Drugs and Drug Candidates

Background: Phytocannabinoids such as cannabidiol (CBD) and cannabigerol (CBG) have received increasing attention in the context of inflammatory and intestinal disorders. However, direct comparisons between their individual and combined effects, as well as the influence of delivery systems, remain limited. Objectives: This study evaluated the biological effects of free and nanoencapsulated CBD and CBG, including a cannabinoid–Eudragit L100 formulation, in an in vitro TNBS-treated intestinal cell model and an in vivo murine model of TNBS-induced colitis. Methods: Cytotoxicity and treatment-associated effects of CBD, CBG, their 1:1 combination, and a nanoencapsulated formulation were assessed in TNBS-exposed Caco-2 cells. In parallel, BALB/c mice with TNBS-induced colitis were evaluated for colonic damage and inflammatory markers. Results: CBD and CBG individually showed dose-dependent effects in Caco-2 cells, while their combined administration produced a greater effect than either compound alone at higher concentrations. The nanoencapsulated formulation preserved cellular metabolic activity following TNBS exposure. In vivo, both free combined and nanoencapsulated cannabinoids were associated with reduced epithelial damage and inflammatory alterations. Conclusions: Nanoencapsulation using Eudragit L100 modulated the biological effects of CBD and CBG in experimental models of TNBS-induced intestinal injury.

Oxidative stress, caused by an imbalance between the production of reactive oxygen species and endogenous antioxidant capacity, is a key etiological factor in numerous pathologies, including neurodegenerative and cardiovascular diseases. The limited clinical efficacy of conventional antioxidants is primarily due to their insufficient accumulation within the mitochondria, the main site of intracellular ROS generation. This article reviews the design and application of Mitochondria-Targeted Antioxidants, which represent a major advance in precision medicine. The design of these compounds involves linking an antioxidant “payload” to a lipophilic cation, such as the triphenylphosphonium group. This positive charge leverages the negative electrochemical gradient across the inner mitochondrial membrane to drive the antioxidant into the organelle. This mechanism allows the drug to reach concentrations over 100 times higher than non-targeted alternatives. The discussion encompasses the structure-activity analysis of the carrier, the payload (e.g., quinone derivatives), and the linker, which determine optimal subcellular partitioning and scavenging efficiency. Preclinical data highlight the therapeutic potential of this approach, showing strong neuroprotection in models of Parkinson’s and Alzheimer’s diseases, as well as improved outcomes in cardiovascular and ocular health. By restoring redox balance specifically within the mitochondria, these targeted therapies offer a more effective way to treat chronic oxidative damage.

Background/Objectives: Recent reports have demonstrated the antiparasitic activity of 1,4-dihydropyridine (1,4-DHPs). This study aimed to assess the in vitro antischistosomal activity of 24 1,4-DHPs against Schistosoma mansoni adult worms. Methods: Sixteen hexahydroquinolines (1–16) and eight Hantzsch esters (17–24) previously obtained through a multicomponent Hantzsch reaction were tested in vitro against Schistosoma mansoni adult worms. In silico studies with the most active compounds were also carried out. Results: Among the tested compounds, the Hantzsch esters 20 (diethyl 4-(4-bromophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate) and 21 (diethyl 4-(3-fluorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate) provided the lowest IC₅₀ (15.2 and 13.1 µM, respectively) and the highest selectivity for this parasite (SI = 2.31 and >4.59, respectively). Conclusions: Docking studies revealed that compound 21 has a high affinity for the S. mansoni target (PDB ID: 6UY4). Furthermore, ADMET predictions indicated that compound 21 meets the drug-likeness criteria without violating any Lipinski, Veber, or Egan’s rules.