In the Central Nervous System (CNS), Nitric Oxide (NO) is mainly biosynthesized by neuronal Nitric Oxide Synthase (nNOS). The dysregulated activation of nNOS in neurons is critical in the development ...of different conditions affecting the CNS. The excessive production of NO by nNOS is responsible for a number of proteins’ post-translational modifications (PTMs), which can lead to aberrant biochemical pathways, impairing CNS functions. In this review, we briefly revise the main implications of dysregulated nNOS in the progression of the most prevalent CNS neurodegenerative disorders, i.e., Alzheimer’s disease (AD) and Parkinson’s disease, as well as in the development of neuronal disorders. Moreover, a specific focus on compounds able to modulate nNOS activity as promising therapeutics to tackle different neuronal diseases is presented.
DES are mixtures of two or more compounds, able to form liquids upon mixing, with lower freezing points when compared to the individual constituents (eutectic mixtures). This attitude is due to the ...specific hydrogen-bond interactions network between the components of the mixture. A notable characteristic of DES is the possibility to develop tailor-made mixtures by changing the components ratios or a limited water dilution, for special applications, making them attractive for pharmaceutical purposes. In this review, we focused our attention on application of ChCl-based DES in the synthesis of pharmaceutical compounds. In this context, these eutectic mixtures can be used as solvents, solvents/catalysts, or as chemical donors and we explored some representative examples in recent literature of such applications.
Nitric oxide (NO) is a small free radical molecule biosynthesized by nitric oxide synthases (NOS), a family of oxidoreductases responsible for the conversion of the natural substrate L-arginine into ...L-citrulline and NO ...
Sulfonamide is a common structural motif in naturally occurring and synthetic medicinal compounds. The rising interest in sulfonamides and N‐acyl derivatives is attested by the large number of drugs ...and lead compounds identified in last years, explored in different fields of medicinal chemistry and showing biological activity. Many acylsulfonamide derivatives were designed and synthesized as isosteres of carboxylic acids, being the characteristics of these functional groups very close. Starting from chemical routes to N‐acylsulfonamides, this review explores compounds of pharmaceutical interest, developed as enzymatic inhibitors or targeting receptors.
Many acylsulfonamide derivatives were designed and synthesized as isosteres of carboxylic acids, being the characteristics of these functional groups very close. Starting from chemical routes to N‐acylsulfonamides, this review explores compounds of pharmaceutical interest, developed as enzymatic inhibitors or targeting receptors.
Nitric oxide (NO) has been defined as the “miracle molecule” due to its essential pleiotropic role in living systems. Besides its implications in physiologic functions, it is also involved in the ...development of several disease states, and understanding this ambivalence is crucial for medicinal chemists to develop therapeutic strategies that regulate NO production without compromising its beneficial functions in cell physiology. Although nitric oxide synthase (NOS), i.e., the enzyme deputed to the NO biosynthesis, is a well-recognized druggable target to regulate NO bioavailability, some issues have emerged during the past decades, limiting the progress of NOS modulators in clinical trials. In the present review, we discuss the most promising advancements in the research of small molecules that are able to regulate NOS activity with improved pharmacodynamic and pharmacokinetic profiles, providing an updated framework of this research field that could be useful for the design and development of new NOS modulators.
Increasing evidence shows that activation of peroxisome proliferator-activated receptors (PPARs) plays an essential role in the regulation of vascular endothelial function through a range of ...mechanisms, including non-metabolic. Among these, the PPAR-mediated activation of endothelial nitric oxide synthase (eNOS) appears to be of considerable importance. The regulated and sustained bioavailability of nitric oxide (NO) in the endothelium is essential to avoid the development of cardiovascular diseases such as hypertension or atherosclerosis. Therefore, a deeper understanding of the different effects of specific PPAR ligands on NO bioavailability could be useful in the development of novel or multi-targeted PPAR agonists. In this review, we report the most meaningful and up-to-date in vitro and in vivo studies of the regulation of NO production performed by different PPAR agonists. Insights into the molecular mechanisms of PPAR-mediated eNOS activation are also provided. Although findings from animal studies in which the activation of PPARα, PPARβ/δ, or PPARγ have provided clear vasoprotective effects have been promising, several benefits from PPAR agonists are offset by unwanted outcomes. Therefore, new insights could be useful in the development of tissue-targeted PPAR agonists with more tolerable side effects to improve treatment options for cardiovascular diseases.
Neurodegenerative diseases are incurable and debilitating conditions that result in progressive degeneration and loss of nerve cells. Oxidative stress has been proposed as one factor that plays a ...potential role in the pathogenesis of neurodegenerative disorders since neuron cells are particularly vulnerable to oxidative damage. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is strictly related to anti-inflammatory and antioxidative cell response; therefore, its activation and the consequent enhancement of the related cellular pathways have been proposed as a potential therapeutic approach. Several Nrf2 activators with different mechanisms and diverse structures have been reported, but those applied for neurodisorders are still limited. However, in the very last few years, interesting progress has been made, particularly in enhancing the blood-brain barrier penetration, to make Nrf2 activators effective drugs, and in designing Nrf2-based multitarget-directed ligands to affect multiple pathways involved in the pathology of neurodegenerative diseases. The present review gives an overview of the most representative findings in this research area.
Nitric oxide (NO) is a key messenger in physiological and pathological processes in mammals. An excessive NO production is associated with pathological conditions underlying the inflammation response ...as a trigger. Among others, dental pulp inflammation results from the invasion of dentin by pathogenic bacteria. Vital functions of pulp mesenchymal stem cells (DPSCs, dental pulp stem cells), such as mineralization, might be affected by the inducible NOS (iNOS) upregulation. In this context, the iNOS selective inhibition can be considered an innovative therapeutic strategy to counteract inflammation and to promote the regeneration of the dentin-pulp complex. The present work aims at evaluating two acetamidines structurally related to the selective iNOS inhibitor
, namely
and
, in a model of LPS-stimulated primary DPSCs. Our data reveal that
and even more
are promising anti-inflammatory compounds, decreasing IL-6 secretion by enhancing CD73 expression-levels, a protein involved in innate immunity processes and thus confirming an immunomodulatory role of DPSCs. In parallel, cell mineralization potential is retained in the presence of compounds as well as VEGF secretion, and thus their angiogenetic potential. Data presented lay the ground for further investigation on the anti-inflammatory potential of acetamidines selectively targeting iNOS in a clinical context.
The manipulation of host metabolisms by viral infections has been demonstrated by several studies, with a marked influence on the synthesis and utilization of glucose, nucleotides, fatty acids, and ...amino acids. The ability of virus to perturb the metabolic status of the infected organism is directly linked to the outcome of the viral infection. A great deal of research in recent years has been focusing on these metabolic aspects, pointing at modifications induced by virus, and suggesting novel strategies to counteract the perturbed host metabolism. In this review, our attention is turned on PPARs, nuclear receptors controlling multiple metabolic actions, and on the effects played by PPAR ligands during viral infections. The role of PPAR agonists and antagonists during SARS-CoV-2, HCV, and HCMV infections will be analyzed.
The management of neurological disorders have huge and increasing human and economic costs. Despite this, there is a scarcity of effective therapeutics, and there is an extreme urgency for new and ...real treatments. In this short review we analyze some promising advancements in the search of new bioactive molecules targeting neuronal nitric oxide synthase （nNOS）, an enzyme deputed to the biosynthesis of nitric oxide （NO）. In different conditions of neuronal damages, this molecule is overproduced, contributing to the pathogenesis and progression of neuronal diseases. Two main approaches to modulate nNOS are discussed： a first one consisting in the direct inhibition of the enzyme by means of small organic molecules, which can be also active against other different targets involved in such diseases. A second section is dedicated to molecules able to prevent the formation of the ternary complex N-methyl-D-aspartate （NMDA）type glutamate receptors, postsynaptic density-95 （PSD95） protein-nNOS, which is necessary to activate the latter for the biosynthesis of NO.
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