Current Medicinal Chemistry - Volume 30, Issue 6, 2023

Background: Alzheimer's disease (AD) is a chronic neurodegenerative disease and the most common form of dementia, especially in the elderly. Due to the increase in life expectancy, in recent years, there has been an excessive growth in the number of people affected by this disease, causing serious problems for health systems. In recent years, research has been intensified to find new therapeutic approaches that prevent the progression of the disease. In this sense, recent studies indicate that the dual-specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) gene, which is located on chromosome 21q22.2 and overexpressed in Down syndrome (DS), may play a significant role in developmental brain disorders and early onset neurodegeneration, neuronal loss and dementia in DS and AD. Inhibiting DYRK1A may serve to stop the phenotypic effects of its overexpression and, therefore, is a potential treatment strategy for the prevention of ageassociated neurodegeneration, including Alzheimer-type pathology. Objective: In this review, we investigate the contribution of DYRK1A inhibitors as potential anti-AD agents. Methods: A search in the literature to compile an in vitro dataset including IC50 values involving DYRK1A was performed from 2014 to the present day. In addition, we carried out structure-activity relationship studies based on in vitro and in silico data. Results: molecular modeling and enzyme kinetics studies indicate that DYRK1A may contribute to AD pathology through its proteolytic process, reducing its kinase specificity. Conclusion: further evaluation of DYRK1A inhibitors may contribute to new therapeutic approaches for AD.

Background: Alzheimer’s disease (AD) is one of the most prevalent types of dementia, affecting millions of older people worldwide. AD is stimulating efforts to develop novel molecules targeting its main features associated with a decrease in acetylcholine levels, an increase in oxidative stress and depositions of amyloid-β (Aβ) and tau protein. In this regard, selenium-containing compounds have been demonstrated as potential multi-targeted compounds in the treatment of AD. These compounds are known for their antioxidant and anticholinesterase properties, causing a decrease in Aβ aggregation. Objective: In this review, we approach structure-activity relationships of each compound, associating the decrease of ROS activity, an increase of tau-like activity and inhibition of AChE with a decrease in the self-aggregation of Aβ. Methods: We also verify that the molecular descriptors apol, nHBAcc and MlogP may be related to optimized pharmacokinetic properties for anti-AD drugs. Results: In our analysis, few selenium-derived compounds presented similar molecular features to FDA-approved drugs. Conclusion: We suggest that unknown selenium-derived molecules with apol, nHBAcc and MlogP like FDA-approved drugs may be better successes with optimized pharmacokinetic properties in future studies in AD.

Background: Alzheimer's disease (AD) is a progressive neurodegenerative disease that compromises the cognitive system and causes dementia. In general, AD affects people over 65 years old, which implies a social impact if we consider future projections due to the increase in life expectancy. The drugs currently marketed only slow the progression of the disease. In this sense, the search for new drugs is a relevant topic in medicinal chemistry. The therapeutic strategy adopted herein is the cholinergic hypothesis, for which acetylcholinesterase enzyme (AChE) inhibitors constitute the main treatment for the disease. Objective: This review compiles research in synthetic and natural compounds with AChE inhibitory function. Methods: Data were collected based on investigations of AChE inhibitors in the last 5 years of the 2010 decade. Synthetic and natural compounds were investigated, for which Ligand Based Drug Design (LBDD) and Structure Based Drug Design (SBDD) strategies were performed to better understand the structure-activity relationship of promising therapeutic agents. Results: Prediction of physicochemical and pharmacokinetic properties used to calculate the bioavailability radar, lipophilicity, drug-likeness, and pharmacokinetics parameters (SwissADME) indicated that most active compounds are associated with the following characteristics: molecular weight above 377 g/mol; molar refractivity over 114; fraction Csp3 below 0.39 and TPSA above 43 Ų. The most active compounds had a lipophilicity parameter in the range between 2.5 and 4.52, a predominating lipophilic character. Atoms and bonds/interactions relevant for drug development were also investigated and the data pointed out the following tendencies: number of heavy atoms between 16 and 41; number of aromatic heavy atoms between 6 and 22; number of rotatable bonds between 1 and 14; number of H-bond acceptors between 1 and 11; number of H-bond donors below 7. Molecular docking studies indicated that all compounds had higher Goldscores than the drugs used as a positive control, indicating a stronger interaction with the enzyme. Conclusion: The selected compounds represent a potential for new anticholinesterase drugs and may be good starting-point for the development of new candidates. Also, design rules can be extracted from our analysis.

Nowadays, lungs are the most common organs affected by diseases due to climate change, tobacco smoking, pollution and genetic factors. Conventional pharmacotherapy (oral medication or injection) is poorly selective; this causes toxicity problems and numerous systemic side effects. Furthermore, although pulmonary administration is an interesting drug administration route for treating lung diseases, inhalation therapy is complex mainly due to the lung defense mechanisms leading to rapid drug elimination. Pulmonary drug delivery using nanocarriers appears to be the best therapeutic strategy to overcome these issues. In fact, these nanosystems can reduce both drug therapeutic dose and side effects, improving patient compliance, avoiding alveolar macrophage clearance, protecting the drug from degradation processes, and providing a controlled and targeted drug release. Therefore, this review aims to analyze the scientific literature regarding the use of nanocarriers to treat the main lung diseases (cancer, asthma, infections). In particular, attention was devoted to liposomes and polymer- and lipid-based nanoparticles, being the topic of most published articles in the last decade.

Objective: The objective of this study is to evaluate the regulatory mechanism between P66Shc and ferroptosis in cisplatin-induced acute kidney injury (CP-AKI). Methods: A CP-AKI model was constructed both in vivo and in vitro using C57BL/6 mice and HK-2 cells, respectively. Renal histopathological injury, reactive oxygen species (ROS), and apoptosis were detected. Some parameters of ferroptosis (e.g. 4HNE and GPX4) and the expression of P66Shc/ P-P66Shc both in mitochondria and cytoplasm were tested. In in vitro studies, HK-2 cells were incubated with CP (50 uM); additionally, Fer1 and P66Shc siRNA were applied to explore the molecular regulatory mechanism of P66Shc in ferroptosis. The levels of mitochondrial ROS, apoptosis and the expression of 4HNE,GPX4, P66Shc, and P-P66Shc were tested. Furthermore, the mitochondrial translocation of P66Shc was detected. Results: CP treatment caused elevation of Scr, BUN and renal MDA levels and decreased renal SOD, GSH-PX and GPX4 levels. CP enhanced the expression of 4HNE, P66Shc and P-P66Shc both in vivo and in vitro. Renal oxidative stress and apoptosis were significantly increased in CP-AKI mice. Electron microscopy examination indicated obvious mitochondria injury in renal tubular cells of CP-AKI mice. The level of ferroptosis and the translocation of P-P66Shc from the cytoplasm to mitochondria were significantly increased in HK-2 cells under CP condition, and these effects were obviously blocked by P66Shc siRNA treatment. Conversely, pretreatment with the ferroptosis inhibitor (Fer1) had no effect on the expression and mitochondria translocation of PP66Shc under CP condition. Conclusion: Mitochondrial translocation of P66Shc could result in mitochondrial injury and lipid peroxide accumulation, which ultimately led to ferroptosis and aggravated CPinduced AKI.

Objective: The aim of the study was to investigate the role of miR-30a-5p in restenosis of rats following vein grafting and the underlying mechanism. Methods: Vein graft rat models were established and perfused with miR-30a-5p antagomir and si-ATG5 to probe the regulation of miR-30a-5p/ATG5 on intimal hyperplasia. Human saphenous vein smooth muscle cells (HSVSMCs) were obtained from the great saphenous veins of patients undergoing coronary artery bypass grafting and subjected to assays for autophagy, proliferation, and migration after gain and loss of function of miR-30a-5p and/or ATG5. The binding of miR-30a-5p and ATG5 was confirmed by RIP and dual-luciferase reporter assays. Results: MiR-30a-5p expression gradually increased, ATG5 expression gradually decreased, and the intima was increasingly thickened during restenosis of grafted veins. Knockdown of miR-30a-5p in rats repressed the restenosis of vein grafts, while a deficiency of ATG5 reversed the effect of miR-30a-5p inhibition. Upregulation of miR-30a-5p enhanced the proliferation and migration of HSVSMCs and inhibited the autophagy, while downregulation of miR-30a-5p or overexpression of ATG5 showed opposite effects. ATG5 is a target gene of miR-30a-5p. Conclusion: MiR-30a-5p exacerbates vein graft restenosis by repressing ATG5 expression and inhibiting autophagy.