Current Topics in Medicinal Chemistry - Volume 23, Issue 6, 2023

The prevalence of depression has increased dramatically over the past few decades. Although depression is categorized as a brain disorder, its symptomatology includes some behaviors that also occur during chronic inflammatory stress. According to research, cytokine production and immune system activation may have a role in depression, so this relationship has received much attention. Moreover, there is a bidirectional relationship between oxidative stress and inflammation. Oxidative stress plays a pathogenic role in chronic inflammatory diseases; depressive disorder is being suggested as one of them. Recent research using several oxidative stress indicators demonstrates that antioxidant defenses are diminished and oxidative stress is elevated in depression. Another cytokine- related mechanism widely known for its association with inflammatory illnesses is the kynurenine pathway (KP). KP is responsible for maintaining the balance between neuroprotective and neurogenerative processes in the brain. Therefore, KP plays a role in the pathophysiology of depression. It is thought to impact neurological processes that stem the depression, making it one of the mainstays in explaining oxidative stress-depression-inflammation interrelation. The mechanism is thought to be driven by increasing the expression of proinflammatory cytokines, IDO, and thus the KYN/TRP ratio. This review aims to evaluate the relationship between oxidative stress, depression, and inflammation through the kynurenine pathway through the current studies in the literature.

Background: Zika virus (ZIKV) remains an important cause of congenital infection, fetal microcephaly, and Guillain-Barré syndrome in the population. In 2016, WHO declared a cluster of microcephaly cases and other neurological disorders reported as a global public health emergency in Brazil. There is still no specific treatment for Zika virus fever, only palliative care. Therefore, there is a need for new therapies against this disease. According to the literature, thiosemicarbazone, phthalimide and thiazole are privileged structures with several biological activities, including antiviral activity against various viruses. Objective: Based on this, this work presents an antiviral screening using previously synthesized compounds derived from thiosemicarbazone, phthalimide, and thiazole as new hits active against ZIKV. Methods: After synthesis and characterization, all compounds were submitted to Cytotoxicity by MTT and Antiviral activity against ZIKV assays. Results: Compounds 63, 64, 65, and 73 exhibited major reductions in the ZIKV title from this evaluation. Compounds 63 (99.74%), 64 (99.77%), 65 (99.92%), and 73 (99.21%) showed a higher inhibition than the standard 6MMPr (98.74%) at the CC20 dose. These results revealed new chemical entities with anti-ZIKV activity. Conclusion: These derivatives are promising candidates for further assays. In addition, the current approach brings a new privileged scaffolding, which may drive future drug discovery for ZIKV.

Objective: Several methods for synthesizing 2-thiohydantoin derivatives have been devised and exploited, and they have found widespread application as antioxidants, antimicrobials, antivirals, and anticancer agents. As a result, we tried to understand the underlying processes of the 2- thiohydantoin derivative's anti-LIHC activity. Methods: We predicted the anticancer mechanism of N-(4-oxo-5-(2-oxo-2-(p-tolylamino)ethyl)-3- phenyl-2-thioxoimidazolidin-1-yl)benzamide as a derivative of 2-thiohydantoin by utilizing molecular docking and molecular dynamic simulation. Furthermore, based on the results of molecular dynamic modelling, we employed bioinformatics to anticipate the immunotherapy of this molecule in the tumor microenvironment (TME) of Liver Hepatocellular Carcinoma (LIHC) patients. Next, we examined how this derivative affected proliferation, cell cycle progression, reactive oxygen species production, and apoptosis in HepG2 cancer cells. Results: Substantially, our investigation revealed that the IC50 value was 2.448 μM and that it arrested the cell cycle of HepG2 in the S phase. Furthermore, molecular docking and dynamics studies revealed a worthy interaction of this compound with AKT1 and CDK2 proteins. Considerably, AKT1 and CDK2 have negative affinity energies of -10.4 kcal/mol and -9.6 kcal/mol, respectively. Several bioinformatic tools were used in this investigation to provide insight into the future clinical application of this derivative as a novel candidate to target immune cells such as macrophages, neutrophils, eosinophils, and CD8+ T cells. Conclusion: The relevance of this 2-thiohydantoin derivative was demonstrated by our experimental tests, docking studies, and bioinformatics analysis, and it may be investigated as a lead molecule for anticancer medicines, notably as AKT1 and CKD2 inhibitors.

Coronary artery disease (CAD) is the leading cause of mortality globally. Although substantial advances have been made in the diagnosis, management, and risk stratification of CAD, there is still a need for novel diagnostic biomarkers and new therapeutic targets to prevent the epidemic of the disease. Recently, growing evidence has linked dysregulated microRNAs (miRNAs) to cardiovascular diseases, including CAD. miRNAs are endogenous, stable, single-stranded, short, non-coding RNAs, and may have utility as diagnostic and prognostic biomarkers for CAD. Dysregulated miRNAs are involved in regulating lipid and glucose homeostasis pathways, reninangiotensin- aldosterone pathways, inflammation, endothelial and vascular smooth cell phenotypes promoting atherosclerotic plaque development, progression, and instability. Additionally, miRNAs are stable and easily accessible in the extracellular space, may reside in microvesicles, and are detectable in serum or plasma, making them attractive biomarkers for the diagnosis and prognosis of cardiovascular disease. Accumulating studies suggest that miRNAs could be useful biomarkers for early discrimination of patients presenting with myocarditis or Takotsubo syndrome from those with a diagnosis of acute myocardial infarction, early prognostication of patients presenting with acute coronary syndromes, and accurate detection of left ventricular remodeling after a chronic or acute ischemic event. Moreover, miRNAs represent potential novel therapeutic targets for CAD or other cardiovascular diseases. This review provides an overview of the effects of the entire spectrum of CAD, its major risk factors, and complications on levels of circulating miRNAs, as well as the limitations and challenges of their potential clinical applications.

As atherosclerosis remains a leading cause of morbidity and mortality worldwide despite the advances in its medical and interventional management, the identification of markers associated with its incidence and prognosis constitutes an appealing prospect. In this regard, asymmetric dimethylarginine (ADMA), a well-studied endogenous endothelial nitric oxide synthase inhibitor, represents a core mediator of endothelial dysfunction in atherosclerotic diseases. Given the pathophysiologic background of this molecule, its importance in the most frequent atherosclerotic manifestation, coronary artery disease (CAD), has been extensively studied in the past decades. The available evidence suggests elevation of ADMA in the presence of common cardiovascular risk factors, namely diabetes mellitus, arterial hypertension, and hypertriglyceridemia, being related to endothelial dysfunction and incident major adverse cardiovascular events in these groups of patients. Moreover, ADMA is associated with CAD occurrence and severity, as well as its prognosis, especially in populations with renal impairment. Interestingly, even in the absence of obstructive CAD, increased ADMA may indicate coronary endothelial dysfunction and epicardial vasomotor dysfunction, which are prognostication markers for incident cardiovascular events. In the case of acute coronary syndromes, high ADMA levels signify an augmented risk of incomplete ST-segment elevation resolution and poorer prognosis. Abnormal ADMA elevations may indicate adverse outcomes following percutaneous or surgical coronary revascularization, such as in-stent restenosis, graft patency, and hard cardiovascular endpoints. Finally, since its association with inflammation is significant, chronic inflammatory conditions may present with coronary endothelial dysfunction and subclinical coronary atherosclerosis by means of increased coronary artery calcium, with augmented ADMA acting as a biomarker.

Atherosclerosis is a progressive disease, culminating in the production of atherosclerotic plaques in arteries through intricate pathophysiological processes. The progression of this disorder is based on the effect of triggering factors -mainly hyperlipidemia, diabetes mellitus, arterial hypertension, and smoking- on the endothelium. Coronary artery disease (CAD) is an atherosclerotic disease with a higher prevalence among individuals. Pro- and anti-inflammatory cytokines are the main contributors to atherosclerotic plaque formation. CAD and its manifestations multifactorial affect patients’ quality of life, burdening the global healthcare system. Recently, the role of adhesion molecules in CAD progression has been recognized. Physicians delve into the pathophysiologic basis of CAD progression, focusing on the effect of adhesion molecules. They are proteins that mediate cell-cell and cell-extracellular matrix interaction and adhesion, driving the formation of atherosclerotic plaques. Several studies have assessed their role in atherosclerotic disease in small cohorts and in experimental animal models as well. Furthermore, several agents, such as nanoparticles, have been introduced modifying the main atherosclerotic risk factors as well as targeting the endothelial inflammatory response and atherosclerotic plaque stabilization. In this review, we discuss the role of adhesion molecules in atherosclerosis and CAD progression, as well as the potential to be used as targeting moieties for individualized treatment.