Mehdi Valipour

Periodontal disease is a chronic inflammatory problem that has destructive effects on the tooth‐supporting tissues. This disease affects a large portion of the population, influencing overall health and quality of life, and significant socioeconomic burden. Therefore, efforts to more effectively manage the problems caused by this disease are a necessity. This review describes the therapeutic potential of Trolox (a water‐soluble analogue of vitamin E) and its modified derivatives as potential candidates for managing periodontal disease, highlighting their multifaceted pharmacological properties. Unlike the lipophilic molecule vitamin E, Trolox can be formulated into aqueous solutions, gels, mouthwashes, or rinses, ensuring optimal bioavailability at sites of inflammation and infection in the oral cavity. This compound can also help treat periodontal disease by combating oxidative stress, where its antioxidant properties neutralize harmful reactive oxygen species (ROS), reducing tissue damage and bone loss caused by undesired conditions such as bacterial imbalance. In addition to antioxidant and anti‐inflammatory properties, Trolox and its derivatives exhibit various pharmacological activities against diabetes, Alzheimer's disease, Plasmodium falciparum malaria infection, and periodontopathogens, all of which are associated with the development of periodontal disease. In conclusion, this review suggests that Trolox and some of its derivatives with favorable activity/toxicity profiles have significant potential to be considered as new drug candidates for combating periodontal diseases.

Coptisine, an isoquinoline‐based phytochemical, exhibits a broad spectrum of biological activities, including anticancer and anti‐inflammatory properties. Its planar chemical structure allows for the induction of anticancer effects by forming telomeric G‐quadruplex structures. Despite its promising medicinal benefits, the clinical utilization of this compound is limited by critical shortcomings such as low efficacy and poor pharmacokinetics. While in vitro studies demonstrate high cytotoxicity, in vivo research highlights its favorable toxicity profile, attributed to the conversion of its iminium form to a less toxic alkanolamine form within the physiological setting. Past endeavors have focused on rectifying these limitations through structural modifications to yield more efficacious molecules. In the current review, we provide an overview of the anti‐inflammatory and anticancer properties of coptisine and its semisynthetic derivatives, in conjunction with its pharmacokinetic profile, synthesis, and safety/toxicity considerations. This review draws upon information sourced from publications indexed in esteemed scientific databases like Web of Science, PubMed, and Scopus, among others. To prepare each section, we utilized Coptisine and section‐specific keywords, emphasizing recent literature findings (2014–2024) while maintaining a broad scope due to the study's nature. In conclusion, this review underscores coptisine's remarkable anticancer and anti‐inflammatory properties, suggesting that further exploration of structural modifications may yield semisynthetic derivatives with enhanced safety/toxicity profiles, pharmacokinetics, and therapeutic potential.

Oxidative stress plays an important role in the occurrence of neurodegenerative diseases. Previous studies indicate a strong connection between oxidative stress, inappropriate activation of the p38 MAPK signaling pathway, and the pathogenesis of neurodegenerative diseases. Although antioxidant therapy is a valid strategy to alleviate these problems, the most important limitation of this approach is the ineffectiveness of drug administration due to the limited permeability of the BBB. Therefore, BBB‐penetrating p38 MAPK modulators with proper antioxidant capacity could be useful in preventing/reducing the complications of neurodegenerative disorders. The current manuscript aims to review the therapeutic capabilities of some recently reviewed naturally occurring p38 MAPK inhibitors in the management of neurodegenerative problems such as Alzheimer's disease. In data collection, we tried to use more recent studies published in high‐quality journals indexed in databases Scopus, Web of Science, PubMed, and so on, but no specific time frame was considered due to the nature of the study. Our evaluations indicate that natural compounds tanshinones, protoberberines, pinocembrin, osthole, rhynchophylline, oxymatrine, schisandrin, piperine, paeonol, ferulic acid, 6‐gingerol, obovatol, and trolox have significant potential for use as supplements/adjuvants in the reduction of neurodegenerative‐related problems. Our findings emphasize the usefulness of BBB‐penetrating phytochemicals with p38 MAPK modulatory activity as potential therapeutic options against neurodegenerative disorders. Of course, the proper use of these compounds depends on considering their toxicity/safety profile and pharmacokinetic characteristics as well as the clinical conditions of users.

Hepatocellular carcinoma is the most common type of primary liver cancer. However, multidrug resistance (MDR) is a major obstacle to the effective chemotherapy of cancer cells. This report documents the rational design, synthesis, and biological evaluation of a novel series of triazolotriazines substituted with CH₂NH‐linked pyridine for use as dual c‐Met/MDR inhibitors. Compound 12g with IC₅₀ of 3.06 μM on HepG2 cells showed more potency than crizotinib (IC₅₀ = 5.15 μM) in the MTT assay. In addition, 12g inhibited c‐Met kinase at a low micromolar level (IC₅₀ = 0.052 μM). 12g significantly inhibited P‐gp and MRP1/2 efflux pumps in both cancerous HepG2 and BxPC3 cells starting from the lower concentrations of 3 and 0.3 µM, respectively. 12g did not inhibit MDR1 and MRP1/2 in noncancerous H69 cholangiocytes up to the concentration of 30 and 60 µM, respectively. Current results highlighted that cancerous cells were more susceptible to the effect of 12g than normal cells, in which the inhibition occurred only at the highest concentrations, suggesting a further interest in 12g as a selective anticancer agent. Overall, 12g, as a dual c‐Met and P‐gp/MRP inhibitor, is a promising lead compound for developing a new generation of anticancer agents.