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 (M_r) 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 NH_n⁺, 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 NH_n⁺ with TPSA and miLogP, as well as with GPCR ligand-ls, KI-ls and NRL-ls were revealed (Δ, ppm H in COOH vs. TPSA, R = -0.9421; Δ, ppm H in COOH vs. NRL-ls, R = -0.9216; Δ, ppm H5 vs. miLogP, R = 0.9962; Δ, ppm H5 vs. KI-ls, R = 0.9969; Δ, ppm NH_n⁺vs. TPSA, R = -0.9875 and Δ, ppm NH_n⁺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, M_r and V were also revealed (Δ, ppm C4 vs. TPSA, R = 0.9964; Δ, ppm C4 vs. miLogP, R = 0.9487; Δ, ppm C4 vs.M_r, R = 0.9629; Δ, ppm C4 vs. KI-ls, R = 0.9461; Δ, ppm C4 vs. NRL-ls, R = 0.9996; Δ, ppm C5 vs. miLogP, R = 0.9994; Δ, ppm C5 vs. KI-ls, R = 0.9990; Δ, ppm C5 vs. NRL-ls, R = 0.9510; Δ, ppm C11 vs. TPSA, R = -0,9958; Δ, ppm C11 vs. NRL-ls, R = -0.9994 and Δ, ppm C11 vs. KI-ls, R = -0.9481).