Current Topics in Medicinal Chemistry - Online First

In recent years, an increasing number of studies have shown that increased activation of aspartic endopeptidases (AEPs) is a common symptom in neurodegenerative diseases (NDDs). AEP cleaves amyloid precursor protein (APP), tau (microtubule-associated protein tau), α-synuclein (α-syn), SET (a 39-KDa phosphoprotein widely expressed in various tissues and localizes predominantly in the nucleus), and TAR DNA-binding protein 43 (TDP-43), and promotes their aggregation, contributing to Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD) pathogenesis. Abundant evidence supports the notion that CCAAT/enhancer-binding protein β (C/EBPβ)/AEP may play an important role in NDDs. Developing its small molecule inhibitors is a promising treatment of NDDs. However, current research suggests that the pathophysiological mechanism of the C/EBPβ/AEP pathway is very complex in NDDs. This review summarizes the structure of C/EBPβ and AEP, their major physiological functions, potential pathogenesis, their small molecule inhibitors, and how C/EBPβ/AEP offers a novel pathway for the treatment of NDDs.

The global rise of drug-resistant malaria parasites is becoming an increasing threat to public health, emphasizing the urgent need for the development of new therapeutic strategies. Artimisinin-based therapies, once the backbone of malaria treatment, are now at risk due to the resistance developed in parasites. The lack of a universally accessible malaria vaccine exacerbates this crisis, underscoring the need to explore new antimalarial drugs. A more comprehensive understanding of the parasites’s life cycle has revealed several promising targets, including enzymes, transport proteins, and essential metabolic pathways that the parasite relies on for its survival and proliferation. This review provides an in-depth analysis of the vulnerabilities displayed by Plasmodium and recent advances that highlight potential drug targets and candidate molecules.

The development of Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors (HIF-PHIs), such as Roxadustat (ROX), Enarodustat (ENA), Desidustat (DES), Vadadustat (VAD), Molidustat (MOL), and Daprodustat (DAP), has significant effects on anemia in chronic kidney disease. This review presents comprehensive information about the synthesis, pharmacology, and analysis of HIF-PHIs across several matrices. The literature has presented several approaches for quantifying HIF-PHIs in diverse sample matrices. Furthermore, HIF-PHIs exhibit similar modes of action, demonstrating distinct pharmacokinetic parameters. The pharmacological insights encompass their half-life, mechanism of action, absorption, distribution, metabolism, excretion, and therapeutic uses. Research indicates that most studies concentrate on hyphenated methodologies for drug estimation in various biological fluids. Consequently, this study assesses the biological efficacy of HIF-PHIs and elucidates the analytical methodologies currently employed for measurement across various matrices.

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.

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.

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.

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.