Reversed-phase TLC and HPLC retention data in correlation studies with in silico molecular descriptors and druglikeness properties of newly synthesized anticonvulsant succinimide derivatives.
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.
Department of Chemistry, Faculty of Sciences, University of Novi Sad, Trg Dositieja Obradovica 3, 21000 Novi Sad, Serbia.
Nada
N
Perisic-Janjic
Roman
R
Kaliszan
Paweł
P
Wiczling
Natasa
N
Milosevic
Gordana
G
Uscumlic
Nebojsa
N
Banjac
D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D056148:Chromatography, Reverse-Phase; D002855:Chromatography, Thin Layer; D006801:Humans; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D004364:Pharmaceutical Preparations; D021281:Quantitative Structure-Activity Relationship; D012984:Software; D013388:Succinimides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000927:Anticonvulsants; D004364:Pharmaceutical Preparations; D013388:Succinimides