Utvrđivanje veze između strukture i retencije oksotiazolidina primenom multivarijantne analize

Abstract

Hromatografsko ponašanje 23 novosintetisana 2-alkiliden-4-oksotiazolidinaispitivano je u uslovima reverzno-fazne planarne hromatografije, uz upotrebu dvestacionarne faze (oktadecil-modifikovan (RP-18) i cijano-modifikovan (CN) silika-gel).Dvokomponentne smeše methanol/voda, acetonitril/voda i tetrahidrofuran/voda sukorišćene kao mobilne faze. Linearna zavisnost RM vrednosti od zapreminskog udelaorganske komponente u mobilnoj fazi utvrđena je za sva ispitivana jedinjenja, savisokom vrednošću korelacionog koeficijenta (r > 0,99).Ispitivani 4-oksotiazolidini predstavljaju kongenernu seriju jedinjenja, štopotvrđuje značajan nivo korelacije dobijen pri poređenju RM0 vrednosti i drugihhromatografskih parametara (m, C0 i PC1). Svi hromatografski parametri lipofilnosti(RM0, m, C0 i PC1) poređeni su sa izračunatim log P vrednostima. Statistički parametriovih zavisnosti pokazali su da RM0 vrednosti mnogo pouzdanije opisuju lipofilnosti odpreostalih hromatografskih parametara (m, C0 i PC1).Analiza glavnih komponenata je primenjena na retencione podatke u ciljuutvrđivanja sličnosti i razlika između upotrebljenih hromatografskih sistema. Višestrukalinearna regresija (MLR) i parcijalna regresija najmanjih kvadrata (PLS) su omogućileispitivanje odnosa između molekulskih deskriptora ispitivanih N-supstituisanih2-alkiliden-4-oksotiazolidina i retencionih podataka određenih primenom dvahromatografska sistema (tetrahidrofuran/voda na RP-18 i CN stacionarnoj fazi).Potpuna geometrijska optimizacija izvršena je pomoću AM1 semi-empirijskemolekulsko-orbitalne metode, nakon čega je set fizičko-hemijskih molekulskihdeskriptora izračunat iz optimizovanih struktura.Poređenjem statističkih parametara odabran je model gde je na najbolji načinopisana veza između seta izračunatih deskriptora i RM0 vrednosti. Dobra prediktivnamoć MLR i PLS modela dobijenih za kalibracioni set podataka potvrđena je napodacima iz test seta. Molekulski deskriptori uključeni u odabrane MLR i PLS modelesu slične prirode, a u sve dobijene modele uključen je parametar lipofilnosti (log P) štoukazuje na značaj lipifilnosti i njen uticaj na retenciju N-supstituisanih 2-alkiliden-4-oksotiazolidina.

The chromatographic behavior of 23 new 2-alkylidene-4-oxothiazolidinederivates was investigated by means of the reversed-phase thin-layer chromatography(RP TLC) on RP-18 and CN stationary phases. Binary mixtures of methanol/water,acetonitrile/water and tetrahydrofuran/water were used as mobile phases. Linearrelationships between the volume fraction of the organic mobile phase modifier and theRM values were established for each solute with the high correlation coefficient values(r > 0.99).The investigated 4-oxothiazolidines are a congeneric set of compounds, andsignificant correlations were obtained between the chromatographically determined RM0and other retention parameters (m, C0, and PC1). All lipophilicity parameters (RM0, m,C0, and PC1) obtained from the reversed-phase experiments were compared with thecalculated log P values. Statistical parameters of these correlations showed that RM0values were more suitable for lipophilicity estimation than other retention parameters(m, C0, and PC1).Principal Component Analysis was performed on retention data in an attempt toreflect the similarities and differences among different chromatographic systems.Multiple linear regression (MLR) and partial least squares regression (PLS) wereperformed to investigate relation between the structural descriptors of N-substituted2-alkylidene-4-oxothiazolidines and chromatographic retention determined for the twochromatographic systems (tetrahydrofuran/water on RP-18 and CN stationary phases).Full geometry optimization based on Austin Model 1 (AM1) semiempirical molecularorbital method was carried out and a set of physicochemical molecular descriptors wascalculated from the optimized structures.The best relationships in a set of calculated descriptors and RM0 values werechosen on the basis of comparison of the statistical parameters. The statisticalparameters of MLR and PLS models built for training set show a significant predictiveability. The descriptors included in the chosen MLR and PLS models were of similarnature. Lipophilicity parameter (log P) selected out of a large set of possible moleculardescriptors in all models, indicated the importance of lipophilicity and its influence onthe retention behavior of the N-substituted 2-alkylidene-4-oxothiazolidines.