Aging and anti-aging strategies: A review of past and future therapeutics.

Aging is a progressive degenerative state characterized by a gradual loss of physiological fitness, resulting in deteriorated functions and susceptibility to age-related diseases. With the progress of research on aging and age-related mechanisms, identifying effective anti-aging drugs has become a key focus. In this review, we summarize aging and its related signaling pathways and targets, mainly including clearance of senescent cells, NAD augmentation, anti-inflammatory and anti-oxidant defense, dysfunction of proteostasis and activation of telomerase.

HDAC6/Trim21 aggravates macrophage inflammatory response and titanium-induced osteolysis via GSDMD signaling pathway.

Total joint arthroplasty is the optimal method for end-stage osteoarticular diseases, but aseptic loosening reduces long-term success. Our prior research demonstrated that wear particles released from loosened prostheses activate macrophages to secrete proinflammatory cytokines, thereby promoting osteoclast formation and osteolysis. Gasdermin D (GSDMD), a key regulator of pyroptosis, is a core step in the production of inflammatory factors after stimulation of macrophage pattern recognition receptors together with downstream inflammatory pathways, and histone deacetylase 6 (HDAC6)/tripartite motif-containing protein 21 (Trim21) is important in regulating activation.

Chiral switch of a butyrylcholinesterase inhibitor for the treatment of Alzheimer's disease.

Butyrylcholinesterase (BChE) is a viable drug target to alleviate the symptoms of Alzheimer's disease (AD). We recently developed and biologically evaluated racemic N-benzylpiperidine-based naphthalene-2-sulfonamide 2, a nanomolar BChE inhibitor with procognitive effects. To optimize it, we performed a chiral switch.

Clinical Investigation of Tyrosinase Inhibitors: Past, Present, and Future.

Tyrosinase (EC 1.14.18.

Lead Optimization of a Butyrylcholinesterase Inhibitor for the Treatment of Alzheimer's Disease.

Butyrylcholinesterase (BChE) is a promising drug target for alleviating the symptoms of canine cognitive dysfunction (CCD) and Alzheimer's disease (AD). We have recently developed lead compound , a racemic, nanomolar BChE inhibitor with procognitive effects in mice with scopolamine-induced AD-like symptoms and dogs suffering from CCD. To overcome its modest brain exposure, we developed compound , a more potent BChE inhibitor with a 7-fold higher in vivo brain exposure.

Brief analysis of Na1.7 inhibitors: Mechanism of action and new research trends.

Na1.7 has been the most studied ion channel among the 9 subtypes of sodium ion, and it is also one of the popular analgesic targets in recent years. Compared with opioid receptors, because of its advantages of targeting a variety of pain types and being unrelated to addiction, many related inhibitors have been excavated for it, including old drugs and new uses, peptides, and new skeleton small molecules.

Dual inhibitors of butyrylcholinesterase and histone deacetylase 6 for the treatment of Alzheimer's disease: design, synthesis, and biological evaluation.

To address the multifactorial pathology of Alzheimer's disease (AD), eighteen butyrylcholinesterase (BChE) and histone deacetylase 6 (HDAC6) dual inhibitors were designed, synthesized, and biologically evaluated. Through structure-activity relationship studies, compound 17 emerged as the most potent candidate, with IC value of 0.3 nM for human BChE and 56.

Discovery of Highly Potent AKR1C3 Inhibitors Treating Sorafenib-Resistant Hepatocellular Carcinoma.

Aldo-keto reductase 1C3 (AKR1C3) plays a key role in tumor progression and chemotherapy resistance, particularly in sorafenib-resistant hepatocellular carcinoma (HCC). Targeting AKR1C3 represents a promising strategy to restore chemosensitivity in resistant HCC. Previous research identified the lead compound through a cascade virtual screening approach (AKR1C3 IC = 130 ± 30 nM, SI (selective index) > 77).

Discovery of highly potent AKR1Cs pan-inhibitors as chemotherapeutic potentiators to restore breast cancer drug resistance.

The acquired resistance of doxorubicin (DOX) significantly limits their application in breast cancer treatment. In earlier investigations, a pan-inhibitor, S07-2010, exhibiting inhibitory activity against Aldo-Keto Reductase 1C1-1C4 (AKR1C1-1C4) was discovered through virtual screening. In this study, four rounds of structural modifications were conducted, and the optimized compound 29 exhibited potent inhibitory activity against AKR1C1-1C4 (AKR1C1 IC = 0.

The design and development of LRRK2 inhibitors as novel therapeutics for Parkinson's disease.

Parkinson's disease (PD) is a common neurodegenerative disease affecting nearly 10 million people worldwide and placing a heavy medical burden on both society and families. However, due to the complexity of its pathological mechanisms, current treatments for PD can only alleviate patients' symptoms. Therefore, novel therapeutic strategies are urgently sought in clinical practice.

New insight into targeting the DNA damage response in the treatment of glioblastoma.

Glioblastoma (GBM) is the most common invasive malignant tumor in human brain tumors, representing the most severe grade of gliomas. Despite existing therapeutic approaches, patient prognosis remains dismal, necessitating the exploration of novel strategies to enhance treatment efficacy and extend survival. Due to the restrictive nature of the blood-brain barrier (BBB), small-molecule inhibitors are prioritized in the treatment of central nervous system tumors.

Optical control of butyrylcholinesterase (BChE) activity via photoswitchable azobenzene for potential treatment of Alzheimer's disease.

Photopharmacology is an emerging method in medicinal chemistry to achieve light-controlled drug activity. Azobenzene-based photoswitchable ligands have found widespread application as chemical tools in photopharmacological studies. This study pioneers the design and synthesis of a novel series of photoswitchabled butyrylcholinesterase (BChE) inhibitors, achieved by strategically integrating an azo moiety into an N-benzyl benzamide scaffold.

Inherent Temporal Metamaterials with Unique Time-Varying Stiffness and Damping.

Time-varying metamaterials offer new degrees of freedom for wave manipulation and enable applications unattainable with conventional materials. In these metamaterials, the pattern of temporal inhomogeneity is crucial for effective wave control. However, existing studies have only demonstrated abrupt changes in properties within a limited range or time modulation following simple patterns.

NRF2 inhibitors: Recent progress, future design and therapeutic potential.

Nuclear factor erythroid 2-related factor 2 (NRF2) is a crucial transcription factor involved in oxidative stress response, which controls the expression of various cytoprotective genes. Recent research has indicated that constitutively activated NRF2 can enhance patients' resistance to chemotherapy drugs, resulting in unfavorable prognosis. Therefore, the development of NRF2 inhibitors has emerged as a promising approach for overcoming drug resistance in cancer treatment.

Antibody-drug conjugates for targeted cancer therapy: Recent advances in potential payloads.

Antibody-drug conjugates (ADCs) represent a promising cancer therapy modality which specifically delivers highly toxic payloads to cancer cells through antigen-specific monoclonal antibodies (mAbs). To date, 15 ADCs have been approved and more than 100 ADC candidates have advanced to clinical trials for the treatment of various cancers. Among these ADCs, microtubule-targeting and DNA-damaging agents are at the forefront of payload development.

Structural modification strategies of triazoles in anticancer drug development.

The triazole functional group plays a pivotal role in the composition of biomolecules with potent anticancer activities, including numerous clinically approved drugs. The strategic utilization of the triazole fragment in the rational modification of lead compounds has demonstrated its ability to improve anticancer activities, enhance selectivity, optimize pharmacokinetic properties, and overcome resistance. There has been significant interest in triazole-containing hybrids in recent years due to their remarkable anticancer potential.

Identification and optimization of nitrophenolic analogues as dopamine metabolic enzyme inhibitors for the treatment of Parkinson's disease.

Progressive loss of dopaminergic neurons leads to the depletion of the striatal neurotransmitter dopamine, which is the main cause of Parkinson's disease (PD) motor symptoms. Simultaneous inhibition of the two key dopamine metabolic enzymes, catechol-O-methyltransferase (COMT) and monoamine oxidase B (MAO-B), could potentially be a breakthrough in achieving clinical efficacy. Representative compound C12 exhibits good COMT inhibitory activity (IC = 0.

Current therapy in amyotrophic lateral sclerosis (ALS): A review on past and future therapeutic strategies.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects the first and second motoneurons (MNs), associated with muscle weakness, paralysis and finally death. The exact etiology of the disease still remains unclear. Currently, efforts to develop novel ALS treatments which target specific pathomechanisms are being studied.

Discovery of 4-benzylpiperazinequinoline BChE inhibitor that suppresses neuroinflammation for the treatment of Alzheimer's disease.

Butyrylcholinesterase (BChE) has attracted wide interest as a promising target in Alzheimer's disease (AD) investigation. BChE is considered to play a compensable role of hydrolyzing acetylcholine (ACh), and its positive correlation with β-amyloid (Aβ) deposition also promotes disease progression. Herein, we uncovered a selective potent BChE inhibitor S21-1011 (eqBChE IC = 0.

Triazoles in Medicinal Chemistry: Physicochemical Properties, Bioisosterism, and Application.

Triazole demonstrates distinctive physicochemical properties, characterized by weak basicity, various dipole moments, and significant dual hydrogen bond acceptor and donor capabilities. These features are poised to play a pivotal role in drug-target interactions. The inherent polarity of triazole contributes to its lower log, suggesting the potential improvement in water solubility.

Butyrylcholinesterase-Activated Near-Infrared Fluorogenic Probe for In Vivo Theranostics of Alzheimer's Disease.

Butyrylcholinesterase (BChE) is a promising biomarker and effective therapeutic target for Alzheimer's disease (AD). Herein, we designed a BChE-activated near-infrared (NIR) probe, , which could be activated by BChE and inhibit its enzymatic activity. is composed of a cyclopropane moiety as the recognition unit, a NIR fluorophore hemicyanine as the NIR reporter, and a BChE inhibitor as the therapeutic unit.

Direct Synthesis of α- and β-2'-Deoxynucleosides with Stereodirecting Phosphine Oxide via Remote Participation.

2'-Deoxynucleosides and analogues play a vital role in drug development, but their preparation remains a significant challenge. Previous studies have focused on β-2'-deoxynucleosides with the natural β-configuration. In fact, their isomeric α-2'-deoxynucleosides also exhibit diverse bioactivities and even better metabolic stability.

Discovery, Structure-Based Modification, , , and Exploration of -Sulfamoyl Benzoamide Derivatives as Selective Butyrylcholinesterase Inhibitors for Treating Alzheimer's Disease.

For the potential therapy of Alzheimer's disease (AD), butyrylcholinesterase (BChE) has gradually gained worldwide interest in the progression of AD. This study used a pharmacophore-based virtual screening (VS) approach to identify as a new BChE inhibitor. Aiding by molecular docking and molecular dynamics, essential binding information was disclosed.