Reversed-Phase TLC and HPLC Retention Data in Correlation Studies with in Silico Molecular Descriptors and Druglikeness Properties of Newly Synthesized Anticonvulsant Succinimide Derivatives

Abstract

The properties relevant to pharmacokinetics of two series of newly synthesized succinimide derivatives have been studied. The properties under consideration have been either determined empirically, by reversed-phase liquid chromatography (TLC and HPLC technique), or calculated with the use of established theoretical medicinal chemistry/drug design software. Chromatographic techniques allowed determination of the retention constants R(M)⁰ and log k(w), which characterize lipophilicity of compounds. Considering potential pharmaceutical importance of succinimide derivatives, we (i) examined the retention behavior in the reversed-phase liquid chromatographic (RP LC) systems, in both planar and column LC, and (ii) determined the relationships between chromatographic data and selected structural features of analytes that are believed to markedly affect their processes of absorption, distribution, metabolism, excretion and toxicity (ADMETox). Significant relationships were found between the retention constants, R(M)⁰ and log k(w), and the in silico calculated bioactivity descriptors, in particular HIA (human intestinal absorption) and PPB (plasma protein binding) parameters. The R(M)⁰ and log k(w) values of the investigated compounds have been recommended for description of their lipophilicity and evaluating pharmacokinetic properties. In view of results of this study the newly synthesized succinimide agents meet pharmacokinetic criteria of preselection of drug candidates and hence qualify for pharmacodynamic phase of antiepileptic drug development. Best compromising human intestinal absorption and plasma protein binding features appear to be compounds A4, A5, A10 and A11.

Synthesis of Isoxazole and 1,2,3-Triazole Isoindole Derivatives via Silver- and Copper-Catalyzed 1,3-Dipolar Cycloaddition Reaction

“…The aim of this present work focuses on the synthesis of N-heterocyclic compounds, namely the synthesis of substituted isoxazole and triazole derivatives, since an important number of compounds containing the isoxazole and the triazole scaffold are known to exhibit a variety of biological activities in the pharmaceutical [16] and medicinal areas [17]. Representative examples of synthetic drugs incorporating these motifs are Tazobactam I [18][19][20][21][22], Rufinamide II [23][24][25], phenylisoxazole derivatives III [26,27], and Bextra (Valdecoxib) IV [28][29][30].…”

“…Tazobactam I [18][19][20][21][22], Rufinamide II [23][24][25], phenylisoxazole derivatives III [26,27], and Bextra (Valdecoxib) IV [28][29][30].…”

Pharmacokinetics, brain distribution and plasma protein binding of carbamazepine and nine derivatives: New set of data for predictive in silico ADME models

“…In addition, only the free fraction of drug is available to cross the BBB (Lange et al, 2005) and a high lipophilicity also makes compounds more vulnerable to bind to plasma and efflux proteins (Perisic-Janjic et al, 2011). Based on the correlation analysis herein reported, it is important to emphasize that MM and PSA appeared to be the most important determinants of brain/plasma ratios and the AUC 0-12h and C max values obtained in brain were also strongly correlated with PSA.…”

Optimization of a Parallel Artificial Membrane Permeability Assay for the Fast and Simultaneous Prediction of Human Intestinal Absorption and Plasma Protein Binding of Drug Candidates: Application to Dibenz[b,f]azepine-5-Carboxamide Derivatives

“…A strong binding of drugs to plasma proteins (above 90%) brings a risk of highly varying free fraction of the drug in plasma, which can cause changes in its bioactivity and safety. [14][15][16] For these reasons, PPB is nowadays considered an important parameter in the optimization of drug properties in initial phases of DDD. As the VD, the PPB of a drug also depends on drug lipophilicity and ionization state.…”

“…The horizontal dashed line separates high and low human absorption compounds; the vertical dashed line corresponds to the experimental apparent permeability value obtained with PAMPA that separates the compounds predicted as high and poorly absorbed; the horizontal full line separates compounds with high and low percentage of plasma protein binding and the vertical full line corresponds to the experimental apparent permeability value obtained with PAMPA that separates the compounds predicted as with high and poor affinity to binding to plasma proteins. Reference compounds are: (1) acetylsalicylic acid, (2) atenolol, (3) chloramphenicol, (4) chlorothiazide, (5) hydrochlorothiazide,(6) ibuprofen, (7) ketoprofen, (8) metoprolol, (9) nadolol, (10) naproxen, (11) norfloxacin, (12) piroxicam,(13) propranolol,(14) ranitidine,(15) sulfasalazine,(16) sulpiride, (17) theophylline, and (18) verapamil.…”