Mini reviews in medicinal chemistry最新文献

Despite the tremendous progress that has occurred in recent years in cell biology and oncology, in chemical, physical and computer sciences, the disease cancer has continued as the major cause of death globally. Research organizations, academic institutions and pharmaceutical companies invest huge amounts of money in the discovery and development of new anticancer drugs. Though much effort is continuing and whatever available approaches are being attempted, the success of bringing one effective drug into the market has been uncertain. To overcome problems associated with drug discovery, several approaches are being attempted. One such approach has been the use of known, approved and marketed drugs to screen these for new indications, which have gained considerable interest. This approach is known in different terms as "drug repositioning or drug repurposing." Drug repositioning refers to the structure modification of the active molecule by synthesis, in vitro/ in vivo screening and in silico computational applications where macromolecular structure-based drug design (SBDD) is employed. In this perspective, we aimed to focus on the application of repositioning or repurposing of essential drug moieties present in drugs that are already used for the treatment of some diseases such as diabetes, human immunodeficiency virus (HIV) infection and inflammation as anticancer agents. This review thus covers the available literature where molecular modeling of drugs/enzyme inhibitors through SBDD is reported for antidiabetics, anti-HIV and inflammatory diseases, which are structurally modified and screened for anticancer activity using respective cell lines.

Background: Metabolic syndrome (METS) is a set of unhealthy medical conditions considered essential health problems today. Cinnamaldehyde (CA) is the major phytochemical present in the essential oil of cinnamon and possesses antioxidant, anti-inflammatory, hypoglycemic, and antihyperlipidemic activities.

Aim: We aim to systematically review the effects of CA in preventing and attenuating METS components. Moreover, the cellular and molecular mechanisms of actions of CA, its pharmacokinetics features, and potential structure-activity relationship (SAR) were also surveyed.

Methods: PubMed, Science Direct, Scopus, and Google Scholar were searched to retrieve the relevant papers.

Results: CA possesses various anti-METS activities, including anti-inflammatory, antioxidant, antidiabetic, antidyslipidemia, antiobesity, and antihypertensive properties. Various molecular mechanisms such as stimulating pancreatic insulin release, exerting an insulinotropic effect, lowering lipid peroxidation as well as pancreatic islet oxidant and inflammatory toxicity, increasing the activities of pancreatic antioxidant enzymes, suppressing pro-inflammatory cytokines production, regulating the molecular signaling pathways of the PPAR-γ and AMPK in preadipocytes and preventing adipocyte differentiation and adipogenesis are involved in these activities.

Conclusions: CA would effectively hinder METS; however, no robust clinical data supporting these effects in humans is currently available. Accordingly, conducting clinical trials to evaluate the efficacy, safe dosage, pharmacokinetics characteristics, and possible unwanted effects of CA in humans would be of great importance.

Viruses cause a variety of diseases in the human body. Antiviral agents are used to prevent the production of disease-causing viruses. These agents obstruct and kill the virus's translation and replication. Because viruses share the metabolic processes of the majority of host cells, finding targeted medicines for the virus is difficult. In the ongoing search for better antiviral agents, the USFDA approved EVOTAZ, a new drug discovered for the treatment of Human Immunodeficiency Virus (HIV). It is a once-daily (OD) fixed-dose combination of Cobicistat, a cytochrome P450 (CYP) enzyme inhibitor, and Atazanavir, a protease inhibitor. The combination drug was created in such a way that it can inhibit both CYP enzymes and proteases at the same time, resulting in the virus's death. The drug is not effective in children under the age of 18; however, it is still being studied for various parameters. This review article focuses on EVOTAZ's preclinical and clinical aspects, as well as its efficacy and safety profiles.

In terms of female reproductive tract cancers, ovarian cancer remains the principal reason for mortality globally and is notably difficult to identify in its early stages. This fact highlights the critical need to establish prevention strategies for patients with ovarian cancer, look for new robust diagnostic and prognostic markers, and identify potential targets of response to treatment. MicroRNAs (miRNAs) are one of the novel treatment targets in cancer treatment. Thus, understanding the part of miRNAs in the pathogenesis and metastasis of ovarian cancer is at the center of researchers' attention. MiRNAs are suggested to play a role in modulating many essential cancer processes, like cell proliferation, apoptosis, differentiation, adhesion, epithelial-mesenchymal transition (EMT), and invasion. In two recent decades, natural polyphenols' anti-cancer features have been a focal point of research. Meanwhile, polyphenols are good research subjects for developing new cancer treatments. Polyphenols can modify miRNA expression and impact the function of transcription factors when used as dietary supplements. Multiple works have indicated the impact of polyphenols, including quercetin, genistein, curcumin, and resveratrol, on miRNA expression in vitro and in vivo. Here, we provide an in-depth description of four polyphenols used as dietary supplements: quercetin, genistein, curcumin, and resveratrol, and we summarize what is currently known about their regulatory abilities on influencing the miRNA functions in ovarian tumors to achieve therapeutic approaches.

Background: Neurodegenerative diseases (NDs) have become a common and growing cause of mortality and morbidity worldwide, especially in older adults. The natural flavonoids found in fruits and vegetables have been shown to have therapeutic effects against many diseases, including NDs; however, in general, flavonoids have limited bioavailability to the target cells. One promising strategy to increase bioavailability is to entrap them in nanocarriers.

Objective: This article aims to review the potential role of nanocarriers in enhancing the antineuroinflammatory efficacy of flavonoids in experimentally induced ND.

Methods: A literature search was conducted in the scientific databases using the keywords "neurodegenerative", "anti-neuroinflammatory", "dietary flavonoids," "nanoparticles", and "therapeutic mechanisms".

Results: A total of 289 articles were initially identified, of which 45 articles reported on flavonoids. After completion of the selection process, five articles that met the criteria of the review were selected for analysis. Preclinical studies identified in this review showed that nanoencapsulated flavonoids attenuated cognitive impairment and seizure, improved behavioral patterns, and reduced levels of astrocytes. Importantly, they exhibited strong antioxidant properties, increasing the levels of antioxidant enzymes and reducing oxidative stress (OS) biomarkers. Moreover, nanocarrier-complexed flavonoids decreased the levels of the pro-inflammatory cytokines, interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α), by inhibiting nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and nod-like receptor protein 3 inflammasome activation (NLRP3). They also had remarkable effects on important ND-related neurotransmitters, improved cognitive function via cholinergic neurotransmission, and increased prefrontal cortical and hippocampal norepinephrine (NE) and 5-hydroxytryptamine (5-HT).

Conclusion: Nanoencapsulated flavonoids should, therefore, be considered a novel therapeutic approach for the treatment of NDs.

Purinergic signaling is a mechanism in which extracellular purines and pyrimidines interact with specialized cell surface receptors known as purinergic receptors. These receptors are divided into two families of P1 and P2 receptors, each responding to different nucleosides and nucleotides. P1 receptors are activated by adenosine, while P2 receptors are activated by pyrimidine and purines. P2X receptors are ligand-gated ion channels, including seven subunits (P2X1-7). However, P2Y receptors are the G-protein coupled receptors comprising eight subtypes (P2Y1/2/4/6/11/12/13/14). The disorder in purinergic signaling leads to various health-related issues and diseases. In various aspects, it influences the activity of non-neuronal cells and neurons. The molecular mechanism of purinergic signaling provides insight into treating various human diseases. On the contrary, stem cells have been investigated for therapeutic applications. Purinergic signaling has shown promising effect in stem cell engraftment. The immune system promotes the autocrine and paracrine mechanisms and releases the significant factors essential for successful stem cell therapy. Each subtype of purinergic receptor exerts a beneficial effect on the damaged tissue. The most common effect caused by purinergic signaling is the proliferation and differentiation that treat different health-related conditions.

Chronic myelogenous leukemia (CML) is a malignant myeloproliferative disease. According to the American Cancer Society's 2021 cancer data report, new cases of CML account for about 15% of all leukemias. CML is generally divided into three stages: chronic phase, accelerated phase, and blast phase. Nearly 90% of patients are diagnosed as a chronic phase. Allogeneic stem cell transplantation and chemotherapeutic drugs, such as interferon IFN-α were used as the earliest treatments for CML. However, they could generate obvious side effects, and scientists had to seek new treatments for CML. A new era of targeted therapy for CML began with the introduction of imatinib, the first-generation BCR-ABL kinase inhibitor. However, the ensuing drug resistance and mutant strains led by T315I limited the further use of imatinib. With the continuous advancement of research, tyrosine kinase inhibitors (TKI) and BCR-ABL protein degraders with novel structures and therapeutic mechanisms have been discovered. From biological macromolecules to classical target protein inhibitors, a growing number of compounds are being developed to treat chronic myelogenous leukemia. In this review, we focus on summarizing the current situation of a series of candidate small-molecule drugs in CML therapy, including TKIs and BCR-ABL protein degrader. The examples provided herein describe the pharmacology activity of small-molecule drugs. These drugs will provide new enlightenment for future treatment directions.

Medicinal insects play an important role in the treatment of refractory diseases due to their unique and rich pharmacological activities. However, compared to plants, microorganisms, and marine organisms, medicinal insects have been largely ignored. Some small molecules isolated from insects are known to have defensive effects, but their majority roles remain unknown. In-depth research on the small molecules of medicinal insects has been conducted in recent years. Then alkaloids, dopamine derivatives, nucleoside derivatives, and other components are obtained. Among them, dopamine derivatives are a unique class of components from medicinal insects. Thus, we present a comprehensive overview of chemical structures and biological activities of dopamine derivatives from some medicinal insects, which will bring more attention to other researchers for further chemical and biological investigations on the unique dopamine derivatives as well as medicinal insects.

Transthyretin amyloid cardiomyopathy and Transthyretin amyloid peripheral neuropathy are progressive disease conditions caused by Transthyretin amyloidosis (ATTR) fibril infiltration in the tissue. Transthyretin (TTR) protein misfolding and amyloid fibril deposits are pathological biomarkers of ATTR-related disorders. There are various treatment strategies targeting different stages in pathophysiology. One such strategy is TTR tetramer stabilization. Recently, a new TTR tetramer stabilizer, tafamidis, has been introduced that reduces the protein misfolding and amyloidosis and, consequently, disease progression in ATTR cardiomyopathy and peripheral neuropathy. This review will provide a comprehensive overview of the literature on tafamidis discovery, development, synthetic methods, pharmacokinetics, analytical methods and clinical trials. Overall, 7 synthetic methods, 5 analytical methods and 23 clinical trials have been summarized from the literature.

Diabetes is a rapidly growing health challenge and epidemic in many developing countries, including India. India, being the diabetes capital of the world, has the dubious dual distinction of being the leading nations for both undernutrition and overnutrition. Diabetes prevalence has increased in both rural and urban areas, affected the younger population and increased the risk of complications and economic burden. These alarming statistics ring an alarm bell to achieve glycemic targets in the affected population in order to decrease diabetes-related morbidity and mortality. In the recent years, diabetes pathophysiology has been extended from an ominous triad through octet and dirty dozen etc. There is a new scope to target multiple pathways at the molecular level to achieve a better glycemic target and further prevent micro- and macrovascular complications. Mitochondrial dysfunction has a pivotal role in both β-cell failure and insulin resistance. Hence, targeting this molecular pathway may help with both insulin secretion and peripheral tissue sensitization to insulin. Imeglimin is the latest addition to our anti-diabetic armamentarium. As imeglimin targets, this root cause of defective energy metabolism and insulin resistance makes it a new add-on therapy in different diabetic regimes to achieve the proper glycemic targets. Its good tolerability and efficacy profiles in recent studies shows a new ray of hope in the journey to curtail diabetes-related morbidity.