Current Topics in Medicinal Chemistry - Online First

Cellular aging is a complicated event known for gradually reducing homeostasis, leading to a higher susceptibility to diseases and mortality. Since the behavior of Hematopoietic Stem Cells (HSCs) is potentially affected by plasma-derived exosomes, this study aimed to investigate whether the plasma-derived exosome of young and elderly human donors can deliver “youth” or “aging” signals into human umbilical cord blood-derived HSCs in vitro.

Exosomes were isolated from four young (Y-exo) and four old (O-exo) donors. Umbilical cord blood-derived HSCs were exposed to two concentrations of exosomes (5 and 10 μg/mL). Then, lineage differentiation (CD41 and CD38), the mRNA and protein expression of IL-1β and IL-6, and NFκB activity were evaluated using flow cytometry, qRT-PCR Enzyme-Linked Immunosorbent Assay (ELISA) methods, and western blot techniques, respectively.

The lineage-specific markers CD41 and CD38 expression were increased after exposure to O-exo compared to Y-exo at the concentration of 10 μg/mL (P<0.001). The HSCs treated with 10 μg/mL O-exo increased protein and mRNA expression of IL-1β and IL-6 compared to Y-exo at 10 μg/mL concentration (P<0.01). Furthermore, a significant difference was seen in p-NF-κB levels between O-exo and Y-exo at the concentration of 10 μg/mL (P=0.0014).

Our findings advocated the concept that circulating exosomes of old and young individuals may differently affect the pathways involved in the aging process in HSCs.Therefore, exosomes may be applied as therapeutic agents for regenerative medicine.

1,4-Dihydropyridines (1,4-DHPs) serve as versatile scaffolds in medicinal chemistry, exhibiting multitarget potential with anticancer, cardiovascular, antioxidant, anti-inflammatory, antimicrobial, and analgesic effects. Structural modifications enhance their binding affinity, bioavailability, and selectivity.

This review aims to explore the broad therapeutic potential of 1,4-DHPs by analyzing their biological activities and structure-activity relationships (SAR). Additionally, it seeks to provide medicinal chemists with insights into key structural modifications that can optimize their pharmacological efficacy.

A comprehensive literature search was conducted in PubMed, ScienceDirect, Elsevier, and Google Scholar, prioritizing peer-reviewed studies from the last decade. Inclusion criteria focused on pharmacological properties, SAR, and therapeutic potential of 1,4-DHPs, while non-peer-reviewed or irrelevant studies were excluded. Data extraction analyzed SAR trends, emphasizing the impact of structural modifications on binding affinity, bioavailability, and biological activity.

The review highlights that specific modifications in aromatic substituents, ester groups, and heterocyclic rings play a crucial role in enhancing the biological activity and selectivity of 1,4-DHPs. Their ability to modulate key enzymes and receptors contributes to their effectiveness as multitarget agents. Comparative SAR analysis provides evidence of the potential of 1,4-DHPs as next-generation therapeutics.

1,4-DHPs offer a promising framework for drug development, with the potential to address complex, multifactorial diseases. By understanding and optimizing SAR, medicinal chemists can design more selective and potent 1,4-DHP-based drugs. Future research should focus on refining these structural modifications to unlock their full therapeutic potential.

Neisseria gonorrhoeae is a notorious superbug responsible for causing ‘Gonorrhoea’ in humans. Recently, it has been classified as a high-priority pathogen by the World Health Organization due to its increasing resistance to available antibiotics. A multi-prolonged approach is needed to combat the growing problem of drug resistance caused by N. gonorrhoeae. This study evaluates Glutamate Racemase (GR), a moonlight protein of N. gonorrhoeae (Ng-GR), as a novel therapeutic target with potential for both inhibitor design and peptide vaccine development. Ng-GR plays a crucial role in the peptidoglycan biosynthetic pathway and is highly conserved across bacterial species. Additionally, this protein moonlights to perform a secondary function by binding to DNA gyrase in various organisms.

Homology modeling, molecular docking, and molecular dynamics simulations were used to design inhibitors targeting the moonlight function of Ng-GR. The immunogenicity of this protein was assessed using ABCPred-2.0, BepiPred-2.0, and ProPred softwares.

Bisleucocurine A was found to bind at the ectopic site of Ng-GR, disrupting its crucial moonlight function and interfering its interaction with N. gonorroheae DNA Gyrase (Ng-gyrase). Interestingly, residues important for its moonlight function were also identified as key immunogenic sites using ABCPred-2.0, BepiPred-2.0, and ProPred softwares, enhancing the potential of this protein as a vaccine candidate.

The GR enzyme’s moonlight function is highlighted as a promising novel target for therapeutic intervention and vaccine development in N. gonorrohoeae.

Alzheimer's disease (AD) is a prominent neurodegenerative ailment characterized by the constraints of conventional therapies stemming from insufficient medication transport to the brain. This review examines the function of polymeric nanocarriers (PNCs) in improving therapeutic efficacy for Alzheimer's disease treatment.

We analyze the principal obstacles to Alzheimer's disease drug delivery: the blood-brain barrier, the blood-cerebrospinal fluid barrier, and multidrug resistance proteins. The review examines three categories of PNCs: polymeric nanoparticles, polymeric micelles, and dendrimers, and their capacity to surmount these obstacles. Literature investigations used search engines like PubMed, Google Scholar, and ScienceDirect.

PNCs exhibit superior drug delivery via better biocompatibility, regulated release, and targeted delivery mechanisms. Recent studies demonstrate the effective delivery of several pharmaceuticals, including rivastigmine and galantamine, resulting in enhanced cognitive outcomes in Alzheimer's disease models. Patent research indicates an increase in innovation for PNC-based Alzheimer's disease treatments.

Despite ongoing hurdles in biocompatibility and scalability, PNCs exhibit significant potential to transform Alzheimer's disease treatment by improving medication delivery across biological barriers. Current investigations in nanotechnology and combinatorial medicines indicate a favorable outlook for PNC-based medicinal strategies.

Colorectal cancer (CRC), the world's third leading cause of death, can be caused by a variety of reasons, one of which is a valine-to-glutamate mutation at position 600 in the BRAF gene. Nonetheless, the prognosis of patients with BRAF mutations remains poor, necessitating additional research in this field.

This work aims to recognize and validate innovative and effective BRAF inhibitor.

A merged-featured ligand-based pharmacophore model was validated and screened against various external databases. The pharmacokinetic and toxicological characteristics of the 102 hits were analyzed, and the appropriate ligands were docked against BRAF protein. The top four protein-ligand complexes with the lowest binding energies were chosen, and their Molecular Dynamic (MD) simulation studies were accomplished.

The finest complex selected has a Root Mean Square Deviation (RMSD) value of 2.229A⁰ and a Radius of Gyration (RoG) value of 25.770A⁰. The LC50 of the best ligand was experimentally calculated to be 102.83 µg/ml. The ligand was found to destroy CRC cells, but it did not affect normal non-cancerous cells much.

This work thus proposes 3-(6,7-dimethoxy-3,4-dihydroisoquinoline-2-carbonyl)-N-(2-methoxyphenyl)benzenesulphonamide as a potential BRAF V600E inhibitor for the CRC treatment.

In this study, we report on the synthesis and characterization of new silicon (IV) phthalocyanine compounds (SiPcs) axially substituted with coumarin-linked derivatives, designed for potential application in photodynamic therapy (PDT) due to their photophysical properties.

Characterization was carried out using FT-IR, UV-Vis, MALDI-TOF-MS, and ¹H NMR spectroscopy. In dimethyl sulfoxide (DMSO), the SiPcs produced singlet oxygen with quantum yields of 0.17 to 0.19, assessed by the DPBF quenching method. DNA binding studies via UV-Vis spectroscopy and molecular docking suggested high binding affinities (ΔG⁰ values between -9.90 to -10.4 kcal/mol) and stable interactions with calf thymus DNA (ct-DNA).

The compounds showed promising inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), with IC50 values indicating higher potency and selectivity compared to galantamine, a known cholinesterase inhibitor.

The combined singlet oxygen generation, DNA binding, and enzyme inhibition data underscore the potential of these SiPc-coumarin derivatives as multifunctional agents for PDT and neuroprotective applications such as Alzheimer's disease (AD).

This study systematically reviews the clinical applications, toxicological profile, and quality markers of Guchang Zhixie Pill, offering a reference for its rational clinical use, as well as its quality and safety assessment.

Relevant literature on the historical development, clinical applications, toxicology, and molecular characteristics of Guchang Zhixie Pill was retrieved from CNKI (https://www.cnki.net/), VIP (https://www.cqvip.com/), Sci-Hub (https://sci-hub.hkvisa.net/), TCMSP (https://old.tcmsp-e.com/tcmsp.php), Google Scholar (https://scholar.google.cz/schhp?hl=zh-CN), and PubMed (https://pubmed.ncbi.nlm.nih.gov/). Quality markers were predicted and analyzed based on established criteria to provide a scientific basis for ensuring clinical safety and efficacy.

Formulated based on Wumei Pill, Guchang Zhixie Pill is widely used in the treatment of ulcerative colitis and irritable bowel syndrome. Quality marker prediction and analysis, conducted in accordance with the “five principles” of quality marker identification, indicated that ursolic acid, oleanolic acid, chlorogenic acid, neochlorogenic acid, citric acid, 5-hydroxymethylfurfural, coptisine, berberine hydrochloride, (+)-magnoflorine, 6-shogaol, 10-gingerol, dehydrocostus lactone, papaverine, noscapine, palmatine, and corydaline serve as potential Q-markers for this formulation.

As a classical prescription for intestinal astringency and antidiarrheal therapy, ensuring its rational clinical application is essential. The identification of 16 quality markers provides a scientific reference for quality control in future research.