Abstract
The development of effective, nontoxic antifungal agents is one of the most important challenges for medicinal chemistry. A series of isoxazolo [3,4-b]pyridine-3(1H)-one derivatives previously synthesized in our laboratory demonstrated promising antifungal properties. The main goal of this study was to investigate their retention behavior in a human serum proteins-high-performance liquid chromatography (HSA-HPLC) system and explore the molecular mechanism of HSA-isoxazolone interactions using a quantitative structure–retention relationship (QSRR) approach. In order to realize this goal, multiple linear regression (MLR) modeling has been performed. The proposed QSRR models presented correlation between experimentally determined lipophilicity and computational theoretical molecular descriptors derived from Dragon 7.0 (Talete, Milan, Italy) software on the affinity of isoxazolones to HSA. The calculated plasma protein binding (PreADMET software) as well as chromatographic lipophilicity (logkw) and phospholipophilicity (CHIIAM) parameters were statistically evaluated in relation to the determined experimental HAS affinities (logkHSA). The proposed model met the Tropsha et al. criteria R2 > 0.6 and Q2 > 0.5 These results indicate that the obtained model can be useful in the prediction of an affinity to HSA for isoxazolone derivatives and they can be considered as an attractive alternative to HSA-HPLC experiments.
Highlights
Fungal infections constitute a significant threat to the public healthcare sector [1,2,3].The development of new antifungal agents is definitely more complex and complicated than the elaboration of antibacterial substances due to the eukaryotic nature of the fungi cells [4]
Dimethyl sulfoxide (DMSO) used to dissolve analytes was purchased from POCH (Gliwice, Poland). 2-Propanol HPLC grade for liquid chromatography, sodium phosphate dibasic dihydrate and sodium phosphate monobasic monohydrate were obtained from Sigma-Aldrich (Steinheim, Germany)
HPLC columns that comprise immobilized human serum albumin (HSA) were introduced for chiral chromatographic separations [18]
Summary
Fungal infections constitute a significant threat to the public healthcare sector [1,2,3].The development of new antifungal agents is definitely more complex and complicated than the elaboration of antibacterial substances due to the eukaryotic nature of the fungi cells [4]. Only a few class of chemicals, such as polyenes, azoles, echinocandins, allylamines, and flucytosine, are used in routine medical practice [3]. Another problem of treatment of fungal infections is systematic increase in resistance to available drugs. It should be highlighted that resistance was reported in cases of well-known drugs such as fluconazole but some cases for recently introduced echinocandin [3,5,6]. The use of numerous effective antifungal drugs including amphotericin B is limited by their unfavorable safety profiles [7]. The search of more effective and safe antifungal molecules is a primary concern in the drug discovery pipeline
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