Aims In this study, new 2,3,4,9-tetrahydro-1H-carbazol-1,3,4-oxadiazole-N-phenylacetamide hybrids 8a-n as potential dual inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) for the treatment of Alzheimer's disease (AD) were introduced.Methods The target compounds were designed using a molecular hybridization strategy and synthesized via straightforward chemical reactions. They were evaluated in vitro for their inhibitory activity against AChE and BChE. The mechanism of inhibition was investigated through kinetic studies. Computational methods, including molecular docking and molecular dynamics simulations, were employed to analyze binding interactions and complex stability. Finally, the drug-likeness and oral bioavailability of the compounds were assessed.Results All synthesized compounds showed significant inhibitory effects against BChE and moderate inhibition against AChE. Compound 8m was identified as the most potent dual inhibitor, being approximately 18-fold more potent against BChE than the standard drug donepezil. Kinetic studies on compound 8m revealed a competitive mode of inhibition against AChE and BChE. Computational analyses confirmed that compound 8m forms more stable interactions and a more stable, compact complex with BChE compared with donepezil, characterized by reduced structural fluctuations and more persistent hydrogen bonding.Conclusions Compound 8m is a potent, competitive inhibitor of both AChE and BChE with a favorable drug-like profile and oral bioavailability.
The eventful saga of insomnia drugs racemic zopiclone to single-enantiomer eszopiclone chiral switches globally is an opportunity to reconsider the scope of the chiral-switches strategy and to analyze the different assessments by the US FDA and the European Medicines Agency (EMA) thereof, including related novel drug designators New Chemical Entity (NCE) and New Active Substance and the lessons thereof. The covered areas are zopiclone and eszopiclone’s events at drug regulatory authorities, including marketing authorizations worldwide and novel drug designations conferring regulatory exclusivities, along with basic and enantiomer patents and litigations thereof. The lessons pertaining to the chiral-switches strategy are: Chiral switches criteria should be restricted to approvals within the relevant jurisdiction. Twisted chiral switches, whereupon components of chiral-switch drugs were patented but the racemic drugs were not approved, should not be considered chiral switches. The EU de facto denial of NAS status to eszopiclone highlights the importance of regulatory exclusivity when patent-exclusivity periods are short. In spite of the chain of events of zopiclone and eszopiclone patents and litigations thereof, the chiral-switches case law was not enriched. The regulatory approvals of eszopiclone in many jurisdictions in the 2020s, many years after zopiclone approvals, confirm the vitality of the chiral-switches strategy.
Primary or acquired temozolomide (TMZ) resistance in glioblastoma (GBM) critically limits clinical efficacy, with O6‑methylguanine‑DNA methyltransferase (MGMT) serving as the key repair protein that directly reverses TMZ-induced O6-methylguanine (O6-MG) lesions. Classical MGMT inactivators such as O6‑benzylguanine (O6‑BG) and O6‑(4‑bromothenyl)guanine (O6‑4‑BTG, lomeguatrib) effectively deplete MGMT activity and sensitize tumor cells to alkylating agents. However, their lack of tumor selectivity depletes MGMT in normal hematopoietic tissues, inducing dose-limiting myelotoxicity and necessitating counterstrategies such as MGMT-tolerant hematopoietic stem cell protection. To overcome this bottleneck, MGMT intervention strategies have expanded from direct enzymatic inhibition toward regulation at the expression level. This review focuses on small molecules that downregulate MGMT expression through transcriptional and epigenetic regulation, CNS-active drug interventions, modulation of MGMT-related signaling pathways, and naturally derived bioactive compounds. It also summarizes emerging technological approaches including tumor-targeted conjugation, blood–brain barrier-penetrating delivery systems, MGMT gene silencing via siRNA, and induced protein degradation through ubiquitin-proteasome modulation. The expression-regulation strategy offers a broader therapeutic window for restoring GBM sensitivity to TMZ. Nevertheless, clinical translation still requires further optimization in tumor selectivity, effective brain exposure, rational combination timing, and robust pharmacodynamic validation to establish meaningful patient benefit. Glioblastoma (GBM) is an aggressive brain cancer with a poor outlook. The standard treatment includes the chemotherapy drug temozolomide (TMZ), but many tumors become resistant to it. This resistance is largely driven by a protein called MGMT, which acts like a “repair worker” inside cancer cells. When TMZ damages the cancer cell’s DNA, MGMT fixes the damage before the cell can be killed. The higher the MGMT levels, the less effective the chemotherapy. Researchers have developed drugs to block MGMT directly, but these drugs also remove MGMT from healthy bone marrow cells, causing serious side effects that limit their use. Therefore, scientists are now looking at ways to lower MGMT levels more selectively – by silencing the MGMT gene, disrupting the signals that turn it on, or breaking down the MGMT protein itself. Some existing drugs, including anti-seizure medications and antidepressants, have been found to reduce MGMT in tumor cells, offering a potential shortcut to new treatments. Other approaches use nanoparticles to deliver MGMT-blocking molecules specifically to brain tumors, or protect healthy bone marrow so stronger chemotherapy can be given. This review summarizes the latest strategies to overcome MGMT-related resistance, highlighting the shift from simply blocking MGMT to more sophisticated methods that aim to make GBM vulnerable to treatment again while sparing healthy tissues.
BACKGROUND Chronic inflammation contributes to several diseases, creating a need for effective anti-inflammatory agents. OBJECTIVE This study aimed to synthesize, characterize, and evaluate coumarin-based Schiff base derivatives for anti-inflammatory activity. METHODS Ten coumarin Schiff base derivatives (SB-1 to SB-10) were synthesized by condensing 7-amino-4-methylcoumarin with substituted aromatic aldehydes. The compounds were characterized using FT-IR and 1H NMR spectroscopy. In vitro activity was evaluated using the egg albumin denaturation assay. The most active compounds were assessed for acute toxicity and in vivo activity using carrageenan-induced paw edema in Wistar rats. Molecular docking was performed against COX-2 protein structures, and drug-likeness and ADME properties were predicted using SwissADME. RESULTS SB-5 and SB-6 exhibited the highest in vitro activity, producing 82.65% and 73.46% inhibition of protein denaturation, respectively, at 250 µg/mL. At 200 mg/kg, SB-5 and SB-6 produced 46.02% and 41.29% inhibition of paw edemarespectively, whereas diclofenac sodium produced 66.90% inhibition at the dose evaluated. Both compounds were well tolerated in the acute toxicity study. Molecular docking indicated favorable interactions with COX-2 targets. SwissADME analysis showed compliance with Lipinski and Veber criteria and favorable gastrointestinal absorption and pharmacokinetic properties. CONCLUSION SB-5 and SB-6 demonstrated promising preliminary anti-inflammatory activity and warrant further target-specific, pharmacological, pharmacokinetic, and toxicity studies to validate their potential for drug development.
