Current topics in medicinal chemistry最新文献

During and after the COVID-19 pandemic,Tuberculosis (TB) has reestablished with higher figures due to interruptions in the Directly Observed Treatment Short course (DOTS) despite underreporting. The rising consequences would have extended to extra-pulmonary forms of TB as well, including Tuberculous Meningitis (TBM). Considering the fact that TBM is the most dangerous and worst form of TB, we found the need to scan the literature to highlight various aspects of TBM. Epidemiology of TBM is proportionally less frightening, but the consequent mortalities and morbidities are more alarming than pulmonary TB. Here, we address critical research gaps in Tuberculous Meningitis that warrant further investigations. The highlighted aspects encompass a comprehensive understanding of TBM's clinical presentation and improved diagnostic tools for timely detection, the exploration of innovative chemotherapies and surgical interventions, the unraveling of the role of the blood-brain barrier in disease onset, investigating of the contributions of various brain cells to TBM development, deciphering the complex inflammatory response, exploring the involvement of Matrix Metalloproteinases in tissue damage, delving into host-pathogen genetics influencing susceptibility, utilizing robust in-vivo and in-vitro models for mechanistic insights, and more importantly between TBM and SARS-COVID-19 are discussed. Addressing these gaps will substantially advance our understanding of TBM's complex pathogenesis, contributing to more effective diagnostic, therapeutic, and preventive strategies against this debilitating disease.

Cancer stem cells (CSCs) have become a key player in the growth of tumors, the spread of cancer, and the resistance to therapeutic interventions. Targeting these elusive cell populations has the potential to fundamentally alter cancer treatment plans. CSCs, also known as tumor-initiating cells (TICs), are thought to play a role in both medication resistance and cancer recurrence. This is explained by their capacity to regenerate themselves and change into different kinds of cancer cells. Due to their higher expression of ATP-binding cassette (ABC) membrane transporters, enhanced epithelial to mesenchymal (EMT) characteristics, improved immune evasion, activation of survival signaling pathways, and improved DNA repair mechanisms, CSCs exhibit extraordinary resistance to therapies. This comprehensive analysis delves into advancements in the domain of Targeted Cancer Stem Cell Therapeutics, concentrating on unraveling the distinctive traits of CSCs and the therapeutic methods devised to eliminate them.

Background: Albatrellus confluens is one of the representative species in the Polyporaceae family. Its major mero terpenoid grifolin and related compounds have the potential for drug applications.

Objective: The current study aims to briefly provide an insightful view of the phytochemistry, biosynthesis, synthesis, and pharmacology of A. confluens metabolites.

Methods: Data collection was performed using electronic resources, e.g., Google Scholar, PubMed, and Sci-Finder from the 1990s to the present, while Albatrellus confluens is the most meaningful keyword in the search for publications. The Latin name Albatrellus confluens (Alb. & Schwein.) Kotl. & Pouzar is in accordance with the name listing on www.mycobank.org.

Results: By chromatography column procedures, it indicated that A. confluens species was associated with the presence of 57 secondary metabolites, in which nitrogenous compounds, meroterpenoids, polyene pyrones, and polyesters can be seen as the main phytochemical classes. L-isoleucine was the parent molecule in biosynthetic and synthetic steps of A. confluens nitrogenous compounds. Numerous experiments revealed that A. confluens isolated compounds have a variety of pharmacological activities, such as anticancer, anti-inflammatory, vasorelaxant, and neuroprotective and skin whitening activities. Some isolates become potential cancer inhibitors. Grifolin induced apoptosis and promoted cell cycle arrest in A2780 ovarian cancer cells via the inactivation of the ERK1/2/Akt signaling pathway. Grifolic acid caused osteosarcoma cancer cell deaths by inhibiting NADH generation and ATP production without obvious toxicity. Neoalbaconol caused apoptosis and necroptosis in mice bearing nasopharyngeal C666-1 cancer cells via PDK1-PI3K/Akt signaling inhibition.

Conclusion: The continuation of chromatographic separation and biomedical research is expected. Modern biological assays for explaining the pharmacological values of A. confluens constituents are warranted. Toxicological and pharmacokinetic assessments are urgently needed.

Respiratory viruses have caused many pandemics from past to present and are among the top global public health problems due to their rate of spread. The recently experienced COVID-19 pandemic has led to an understanding of the importance of rapid diagnostic tests to prevent epidemics and the difficulties of developing new vaccines. On the other hand, the emergence of resistance to existing antiviral drugs during the treatment process poses a major problem for society and global health systems. Therefore, there is a need for new approaches for the diagnosis, prophylaxis, and treatment of existing or new types of respiratory viruses. Immunoglobulin Y antibodies (IgYs) obtained from the yolk of poultry eggs have significant advantages, such as high production volumes, low production costs, and high selectivity, which enable the development of innovative and strategic products. Especially in diagnosing respiratory viruses, antibody-based biosensors in which these antibodies are integrated have the potential to provide superiority in making rapid and accurate diagnosis as a practical diagnostic tool. This review article aims to provide information on using IgY antibodies in diagnostic, prophylactic, and therapeutic applications for respiratory viruses and to provide a perspective for future innovative applications.

Chitosan-based nanoparticles have emerged as a promising tool in the realm of cancer therapy, particularly for gene delivery. With cancer being a prevalent and devastating disease, finding effective treatment options is of utmost importance. These nanoparticles provide a unique solution by encapsulating specific genes and delivering them directly to cancer cells, offering immense potential for targeted therapy. The biocompatibility and biodegradability of chitosan, a naturally derived polymer, make it an ideal candidate for this purpose. The nanoparticles protect the genetic material during transportation and enhance its cellular uptake, ensuring effective delivery to the site of action. Furthermore, the unique properties of chitosan-based nanoparticles allow for the controlled release of genes, maximizing their therapeutic effect while minimizing adverse effects. By advancing the field of gene therapy through the use of chitosan-based nanoparticles, scientists are making significant strides toward more humane and personalized treatments for cancer patients.

Objective: In this study, we have synthesized 19 Thiazolidine (TZD) derivatives to investigate their potential anti-ZIKV effects.

Methods: Nineteen thiazolidine derivatives were synthesized and evaluated for their cytotoxicity and antiviral activity against the ZIKA virus.

Results: Among them, six demonstrated remarkable selectivity against the ZIKV virus, exhibiting IC50 values of <5μM, and the other compounds did not demonstrate selectivity for the virus. Interestingly, several derivatives effectively suppressed the replication of ZIKV RNA copies, with derivatives significantly reducing ZIKV mRNA levels at 24 hours post-infection (hpi). Notably, two derivatives (ZKC-4 and -9) stood out by demonstrating a protective effect against ZIKV cell entry. Informed by computational analysis of binding affinity and intermolecular interactions within the NS5 domain's N-7 and O'2 positions, ZKC-4 and FT-39 displayed the highest predicted affinities. Intriguingly, ZKC-4 and ZKC-9 derivatives exhibited the most favorable predicted binding affinities for the ZIKV-E binding site.

Conclusion: The significance of TZDs as potent antiviral agents is underscored by these findings, suggesting that exploring TZD derivatives holds promise for advancing antiviral therapeutic strategies.

Alzheimer's disease is a multifaceted neurodegenerative disease. Cholinergic dysfunction, amyloid β toxicity, tauopathies, oxidative stress, neuroinflammation are among the main pathologies of the disease. Ligands targeting more than one pathology, multi-target directed ligands, attract attention in the recent years to tackle Alzheimer's disease. In this review, we aimed to cover different biochemical pathways, that are revealed in recent years for the pathology of the disease, as druggable targets such as cannabinoid receptors, matrix metalloproteinases, histone deacetylase and various kinases including, glycogen synthase kinase-3, mitogen-activated protein kinase and c-Jun N-terminal kinase, and their ligands for the treatment of Alzheimer's disease in the hope of providing more realistic insights into the field.

Background: Cannabis is the most widely used illicit substance. Numerous scientific evidence confirm the strong association between cannabis and psychosis. Exposure to cannabis can induce the development of psychosis and schizophrenia in vulnerable individuals. However, the neurobiological processes underlying this relationship are unknown. Neurotrophins are a class of proteins that serve as survival factors for central nervous system (CNS) neurons. In particular, Nerve Growth Factor (NGF) plays an important role in the survival and function of cholinergic neurons while Brain Derived Neurotrophic Factor (BDNF) is involved in synaptic plasticity and the maintenance of midbrain dopaminergic and cholinergic neurons. Glial Cell Derived Neurotrophic Factor (GDNF) promotes the survival of midbrain dopaminergic neurons and Neuregulin 1 (NrG- 1) contributes to glutamatergic signals regulating the N-methyl-D-aspartate (NMDA). They have a remarkable influence on the neurons involved in the Δ-9-THC (tethra-hydro-cannabinol) action, such as dopaminergic and glutamatergic neurons, and can play dual roles: first, in neuronal survival and death, and, second, in activity-dependent plasticity.

Methods: In this brief update, reviewing in a narrative way the relevant literature, we will focus on the effects of cannabis on this class of proteins, which may be implicated, at least in part, in the mechanism of the psychostimulant-induced neurotoxicity and psychosis.

Conclusion: Since altered levels of neurotrophins may participate in the pathogenesis of psychotic disorders which are common in drug users, one possible hypothesis is that repeated cannabis exposure can cause psychosis by interfering with neurotrophins synthesis and utilization by CNS neurons.