigidity, bradykinesia, tremor, postural instability and disability in functional performance. Considering that there are no laboratory tests, biomarkers or imaging studies to confirm the disease, the diagnosis of PD is made by analyzing the motor features. There is no cure for PD, and the pharmacological treatment consists of a dopaminergic supplement with levodopa, COMT inhibitors, anticholinergics agents, dopaminergic agonists, and inhibitors of MAO-B, which basically aims to control the symptoms, enabling better functional mobility and increasing life expectancy of the treated PD patients. Due to the importance and increasing prevalence of PD in the world, this study reviews information on the pathophysiology, symptomatology as well as the most current and relevant treatments of PD patients.

A series of quinazolin-4-one based hydroxamic acids was rationally designed and synthesized as novel dual PI3K/HDAC inhibitors by incorporating an HDAC pharmacophore into a PI3K inhibitor (Idelalisib) via an optimized linker. Several of these dual inhibitors were highly potent (IC 50 < 10 nM) and selective against PI3Kγ, δ and HDAC6 enzymes and exhibited good antiproliferative activity against multiple cancer cell lines. The lead compound 48c, induced necrosis in several mutant and FLT3-resistant AML cell lines and primary blasts from AML patients, while showing no cytotoxicity against normal PBMCs, NIH3T3, and HEK293 cells. Target engagement of PI3Kδ and HDAC6 by 48c was demonstrated in MV411 cells using the cellular thermal shift assay (CETSA). Compound 48c showed good pharmacokinetics properties in mice via intraperitoneal (ip) administration and provides a means to examine the biological effects of inhibiting these two important enzymes with a single molecule, either in vitro or in vivo.

Lactate dehydrogenase (LDH) catalyzes the conversion of pyruvate to lactate, with concomitant oxidation of reduced nicotinamide adenine dinucleotide as the final step in the glycolytic pathway. Glycolysis plays an important role in the metabolic plasticity of cancer cells and has long been recognized as a potential therapeutic target. Thus, potent, selective inhibitors of LDH represent an attractive therapeutic approach. However, to date, pharmacological agents have failed to achieve significant target engagement in vivo, possibly because the protein is present in cells at very high concentrations. We report herein a lead optimization campaign focused on a pyrazole-based series of compounds, using structure-based design concepts, coupled with optimization of cellular potency, in vitro drug−target residence times, and in vivo PK properties, to identify first-in-class inhibitors that demonstrate LDH inhibition in vivo. The lead compounds, named NCATS-SM1440 (43) and NCATS-SM1441 (52), possess desirable attributes for further studying the effect of in vivo LDH inhibition.

The peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor that acts as a transcription factor, regulating glucose, lipid and inflammation signaling and it is exploited in type 2 diabetes treatment. However, the selective activation of this PPAR subtype has been linked to important adverse effects which can be mitigated through concomitant activation of PPARα and PPARδ. In this study, we proposed new PPARγ agonists using PharmaGist Server for pharmacophore prediction, the molecular docking was performed by GOLD (genetic optimization for ligand docking) v2.2, AutoDock 4.2 and AutoDock Vina 1.1 and QikProp v4.0 and Derek for absorption, distribution, metabolism, excretion and toxicity (ADMET) assessment. One molecule showed high predicted affinity to PPARγ and favorable pharmacokinetic and toxicity properties. It was then evaluated against PPARα and PPARδ and showed greater affinity to these receptors than the controls. Therefore this molecule is a promising drug lead for the development of derivatives and for the treatment of metabolic syndrome with the benefits of a PPAR pan activation.Keywords: type 2 diabetes, PPAR pan agonist, molecular modeling, ADMET prediction IntroductionThe general cause of mortality among type 2 diabetes mellitus patients is due to dyslipidemia leading to cardiovascular complications. Currently, the drugs used to control these disorders act separately either on reducing blood glucose or lowering triglyceride levels, free fatty acid and low-density lipoprotein. However, the increasing number of cases of patients with diabetic metabolic syndrome requires the development of therapies that act simultaneously reducing glicidic and lipidic levels in a combined effort to ease cardiovascular disorders. 1 Peroxisome proliferatoractivated receptors (PPARs) are nuclear receptors that act as transcription factors, regulating glucose homeostasis, lipid metabolism and inflammation signaling, making them attractive targets for the development of new therapies for metabolic syndromes. They regulate the expression of target genes after forming a heterodimer with 9-cis-retinoic acid receptor (RXR) and bind to the peroxisome proliferators response elements (PPRE) in the regulatory region of the target gene. The increased transcriptional rates of their target genes may be increased after interaction with an agonist ligand which alters the conformation of PPAR, exposing the DNA (deoxyribonucleic acid) binding site. Three distinct receptors have already been described, PPARα, PPARδ and PPARγ. 2 Padilha et al. 1637 Vol. 27, No. 9, 2016 PPARγ plays an important role in the regulation of glucose and lipid metabolism and it is widely distributed in adipose tissue. 3,4 In adipocytes, the PPARγ activity regulates the expression of genes involved in lipid metabolism, 5-7 in addition to the control of the expression of proteins involved in the uptake of lipids by adipocytes. 8 The PPARγ activation in adipose tissue presents an indirect activity in tissues which respond to insulin. 9 This e...

Plasmodium vivax is the most prevalent of the five species causing malaria in humans. The current available treatment for P. vivax malaria is limited and unsatisfactory due to at least two drawbacks: the undesirable side effects of primaquine (PQ) and drug resistance to chloroquine. Phenylalanine-alanine-PQ (Phe-Ala-PQ) is a PQ prodrug with a more favorable pharmacokinetic profile compared to PQ. The toxicity of this prodrug was evaluated in in vitro assays using a human hepatoma cell line (HepG2), a monkey kidney cell line (BGM), and human red blood cells deficient in the enzyme glucose-6-phosphate-dehydrogenase (G6PD). In addition, in vivo toxicity assays were performed with rats that received multiple doses of Phe-Ala-PQ to evaluate biochemical, hematological, and histopathological parameters. The activity was assessed by the inhibition of the sporogonic cycle using a chicken malaria parasite. Phe-Ala-PQ blocked malaria transmission in Aedes mosquitoes. When compared with PQ, it was less cytotoxic to BGM and HepG2 cells and caused less hemolysis of G6PD-deficient red blood cells at similar concentrations. The prodrug caused less alteration in the biochemical parameters than did PQ. Histopathological analysis of the liver and kidney did show differences between the control and Phe-Ala-PQ-treated groups, but they were not statistically significant. Taken together, the results highlight the prodrug as a novel lead compound candidate for the treatment of P. vivax malaria and as a blocker of malaria transmission.

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Inappropriate use of prescription drugs is potentially more harmful in fetuses/neonates than in adults. Cytochrome P450 (CYP) 3A subfamily undergoes developmental changes in expression, such as a transition from CYP3A7 to CYP3A4 shortly after birth, which provides a potential way to distinguish medication effects on fetuses/neonates and adults. The purpose of this study was to build first-in-class predictive models for both inhibitors and substrates of CYP3A7/CYP3A4 using chemical structure analysis. Three metrics were used to evaluate model performance: area under the receiver operating characteristic curve (AUC-ROC), balanced accuracy (BA), and Matthews correlation coefficient (MCC). The performance varied for each CYP3A7/CYP3A4 inhibitor/ substrate model depending on the data set type, model type, rebalancing method, and specific feature set. For the active inhibitor/ substrate data set, the optimal models achieved AUC-ROC values ranging from 0.77 ± 0.01 to 0.84 ± 0.01. For the selective inhibitor/substrate data set, the optimal models achieved AUC-ROC values ranging from 0.72 ± 0.02 to 0.79 ± 0.04. The predictive power of the optimal models was validated by compounds with known potencies as CYP3A7/CYP3A4 inhibitors or substrates. In addition, we identified structural features significant for CYP3A7/CYP3A4 selective or common inhibitors and substrates. In summary, the top performing models can be further applied as a tool to rapidly evaluate the safety and efficacy of new drugs separately for fetuses/neonates and adults. The significant structural features could guide the design of new therapeutic drugs as well as aid in the optimization of existing medicine for fetuses/neonates.