Harnessing the power of α-diazo compounds: emerging strategies and expanding applications.

α-Diazo compounds have long been recognized as versatile reagents in organic synthesis, traditionally employed in metallocarbene chemistry. Recent advances have expanded their scope beyond conventional carbene-based transformations, leading to diverse applications in heterocycle synthesis and functionalization strategies. This review highlights the evolution of α-diazo compounds as key reagents in modern synthetic methodologies, focusing on their unique reactivity patterns, including cycloadditions, homologations, ring expansions, and carbene-free functionalizations.

Functionalized biochar catalysts: Advancing green chemistry in synthesis of O- and N-heterocycles.

The global shift toward sustainable chemistry has catalyzed the development of biochar as a versatile and eco-friendly catalyst in organic synthesis. Biochar, derived from biomass pyrolysis, offers tunable surface functionalities, high stability, and cost-effectiveness, establishing it as a viable alternative to conventional catalyst support. This review offers the first comprehensive overview of recent advancements in functionalized biochar-based catalysts for the synthesis of O and N-heterocycles.

The Groebke-Blackburn-Bienaymé (GBB) reaction: A powerful tool for generating diverse heterocyclic scaffold libraries in anticancer drug discovery.

The Groebke-Blackburn-Bienaymé (GBB) reaction is a versatile multi-component (MCR) synthetic methodology that has transformed anticancer drug discovery by enabling the rapid and efficient generation of diverse heterocyclic scaffolds. These scaffolds, such as imidazo[1,2-a]pyridines, imidazo[1,2-a]pyrimidines, and their derivatives, are highly valuable moieties for targeting critical cancer pathways. The modular nature of the GBB reaction, coupled with post-reaction modifications, allows the design of compounds with tailored structures and enhanced pharmacological properties.

Microglial NOX2 as a therapeutic target in traumatic brain injury: Mechanisms, consequences, and potential for neuroprotection.

Traumatic brain injury (TBI) is a leading cause of long-term disability worldwide, with secondary injury mechanisms, including neuroinflammation and oxidative stress, driving much of its chronic pathology. While NADPH oxidase 2 (NOX2)-mediated reactive oxygen species (ROS) production is a recognized factor in TBI, the specific role of microglial NOX2 in perpetuating oxidative and inflammatory damage remains underexplored. Addressing this gap is critical, as current therapeutic approaches primarily target acute symptoms and fail to interrupt the persistent neuroinflammation that contributes to progressive neurodegeneration.

Phytomolecules as Alzheimer's therapeutics: A comprehensive review.

Alzheimer's disease (AD) is a leading neurodegenerative disorder recognized by progressive cognitive decline and behavioral changes. The pathology of AD is characterized by the accumulation of amyloid-β (Aβ) plaques and the hyperphosphorylation of tau protein, which leads to synaptic loss and subsequent neurodegeneration. Additional contributors to disease progression include metabolic, vascular, and inflammatory factors.

The Huntington's disease drug pipeline: a review of small molecules and their therapeutic targets.

Huntington's disease (HD) is a progressive neurodegenerative condition resulting from a CAG repeat expansion in the huntingtin gene (HTT). Recent advancements in understanding HD's cellular and molecular pathways have paved the way for identifying various effective small-molecule candidates to treat the disorder. Two small molecules, Tetrabenazine and Deutetrabenazine, are approved for managing chorea associated with HD, and several others are under clinical trials.

Microglial Autophagic Dysregulation in Traumatic Brain Injury: Molecular Insights and Therapeutic Avenues.

Traumatic brain injury (TBI) is a complex and multifaceted condition that can result in cognitive and behavioral impairments. One aspect of TBI that has received increasing attention in recent years is the role of microglia, the brain-resident immune cells, in the pathophysiology of the injury. Specifically, increasing evidence suggests that dysfunction in microglial autophagy, the process by which cells degrade and recycle their own damaged components, may contribute to the development and progression of TBI-related impairments.

Targeting Wnt signaling pathway with small-molecule therapeutics for treating osteoporosis.

Small molecules are emerging as potential candidates for treating osteoporosis by activating canonical Wnt signaling. These candidates work either by inhibiting DKK-1, sclerostin, SFRP-1, NOTUM, and S1P lyase or by preventing β-catenin degradation through inhibition of GSK-3β, or by targeting Dvl-CXXC5 and axin/β-catenin interactions. While many of these anti-osteoporotic small molecules are in preclinical development, the paucity of FDA-approved small molecules, or promising candidates, that have progressed to clinical trials for treating bone disorders through this mechanism poses a challenge.

Exploring the anticancer potential and mechanisms of action of natural coumarins and isocoumarins.

Natural coumarins and isocoumarins show significant therapeutic potential against cancer in preclinical studies by targeting multiple pathways and processes. These compounds influence several critical cellular processes, such as apoptosis, autophagy, and cell cycle regulation, which are pivotal in cancer development and progression. Their capability to target multiple signalling pathways provides a strategic advantage over single-target therapies, which are often limited by drug resistance.

Therapeutic targeting of Wnt antagonists by small molecules for treatment of osteoporosis.

Wnt signaling is one of the key regulators of bone development and homeostasis. Wnt signaling regulates key biological events, including stem cell fate and osteoblast and osteoclast activity, leading to the maintenance of bone mass and strength. Wnt ligands are secreted glycoproteins that bind to Frizzled (FZD) receptors and their coreceptors, lipoprotein receptor-related proteins-5/6 (LRP5/6).

Excitotoxicity, Oxytosis/Ferroptosis, and Neurodegeneration: Emerging Insights into Mitochondrial Mechanisms.

Mitochondrial dysfunction plays a pivotal role in the development of age-related diseases, particularly neurodegenerative disorders. The etiology of mitochondrial dysfunction involves a multitude of factors that remain elusive. This review centers on elucidating the role(s) of excitotoxicity, oxytosis/ferroptosis and neurodegeneration within the context of mitochondrial bioenergetics, biogenesis, mitophagy and oxidative stress and explores their intricate interplay in the pathogenesis of neurodegenerative diseases.

Trifluoromethylnitrone: a versatile building block for synthesizing trifluoromethyl-containing heterocyclic compounds.

This review explores the significance of trifluoromethylnitrones in synthesizing fluorine-containing compounds, with a particular focus on trifluoromethylated heterocycles. It explores the versatility of trifluoromethylnitrones, especially in [3 + 2] cycloaddition reactions, highlighting their unique reactivity with various dienophile substrates. Trifluoromethylnitrones are valuable precursors for the rapid synthesis of medicinally important trifluoromethylated heterocycles, including isoxazolidines, dihydroisoxazoles, oxathiazolidines, β-lactams, and aziridines.

Pseudo-Natural Products: Expanding chemical and biological space by surpassing natural constraints.

This review explores the recent advancements in the design and synthesis of pseudo-natural products (pseudo-NPs) by employing innovative principles and strategies, heralding a transformative era in chemistry and biology. Pseudo-NPs, produced through in silico fragmentation and the de novo recombination of natural product fragments, reveal compounds endowed with distinct biological activities. Their advantage lies in transcending natural product structures, fostering diverse possibilities.

Unraveling the Puzzle of Therapeutic Peptides: A Promising Frontier in Huntington's Disease Treatment.

Huntington's disease (HD) is a neurodegenerative genetic disorder characterized by a mutation in the huntingtin (HTT) gene, resulting in the production of a mutant huntingtin protein (mHTT). The accumulation of mHTT leads to the development of toxic aggregates in neurons, causing cell dysfunction and, eventually, cell death. Peptide therapeutics target various aspects of HD pathology, including mHTT reduction and aggregation inhibition, extended CAG mRNA degradation, and modulation of dysregulated signaling pathways, such as BDNF/TrkB signaling.

The Emerging Landscape of Natural Small-molecule Therapeutics for Huntington's Disease.

Huntington's disease (HD) is a rare and fatal neurodegenerative disorder with no diseasemodifying therapeutics. HD is characterized by extensive neuronal loss and is caused by the inherited expansion of the huntingtin (HTT) gene that encodes a toxic mutant HTT (mHTT) protein having expanded polyglutamine (polyQ) residues. Current HD therapeutics only offer symptomatic relief.

The Emerging Landscape of Small-Molecule Therapeutics for the Treatment of Huntington's Disease.

Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene (HTT). The new insights into HD's cellular and molecular pathways have led to the identification of numerous potent small-molecule therapeutics for HD therapy. The field of HD-targeting small-molecule therapeutics is accelerating, and the approval of these therapeutics to combat HD may be expected in the near future.

Recent Update on the Development of PCSK9 Inhibitors for Hypercholesterolemia Treatment.

The proprotein convertase subtilisin/kexin-type 9 (PCSK9) binds to low-density lipoprotein receptors (LDLR), thereby trafficking them to lysosomes upon endocytosis and enhancing intracellular degradation to prevent their recycling. As a result, the levels of circulating LDL cholesterol (LDL-C) increase, which is a prominent risk factor for developing atherosclerotic cardiovascular diseases (ASCVD). Thus, PCSK9 has become a promising therapeutic target that offers a fertile testing ground for new drug modalities to regulate plasma LDL-C levels to prevent ASCVD.

Development of small-molecule PCSK9 inhibitors for the treatment of hypercholesterolemia.

When secreted into the circulation, proprotein convertase subtilisin kexin type 9 (PCSK9) blocks the low-density lipoprotein receptors (LDL-R) and, as a consequence, low-density lipoprotein cholesterol (LDL-C) levels increase. Therefore, PCSK9 has emerged as a potential therapeutic target for lowering LDL-C levels and preventing atherosclerosis. The US Food and Drug Administration (FDA) has approved two monoclonal antibodies (mAbs) against PCSK9, but the expensive manufacturing process limits their use.

Primed for global coronavirus pandemic: Emerging research and clinical outcome.

The global effort to combat and contain the coronavirus disease 2019 (COVID-19) caused by the recently discovered severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is now proceeding on a war footing. The world was slow to react to the developing crisis, but once the contours of the impending calamity became evident, the different state and non-state actors have raced to put their act together. The COVID-19 pandemic has blatantly exposed the shortcomings of our healthcare system and the limitations of medical science, despite considerable advances in recent years.

Silver-Catalyzed Three-Component Route to Trifluoromethylated 1,2,3-Triazolines Using Aldehydes, Amines, and Trifluorodiazoethane.

A novel silver-catalyzed domino three-component synthetic route to trifluoromethyl-substituted 1,2,3-triazolines has been realized by employing 2,2,2-trifluorodiazoethane as a 1,3-dipole for the cycloaddition reaction with the Schiff base formed from aldehydes and amines. This step and atom-economic protocol requires only a very low catalyst loading (3 mol %), displays a broad substrate scope with good functional group tolerance, and provides good to excellent yields with high diastereoselectivities.