Current topics in medicinal chemistry最新文献

This review highlights major developments in the application of green organocatalytic and enzymatic dynamic kinetic resolutions (DKRs) in the total synthesis of biorelevant scaffolds. It illustrates the diversity of useful bioactive products and intermediates that can be synthesized under greener and more economic conditions through the combination of the powerful concept of DKR, which allows the resolution of racemic compounds with up to 100% yield, with either asymmetric organocatalysis or enzymatic catalysis, avoiding the use of toxic and expensive metals. With the need for more ecologic synthetic technologies, this field will undoubtedly expand its scope in the future with the employment of other organocatalysts/enzymes to even more types of transformations, thus allowing powerful greener and more economic strategies to reach other biologically important molecules.

Alzheimer's Disease (AD), a prevalent neurodegenerative disorder, poses a significant global health challenge with complicated pathogenesis. Pathological characteristics of AD include increasing loss of cholinergic neurons, oxidative stress, mitochondrial dysfunction, and amyloid beta accumulation. Due to the limited availability of effective therapeutic options with only symptomatic relief and their severe adverse effects, there is a significant need to search and explore new agents for the management of AD. Recently, natural products and/or phytoconstituents of plants have gained notable attention as potential sources of neuroprotective agents due to their diverse chemical constituents, mechanism of action, and relatively safe profiles. In view of this, Glycyrrhiza glabra has been recognized for its several therapeutic properties in traditional medicine systems for centuries. Further, neuroactive phytoconstituents of this plant, including glycyrrhizin, liquiritigenin, isoliquiritigenin, glabridin, and glycyrrhizic acid, exhibit significant pharmacological advantages along with potential neuroprotective effects against AD. Glycyrrhiza glabra and its phytoconstituents have gained significant interest due to its ability to exert a neuroprotective impact by influencing multiple signaling pathways, inhibiting AChE and BACE1 activity, reducing Aβ accumulation, plaque formation, and tau phosphorylation, and quenching the free radical in experimentally-induced AD-like brain. The present review summarizes available in vitro and in vivo preclinical studies that have been performed to evaluate the beneficial neuroprotective effect of Glycyrrhiza glabra and its phytoconstituents against AD-like pathology. Based on available facts, it can be concluded that neuroactive phytoconstituents of Glycyrrhiza glabra could be significant lead molecules for the drug discovery of anti-AD medicines in the future.

Introduction/objective: Tuberculosis (TB) remains a persistent global health challenge, with an increasing incidence of cases and limitations in current treatment strategies. Traditional therapy involves long drug treatments that can cause side effects and lead to drug-resistant strains, making treatment less effective. This study aimed to explore the therapeutic potential of a novel nanoparticle-based delivery system for Thymol (THY), a natural antibacterial bioactive molecule, to combat Mycobacterium smegmatis, a model organism for Mycobacterium tuberculosis.

Methods: A nanoparticle-based delivery system was developed using biocompatible Thymolconjugated Chitosan Zinc Ferrite Nanoparticles (THY-CH-ZnFe2O4 NPs). The nanoconjugates were characterized for their morphological and chemical properties.

Results: The characterization of synthesised nanoparticles showed THY-CH-ZnFe2O4 NPs to exhibit enhanced biocompatibility and antibacterial activity against M. smegmatis compared to THY alone. The nanoconjugates induced Reactive Oxygen Species (ROS)-mediated damage to the bacterial cell membrane, effectively inhibiting bacterial replication, dormancy, and biofilm formation. Additionally, the nanoconjugates demonstrated low cytotoxicity towards the human kidney cell line.

Conclusion: The study's findings highlighted a new direction for developing nanoparticle-based antimycobacterial agents with a wide application in treating TB and other bacterial diseases. The THY-CH-ZnFe2O4 NPs show promise as a safe and effective therapeutic agent, offering a potential solution to the limitations of current TB treatment strategies.

Despite extensive research, there is an unmet need for developing disease-modifying therapies for Parkinson's disease (PD). Failure of certain landmark clinical trials has highlighted the need for a better understanding of the disease pathogenesis as well as identifying the hurdles in developing drug candidates and designing clinical trials. While adhering to these needs, several promising trials are currently underway with the hope of developing reliable targets. There is also a need to conduct research on plant-based natural products and use them as therapeutic candidates for PD. In this context, many studies have demonstrated the efficacy of medicinal plants and their principal phytochemicals. This review provides an update on the presently underway clinical trials with a small emphasis on the disease modifying therapies that target small molecules, mitochondria, and oligodendrocytes. The role of ethnopharmacology-based approaches for treatment of PD has also been discussed. The third aspect of the article considers the importance of nanomedicine in this area, including the use of liposomes and nanoparticles to provide a novel approach for the treatment of PD.

Introduction: DNA repeats and motifs are specific nucleotide patterns/DNA sequences frequently present in the genomes of prokaryotes and eukaryotes. Computational identification of these discrete patterns is of considerable importance since they are associated with gene regulation, genomic instability, and genetic diversity and result in a variety of diseases/disorders.

Objective: In this article, the myriad of computational tools/algorithms and databases (~200 distinct resources) implicated in the detection of DNA repeats and motifs have been enlisted. This article will not only provide guidance to the users regarding the accuracy, reliability, and popularity (reflected by the citation index) of currently available tools but also enable them to select the best tool(s) to carry out a desired task.

Methods: The structured literature review, with its dependable and reproducible research process, allowed us to acquire 200 peer-reviewed publications from indexing databases, such as Scopus, ScienceDirect, Web of Science (WoS), PubMed, and EMBASE, by utilizing PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) regulations. Numerous keyword combinations regarding DNA repeats and motifs were used to create the query syntax.

Results: Initially, 3,233 research publications were retrieved, and 200 of them that satisfied the eligibility criteria for the detection and identification of DNA repeats and motifs by computational tools were chosen. A total of 200 research publications were recovered, of which 99 dealt with repeat prediction tools, 12 with repetitive sequence databases, 19 with specialized regulatory element databases, and 69 with motif prediction tools.

Conclusion: This article lists numerous databases and computational tools/algorithms (~ 200 different resources) that are involved in the identification of DNA repeats and motifs. It will help users choose the appropriate tool(s) for carrying out a particular task in addition to offering guidance on the reliability, dependability, and popularity (as indicated by the citation index) of currently available tools.

Objective: NLRP3 inflammasomes are considered to be key factors in the pathogenesis of Acute Liver Failure (ALF). Some Traditional Chinese Medicines (TCMs) have shown protective and therapeutic effects against ALF by inhibiting NLRP3 inflammasomes. However, the inhibitory effects of most TCMs on ALF remain to be further elucidated. This study aimed to screen potential herbs that can treat ALF based on the inhibition of NLRP3 inflammasomes.

Methods: Initially, we constructed the target set for 502 herbs. Subsequently, based on the target set and the gene set related to the NLRP3 inflammasome, using the ssGSEA algorithm, we evaluated herb scores and NLRP3 scores in the ALF expression matrix and performed a preliminary herb screening based on score correlations. Through bioinformatics approaches, we identified the key targets for candidate herbs and determined core herbs based on the herb-compound-target network. Furthermore, molecular docking and molecular biology methods validated the screening results of the herbs.

Results: A total of 18 crucial targets associated with the inhibition of the NLRP3 inflammasome were identified, which included ALDH2, HMOX1, and VEGFA. Subsequently, based on these key targets, a set of 10 primary herbs was chosen, notably Qinghao, Duzhong, and Gouteng. Moreover, the results were verified through molecular docking and molecular dynamic simulation.

Conclusion: Ten key herbs have been identified as potential inhibitors of the NLRP3 inflammasome, offering insights into ALF therapy for drug development.

Numerous studies suggest that common genetic and epigenetic factors such as p53, histone deacetylase (HDAC), brain-derived neurotrophic factor (BDNF), the (Ataxia Telangiectasia mutated) ATM gene, cyclin-dependent kinase 5 (CDK5), glycogen synthase kinase 3 (GSK3) and altered expression of microRNA (miRNA) play a crucial role in cancer and neurodegeneration. As there is growing evidence that epigenetic aberrations in cancer and neurological diseases lead to complex pathophysiological changes, the simultaneous targeting of epigenetic and other related pathways by dual-target inhibitors may contribute to the discovery of more effective and personalized therapeutic options. Computer-Aided Drug Design (CADD) provides comprehensive bioinformatic, chemoinformatic, and chemometric approaches for the design of novel chemotypes of epigenetic dual-target inhibitors, enabling efficient discovery of new drug candidates for innovative treatments of these multifactorial diseases. The detailed anticancer mechanisms by which the epigenetic dual-target inhibitors alter metastatic and tumorigenic properties, influence the tumor microenvironment, or regulate the immune response are also presented and discussed in the review. To improve our understanding of the pathogenesis of cancer and neurodegeneration, this review discusses novel therapeutic agents targeting different molecular mechanisms involved in these multifactorial diseases.

Filariasis is one of the oldest, most dangerous, debilitating, disfiguring diseases and often ignores tropical disorders. It presents with a range of clinical symptoms, a low death rate, and a high morbidity rate, which contributes to social discrimination. This condition has major effects on people's socioeconomic circumstances. This illness is carried by mosquitoes that have spread malaria. Lymphatic filariasis, caused by Wuchereria bancrofti, Brugia malayi, and Brugia timori, is a crippling illness with serious social and economic consequences. The infection persisted despite therapy with conventional antifilarial medications such as diethylcarbamazine (DEC), albendazole, and ivermectin, which are mostly microfilaricides. Current treatments (ivermectin, diethylcarbamazine, and albendazole) have limited effectiveness against adult parasites and produce side effects; therefore, innovative antifilarial medications are urgently required. Hence, macrofilaricides, embryostatic agents, and improved microfilaricides are required. The following article discusses the typical synthetic methodologies established for antifilarial activity as well as their marketed pharmaceuticals, which will help researchers, medicinal chemists, and pharmaceutical scientists to develop new and effective antifilarial therapies. This review can help to identify new lead compounds and optimize existing commercial medications to improve their therapeutic efficacy. The majority of the studies addressed in this review concern the forms of filariasis, parasite life cycle, symptoms, medications used to treat filariasis, synthetic schemes, SAR, and results from the reported research.

The c-Met receptor, a pivotal player in oncogenesis and tumor progression, has become a compelling target for anticancer drug development. This review explores the intricate landscape of Structure-Activity Relationship [SAR] studies and molecular binding analyses performed on c-Met inhibitors. Through a comprehensive examination of various chemical scaffolds and modifications, SAR investigations have elucidated critical molecular features essential for the potent inhibition of c-Met activity. Additionally, molecular docking studies have provided invaluable insights into how c-Met inhibitors interact with their target receptor, facilitating the rational design of novel compounds with enhanced efficacy and selectivity. This review highlights key findings from recent SAR and docking studies, particularly focusing on the structural determinants that govern inhibition potency and selectivity. Furthermore, the integration of computational methodologies with experimental approaches has accelerated the discovery and optimization of c-Met inhibitors, fostering the advancement of promising candidates for clinical applications. Overall, this review underscores the pivotal role of SAR and molecular docking studies in advancing our understanding of c-Met inhibition and guiding the rational design of next-generation anticancer agents targeting this pathway.

Diabetes mellitus, characterized as a chronic metabolic disorder or a polygenic syndrome; is increasing at a very fast pace among every group of the population worldwide. It arises due to the inability of the body to produce enough insulin (the hormone responsible for controlling blood sugar levels) or inability to utilize the insulin, leading to hyperglycaemic condition, which, if left uncontrolled gives rise to chronic microvascular and macrovascular complications like retinopathy, neuropathy, nephropathy, coronary artery disease, cognitive impairment, etc. Several therapeutic approaches are available for the treatment of diabetes; among which dipeptidyl peptidase (DPP-IV) inhibitors (gliptins) hold a significant place. DPP-IV is a multifunctional enzyme or a serine exopeptidase that plays an imperative role in cleaving bioactive molecules. DPP-IV causes the breakdown of incretin hormone (GLP-1: Glucagon-like peptide 1 and GIP: Glucose-dependent insulinotropic peptide) that is essential for controlling glycaemic levels in the body. Inhibition of DPP-IV enzyme (DPP-IV inhibitors: Sitagliptin, Saxagliptin, Linagliptin, Alogliptin) prevents this breakdown, thereby controlling blood glucose levels and saving the patients from deleterious effects of prolonged hyperglycaemic conditions. Triazole-based DPP-IV inhibitors are a significant class of drugs used to treat Type 2 diabetes mellitus in a dose-dependent manner. Clinical trials have demonstrated their efficacy as monotherapy or in combination with other antidiabetic agents. This review highlights the molecular docking studies and structure-activity relationship of potential synthetic derivatives that may act as lead molecules for future drug discovery and yield drug molecules with enhanced efficacy, potency and reduced toxicity profile.