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Effects of substituents on the NMR features of basic bicyclic ring systems of fluoroquinolone antibiotics and the relationships between NMR chemical shifts, molecular descriptors and drug-likeness parameters

In the present study, the NMR spectroscopic features of trovafloxacin (TVA) mesylate, pefloxacin (PFX) mesylate dihydrate and ciprofloxacin (CIP) hydrochloride monohydrate were studied in DMSO-d6 solution with the aim of investigating the effects of substituents and the type of salt on the NMR parameters of basic bicyclic fluoroquinolone and fluoronaphthyridone ring systems. For this purpose, the 1H- and 13C- one- and two-dimensional homo- and heteronuclear NMR methods were used. The analysis of 1H- and 13C-NMR spectra confirmed the structures of investigated fluoroquinolone salts. Relationships between 1H- and 13C-NMR chemical shifts of fluoronaphthyridone and fluoroquinolone ring systems, calculated molecular descriptors (MDs) and drug-likeness scores (DLSs), computed for monoprotonic cations of investigated fluoroquinolone salts (TVAH+, PFXH+ and CIPH+), were also explored. The topological polar surface area (TPSA), the parameter of lipophilicity (miLogP), the relative molecular mass (Mr) and the volume (V) of computed molecular descriptors (MDs), as well as the G protein-coupled receptor ligand-likeness (GPCR ligand-ls), the ion channel ligand-likeness (ICL-ls), the kinase inhibitor-likeness (KI-ls) and the nuclear receptor ligand-likeness (NRL-ls) were used in this study. The 1H-NMR chemical shifts of protons in COOH, H5 and NHn+, as well as 13C-NMR chemical shifts of C4, C5 and C11 shown to be good parameters in exploration of property-property and property-drug-likeness relationships for investigated fluoroquinolone salts. Thus, collinear relationships of 1H-NMR chemical shifts of protons in COOH, H5 and NHn+ with TPSA and miLogP, as well as with GPCR ligand-ls, KI-ls and NRL-ls were revealed (delta, ppm H in COOH vs. TPSA, R = –0.9421 ; delta, ppm H in COOH vs. NRL-ls, R = –0.9216 ; delta, ppm H5 vs. miLogP, R = 0.9962 ; delta, ppm H5 vs. KI-ls, R = 0.9969 ; delta, ppm NHn+ vs. TPSA, R = –0.9875 and , ppm NHn+ vs. NRL-ls, R = –0.9948). The collinearities between, 13C-NMR chemical shifts of C4, C5 and C11 with KI-ls and NRL-ls, as well as with TPSA, miLogP, Mr and V were also revealed (delta, ppm C4 vs. TPSA, R = 0.9964 ; delta, ppm C4 vs. miLogP, R = 0.9487 ; delta, ppm C4 vs. Mr, R = 0.9629 ; delta, ppm C4 vs. KI-ls, R = 0.9461 ; delta, ppm C4 vs. NRL-ls, R = 0.9996 ; delta, ppm C5 vs. miLogP, R = 0.9994 ; delta, ppm C5 vs. KI-ls, R = 0.9990 ; delta, ppm C5 vs. NRL-ls, R = 0.9510 ; delta, ppm C11 vs. TPSA, R = –0, 9958 ; delta, ppm C11 vs. NRL-ls, R = –0.9994 and delta, ppm C11 vs. KI-ls, R = –0.9481).

fluoroquinolone antibiotics; trovafloxacin; pefloxacin; ciprofloxacin; 1H-NMR spectroscopy; 13C-NMR spectroscopy; molecular descriptors; drug-likeness score; QSAR

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