Lipophilicity Determination of Antifungal Isoxazolo[3,4-b]pyridin-3(1H)-ones and Their N1-Substituted Derivatives with Chromatographic and Computational Methods

Abstract

The lipophilicity of a molecule is a well-recognized as a crucial physicochemical factor that conditions the biological activity of a drug candidate. This study was aimed to evaluate the lipophilicity of isoxazolo[3,4-b]pyridine-3(1H)-ones and their N1-substituted derivatives, which demonstrated pronounced antifungal activities. Several methods, including reversed-phase thin layer chromatography (RP-TLC), reversed phase high-performance liquid chromatography (RP-HPLC), and micellar electrokinetic chromatography (MEKC), were employed. Furthermore, the calculated logP values were estimated using various freely and commercially available software packages and online platforms, as well as density functional theory computations (DFT). Similarities and dissimilarities between the determined lipophilicity indices were assessed using several chemometric approaches. Principal component analysis (PCA) indicated that other features beside lipophilicity affect antifungal activities of the investigated derivatives. Quantitative-structure-retention-relationship (QSRR) analysis by means of genetic algorithm—partial least squares (GA-PLS)—was implemented to rationalize the link between the physicochemical descriptors and lipophilicity. Among the studied compounds, structure 16 should be considered as the best starting structure for further studies, since it demonstrated the lowest lipophilic character within the series while retaining biological activity. Sum of ranking differences (SRD) analysis indicated that the chromatographic approach, regardless of the technique employed, should be considered as the best approach for lipophilicity assessment of isoxazolones.

Affinity of Antifungal Isoxazolo[3,4-b]pyridine-3(1H)-Ones to Phospholipids in Immobilized Artificial Membrane (IAM) Chromatography

“…Notably, all model GETAWAY descriptors included in the QSRR are weightings of van der Waals volume. Through comparing the proposed DE-PLS model with the previously obtained GA-PLS models [ 23 ] describing the RP-LC retention parameters of the studied isoxazolone derivatives, some conclusions can be generalized. Similarities in the nature of the valid descriptors are evident.…”

“…However, a significant difference of the QSRR models pertains to the lack of polarizability-related descriptors in the IAM scheme, even though it has been shown previously that these descriptors noticeably influence the retention parameters in RP-LC models. Chemically advanced template search (CATS) descriptors, which comprise information regarding lipophilicity, are not included in the QSRR model describing the IAM chromatographic separations, whereas these descriptors have been shown to impose a significant impact on retention under RP-LC conditions [ 23 ].…”

“…The molecular descriptors were calculated for the geometries obtained previously [ 23 ]. Briefly, the structures were optimized with the Gaussian 16 package by means of density functional theory (DFT) at the PBE0/6-311G++(2df,2pd) level of theory [ 34 ] and the SMD solvation model [ 35 ].…”

“…The present study is a continuation of our research focusing on the physiochemical characterization of biologically active isoxazolo[3,4- b ]pyridine-3(1 H )-one derivatives [ 23 ]. The main aim of this study was to assess the affinity of isoxazolone derivatives to phospholipids using IAM-HPLC.…”

Biomembrane Modelling in Planar Chromatographic Determination of Lipophilicity Using Olive and Castor Oils

“…In fact, its use alone in prediction of in vivo drug absorption has been reported to be an oversimplification of a biological complex process leading to inaccuracy in estimation; due to lack of real physiological conditions regulating in vivo membrane permeability (Balimane and Chong, 2008;Hermens, De Bruijn and Brooke, 2013). Several alternative methods such as reversed phase planar chromatography (RPTLC), reversed phase high performance chromatography (RP-HPLC), have been reported for lipophilicity determination of drugs (Ilijas et al, 2013;Hawryl et al 2015;Ciura et al, 2019) but come with flaws of inaccurate measurements due to poor structural similarity of their stationary phase compared to the bio-membrane amphiphilicity. These have made bio-membrane modeling challenging and complex; necessitating use of stationary phase with more complex surface chemistry in reliable simulation of in vivo bio-partitioning process.…”