Search Results (3)

A hybrid method—combining liquid biomimetic chromatography techniques (immobilized artificial membrane chromatography and biopartitioning micellar chromatography) and Quantitative Structure–Activity Relationships—was used to derive helpful models for predicting selected biological properties such as penetration through the plant cuticle, the skin and the blood–brain barrier, and binding to human serum albumin of phenoxyacetic acid-derived congeners regarded as potential herbicides. Reliable, high-concept models were developed indicating the lipophilicity, polarizability, and sum of hydrogen bond donors and acceptors as properties that determine the biological efficacy of the title compounds. These models were validated by leave-one-out cross-validation. Modeling the toxicity of phenoxyacetic acid-derived congeners to red blood cells allowed the identification of the most toxic substances as well as those molecular descriptors that determine their hemolytic properties. Full article

Evaluation of pharmacokinetic properties is a significant step at the early stages of drug development. In this study, an in vitro evaluation of the pharmacokinetic properties of five newly synthesized compounds was performed. These compounds belong to N-hydroxyurea and hydroxamic acid derivatives and analogs of NSAIDs indomethacin, flurbiprofen, diclofenac, ibuprofen, and naproxen (compounds 1, 2, 3, 11, and 12, respectively) with dual COX-2 and 5-LOX inhibitory activity. Two in vitro methods (biopartitioning micellar chromatography (BMC) and PAMPA) were used to evaluate passive gastrointestinal absorption, while high-performance affinity chromatography (HPAC) and differential pulse voltammetry (DPV) were used to evaluate binding to human serum albumin (HSA). The introduction of N-hydroxyurea and hydroxamic acid groups into the structure of NSAIDs decreases both expected passive gastrointestinal absorption (BMC k values were from 3.02 to 9.50, while for NSAIDs were from 5.29 to 13.36; PAMPA –logPe values were between 3.81 and 4.76, while for NSAIDs were ≤3.46) and HSA binding (HPAC logk values were from 2.03 to 9.54, while for NSAIDs were ≥11.03; DPV peak potential shifts were between 7 and 34, while for NSAIDs were ≥54). Structural modifications of all tested compounds that increase lipophilicity could be considered to enhance their passive gastrointestinal absorption. Considering lower expected HSA binding and higher lipophilicity of tested compounds compared to corresponding NSAIDs, it can be expected that the volume of distribution of compounds 1, 2, 3, 11, and 12 will be higher. Reduced HSA binding may also decrease interactions with other drugs in comparison to corresponding NSAIDs. All tested compounds showed significant microsomal instability (25.07–58.44% decrease in concentration) in comparison to indomethacin (14.47%) and diclofenac (20.99%). Full article

Biomimetic (non-cell based in vitro) and computational (in silico) studies are commonly used as screening tests in laboratory practice in the first stages of an experiment on biologically active compounds (potential drugs) and constitute an important step in the research on the drug design process. The main aim of this study was to evaluate the ability of triterpenoid saponins of plant origin to cross the blood–brain barrier (BBB) using both computational methods, including QSAR methodology, and biomimetic chromatographic methods, i.e., High Performance Liquid Chromatography (HPLC) with Immobilized Artificial Membrane (IAM) and cholesterol (CHOL) stationary phases, as well as Bio-partitioning Micellar Chromatography (BMC). The tested compounds were as follows: arjunic acid (Terminalia arjuna), akebia saponin D (Akebia quinata), bacoside A (Bacopa monnieri) and platycodin D (Platycodon grandiflorum). The pharmacokinetic BBB parameters calculated in silico show that three of the four substances, i.e., arjunic acid, akebia saponin D, and bacoside A exhibit similar values of brain/plasma equilibration rate expressed as logPS_Fubrain (the average logPS_Fubrain: −5.03), whereas the logPS_Fubrain value for platycodin D is –9.0. Platycodin D also shows the highest value of the unbound fraction in the brain obtained using the examined compounds (0.98). In these studies, it was found out for the first time that the logarithm of the analyte–micelle association constant (logK_MA) calculated based on Foley’s equation can describe the passage of substances through the BBB. The most similar logBB values were obtained for hydrophilic platycodin D, applying both biomimetic and computational methods. All of the obtained logBB values and physicochemical parameters of the molecule indicate that platycodin D does not cross the BBB (the average logBB: −1.681), even though the in silico estimated value of the fraction unbound in plasma is relatively high (0.52). As far as it is known, this is the first paper that shows the applicability of biomimetic chromatographic methods in predicting the penetration of triterpenoid saponins through the BBB. Full article