Milena Jadrijević-Mladar Takač

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

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 (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 NHn+vs. TPSA, R = -0.9875 and Δ, 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 (Δ, ppm C4 vs. TPSA, R = 0.9964; Δ, ppm C4 vs. miLogP, R = 0.9487; Δ, ppm C4 vs.Mr, 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). Utjecaj supstituenata na NMR značajke temeljnog bicikličkog prstenastog sustava fluorokinolonskih antibiotika i odnos između NMR kemijskih pomaka, molekulskih opisivača i parametara sličnosti s lijekovima U radu je opisano ispitivanje NMR spektroskopskih značajki trovafloksacin (TVA) mesilata, pefloksacin (PFX) mesilata i ciprofloksacin (CIP) hidroklorida u DMSO-d6 otopini s ciljem da se istrazcari utjecaj supstituenata i tipa soli na NMR parametre bicikličkog fluorokinolonskog i fluoronaftiridonskog prstenastog sustava. Analizom jedno- i dvo-dimenzijskih, homo- i hetero-nuklearnih 1H- i 13C-NMR spektara potvrđena je struktura ispitivanih fluorokinolonskih soli. 1H- i 13C-NMR kemijski pomaci temeljnih prstenastih sustava korelirani su s izračunatim molekulskim opisivačima (relativnom molekulskom masom, Mr, topologijskom polarnom površinom, TPSA, lipofilnošću, miLogP i volumenom, V) te s parametrima sličnosti s lijekovima poznate biološke aktivnosti, tj. s ligandom G protein-spregnutog receptora (GPCR ligand), ligandom ionskih kanala (ICL), inhibitorom kinaze (KI) i ligandom nuklearnog receptora (NRL) koji su izračunati za monoprotonske katione ispitivanih fluorokinolonskih soli (TVAH+, PFXH+ and CIPH+). 13C-NMR kemijski pomaci C4, C5 i C11 atoma i 1H-NMR kemijski pomaci protona u COOH, H5 i NHn+ ispitivanih fluorokinolonskih soli pokazali su se kao dobri parametri za istraživanje odnosa svojstvo-svojstvo i svojstvo-sličnost s lijekovima poznate biološke aktivnosti. Tako je otkriven kolinearan odnos između 13C-NMR kemijskih pomaka C4, C5 i C11 atoma i izračunatih parametara za sličnost s KI-ls i NRL-ls, kao i kolinearnost s TPSA, miLogP, Mr i V (C4 Δ, ppm s TPSA, R = 0,9964; C4 Δ, ppm s miLogP, R = 0,9487; C4 Δ, ppm s Mr, R = 0,9629; C4 Δ, ppm s V, R = 0,8547; C4 Δ, ppm s KI-ls, R = 0,9461 i C4 Δ, ppm s NRL-ls, R = 0,9996; C5 Δ, ppm s miLogP, R = 0,9994; C5 Δ, ppm s KI-ls, R = 0,9990 i C5 Δ, ppm s NRL-ls, R = 0,9510; C11 Δ, ppm s TPSA, R = -0,9958; C11 Δ, ppm s KI-ls, R = -0,9481 i C11 Δ, ppm s NRL-ls, R = -0,9994). 1H-NMR kemijski pomaci protona COOH, H5 i NHn+ pokazali su kolinearnost odnosa s TPSA i miLogP, te s izračunatim parametrima za KI-ls, NRL-ls i GPCRl-ls (Δ, ppm H u COOH s TPSA, R = -0,9421; Δ, ppm H u COOH s NRL-ls, R = -0,9216; H5 Δ, ppm s miLogP, R = 0,9962; Δ, ppm H5 s KI-ls, R = 0,9969; Δ, ppm NHn+ s TPSA, R = -0,9875; Δ, ppm NHn+ s NRL-ls, R = -0,9948; Δ, ppm NHn+ s GPCR ligandom, R = 0,9873). Rezultati istraživanja pokazali su razliku u eksperimentalnim i izračunatim parametrima za TVA mesilat u usporedbi s PFX mesilatom i CIP hidrokloridom, te je nađena značajna kolinearnost među ispitivanim parametrima ovih fluorokinolonskih antibiotika.

Cyclic trihydroxamic acid derivatives.

In the crystal structures of two cyclic trihydroxamic acid derivatives containing the same substructure unit, viz. 1,3,5-trihydroxy-1,3,5-triazinane-2,4,6-trione dihydrate, C3H3N3O6.2H2O, (I), and 1,3,5-benzyloxy-1,3,5-triazinane-2,4,6-trione, C24H21N3O6, (II), there is no significant difference in the geometric parameters. In (I), there are 11 hydrogen bonds of the O-H...O type interconnecting the molecules in a three-dimensional network, while in (II) there are only two weak C-H...O hydrogen bonds. The results of IR spectroscopic analysis are in good agreement with the crystallographic study.