Utjecaj supstituenata na NMR značajke temeljnog bicikličkog prstenastog sustava fluorokinolonskih antibiotika, odnos između NMR kemijskih pomaka, molekulskih opisivača i parametara sličnosti s lijekovima

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. Relationship between 1H- and 13C-NMR chemical shifts of fluoronaphthyridone and fluoroquinolone ring systems and 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 lipophylicity (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 between 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 (, ppm H in COOH vs. TPSA, R = 0.9421; , ppm H in COOH vs. NRL-ls, R = 0.9216; , ppm H5 vs. miLogP, R = 0.9962; , ppm H5 vs. KI-ls, R = 0.9969; , 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 (, ppm C4 vs. TPSA, R = 0.9964; , ppm C4 vs. miLogP, R = 0.9487; , ppm C4 vs. Mr, R = 0.9629; , ppm C4 vs. KI-ls, R = 0.9461; , ppm C4 vs. NRL-ls, R = 0.9996; , ppm C5 vs. miLogP, R = 0.9994; , ppm C5 vs. KI-ls, R = 0.9990; , ppm C5 vs. NRL-ls, R = 0.9510; , ppm C11 vs. TPSA., R = 0.9958; , ppm C11 vs. NRL-ls, R = 0.9994 and , ppm C11 vs. KI-ls, R = 0.9481).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 istraži utjecaj supstituenata i tip 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 (, ppm) temeljnih prstenastih sustava korelirani su s izračunatim molekulskim opisivačima (relativnom molekulskom masom, Mr, topologijskom polarnom površinom, TPSA, lipofilnošću, miLogP i s 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 (/ppm) C4, C5 i C11 atoma i 1H-NMR kemijski pomaci (/ppm) 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 (/ppm) C4, C5 i C11 atoma i izračunatih parametara za sličnost s kinaza inhibitorom (KI-ls) i ligandom nuklearnog receptora (NRL-ls) pored kolinearnosti s TPSA, miLogP, Mr i V (C4 /ppm s TPSA, R = 0,9964; C4 /ppm s miLogP, R = 0,9487; C4 /ppm s Mr, R = 0,9629; C4 /ppm s V, R = 0,8547; C4 /ppm s KI-ls, R = 0,9461 i C4 /ppm s NRL-ls, R = 0,9996; C5 s miLogP, R = 0,9994; C5 s KI-ls, R = 0,9990 i C5 s NRL-ls, R = 0,9510; C11 s TPSA, R = 0,9958; C11 /ppm s KI-ls, R = 0,9481 i C11 /ppm s NRL-ls, R = 0,9994). 1H-NMR kemijski pomaci (/ppm) protona COOH, H5 i NHn+ pokazali su kolinearanost odnosa s TPSA i miLogP, te s izračunatim parametrima za sličnost s kinaza inhibitorom (KI-ls), ligandom nuklearnog receptora (NRL-ls) i GPCR ligandom (GPCRl-ls) (/ppm H u COOH s TPSA, R = 0,9421; /ppm H u COOH s NRL-ls, R = 0,9216; H5 /ppm s miLogP, R = 0,9962; /ppm H5 s KI-ls, R = 0,9969; /ppm NHn+ s TPSA, R = 0,9875; /ppm NHn+ s NRL-ls, R = 0,9948; /ppm NHn+ s GPCR ligandom, R = 0,9873). Rezultati istraživanja su pokazali razliku u eksperimentalnim i izračunatim parametrima za trovafloksacin mesilat u usporedbi s pefloksacin mesilatom i ciprofloksacin hidrokloridom, te je nađena značajna kolinearnost među ispitivanim parametrima ovih fluorokinolonskih antibiotika

Reactions with 1-Benzotriazolecarboxylic Acid Chloride. VIII. Synthesis of N-Hydroxyisocyanate Derivatives

1,3,5-Trihydroxy-1,3,5-triazine-2,4,6(1H,3H,5H)-trione (5), the trimer of hypothetical acid HO-N=C=O, was synthesized by hydrogenolysis of 1,3,5-tribenzyloxy-1,3,5-triazine-2,4,6(1H,3H,5H)-trione (4). Similarly, the 1-(N-hiydroxycarbamoyl)benzotriazole (6), as »solid HONCO donor«, was prepared by hydrogenolysis of its benzyl derivatives 2. Compound 4 was obtained by trimerization of intermediary N-benzyloxyisocyanate (3), which liberates in the thermal dis-sociation of 1-(N-benzyloxycarbamoyl)benzotriazole (2). In the reaction with 2-phenylethylamine, compound 6 gave N-hydroxy-N\u27-(2-phenylethyl)urea (7)

FT-IR i NMR spektroskopska istraživanja derivata salicilne kiseline. II. Usporedba 2-hidroksi- i 2,4- i 2,5-dihidroksi derivata

The 2,4- and 2,5-dihydroxybenzamides (8, 9) were synthesized from their corresponding methyl esters. The structures and the spectral properties of investigated salicylic acid (1), 2,4- and 2,5-dihydroxy benzoic acids (2, 3), their methyl esters (4-6) and amides (7-9) were analyzed by means of FT-IR and one- and two-dimensional homo- and heteronuclear 1H and 13C NMR spectroscopies. Comparison of FT-IR and NMR spectral data of investigated compounds showed that the spectral characteristics of 2,4-dihydroxy benzoic acid derivatives are more similar to those of 2-hydroxy benzoic acid (salicylic acid) derivatives than to those of 2,5-dihydroxy benzoic acid derivatives. The results suggest that the spatial orientation of amide protons in 2,4-dihydroxy benzamide resembles more that in salicylamide than that in 2,5-dihydroxy benzamide.Spektroskopska svojstva derivata salicilne kiseline i 2,4- i 2,5-dihidroksi derivata benzojeve kiseline (metilnih estera i amida), 1 do 9, analizirana su pomoću FT-IR te jedno- i dvodimenzijske homo- i heteronuklearne 1H i 13C NMR spektroskopije. Dobiveni rezultati pokazuju da su FT-IR i NMR spektralne karakteristike derivata 2,4-dihidroksi-benzojeve kiseline (2,5,9) sličnije karakteristikama derivata salicilne kiseline (1,4,7) nego derivata 2,5-dihidroksi-benzojeve kiseline (3,6,9). Rezultati istraživaja ukazuju da je prostorna orijentacija amidnih protona 2,4-dihidroksibenzamida (8) sličnija orijentaciji amidnih protona salicilamida (7) nego 2,5-dihidroksibenzamida (9)

FT-IR i NMR spektroskopska istraživanja derivata salicilne kiseline. II. Usporedba 2-hidroksi- i 2,4- i 2,5-dihidroksi derivata

The 2,4- and 2,5-dihydroxybenzamides (8, 9) were synthesized from their corresponding methyl esters. The structures and the spectral properties of investigated salicylic acid (1), 2,4- and 2,5-dihydroxy benzoic acids (2, 3), their methyl esters (4-6) and amides (7-9) were analyzed by means of FT-IR and one- and two-dimensional homo- and heteronuclear 1H and 13C NMR spectroscopies. Comparison of FT-IR and NMR spectral data of investigated compounds showed that the spectral characteristics of 2,4-dihydroxy benzoic acid derivatives are more similar to those of 2-hydroxy benzoic acid (salicylic acid) derivatives than to those of 2,5-dihydroxy benzoic acid derivatives. The results suggest that the spatial orientation of amide protons in 2,4-dihydroxy benzamide resembles more that in salicylamide than that in 2,5-dihydroxy benzamide.Spektroskopska svojstva derivata salicilne kiseline i 2,4- i 2,5-dihidroksi derivata benzojeve kiseline (metilnih estera i amida), 1 do 9, analizirana su pomoću FT-IR te jedno- i dvodimenzijske homo- i heteronuklearne 1H i 13C NMR spektroskopije. Dobiveni rezultati pokazuju da su FT-IR i NMR spektralne karakteristike derivata 2,4-dihidroksi-benzojeve kiseline (2,5,9) sličnije karakteristikama derivata salicilne kiseline (1,4,7) nego derivata 2,5-dihidroksi-benzojeve kiseline (3,6,9). Rezultati istraživaja ukazuju da je prostorna orijentacija amidnih protona 2,4-dihidroksibenzamida (8) sličnija orijentaciji amidnih protona salicilamida (7) nego 2,5-dihidroksibenzamida (9)

Chemistry of 1,3-Dioxepins. XII.\u27 4,7-Dihydro-5-nitro-1,3-dioxepins in the Diels-Alder Reaction with 4-Methyloxazole

4,7-Dihydro-5-nitro-l,3-dioxepins 4\u27 prepared by dehydrohalogenation of vic-chloronitro-dioxepanes 2 and/or dehydrohalogenationdemercuration of vic-chloromercurynitro-dioxepanes 3 represent reactive dienophiles in the Diels-Alder cycloaddition with 4-methyloxazole (5), giving pyridoxine (8) intermediates 1,5-dihydro-9-hydroxy- 8-methyl-3H-[1,3]dioxepino[5,6-c]pyridines 6 in poor yields. The side products of this reaction were 4,7-dihydro-4-hydroxyimino- 6-nitro-l,3-dioxepins 7, the structure of which was confirmed by parallel synthesis, i.e. by nitrosation of 4 with ethyl nitrite. The order of reactivity in the series of 5-substituted-4, 7-dihydro- 1,3-dioxepins, calculated by AMI semiempirical method, is predicted to be 5-nitro- > 5-unsubstituted- > 5-cyano- > 5-chloro-4,7-dihydro- 1,3-dioxepin, and it is in agreement with experimental data

FT-IR i NMR spektroskopska istraživanja derivata salicilne kiselina. I. Gentizinamid- metabolit salicilamida

Gentisamide (GAM, 2,5-dihydroxybenzamide), a minor first-pass metabolite of salicylamide (SAM, 2-hydroxybenzamide), was studied using FT-IR, 1D and 2D homo- and heteronuclear 1H and 13C NMR spectroscopy. GAM was isolated from human urine eight hours after oral administration of SAM. FT-IR, 1H and 13C NMR spectra unequivocally confirmed the chemical structure of GAM through chemical and substituent shifts, coupling constants and connectivities in COSY, NOESY, HETCOR and HBMC spectra. From NOESY spectra of GAM in DMSO-d6, it was concluded that the amide protons are oriented toward the ortho-proton at C-6. Obtained results indicate that the presence of the additional phenol group at C-5 in GAM favours the formation of intramolecular hydrogen bonding of the O…HO type between C2-OH proton and oxygen atom of the amide group.Gentizinamid (GAM), metabolit prvog prolaska salicilamida (SAM), analiziran je uporabom FT-IR, te jednodimenzijskom i dvodimenzijskom homo- i heteronuklearnom 1H i 13C NMR spektroskopijom. GAM je izoliran iz ljudskog urina osam sati nakon oralne primjene SAM-a, a strukturna analiza provedena je pomoću FT-IR, 1H i 13C NMR uporabom kemijskih i supstituentnih pomaka, konstanti spin-spin sprege, te povezanosti u COSY, NOESY, HETCOR i HBMC spektrima. Iz NOESY spektra DMSO-d zaključeno je da su protoni amidne skupine gentizinamida usmjereni prema orto-protonu na C-6 položaju. Rezultati ukazuju na to da prisustvo dodatne fenolne skupine C5-OH u GAM favorizira stvaranje intramolekulske vodikove veze O...HO tipa između C2-OH protona i kisika amidne skupine

Chemistry of 1,3-Dioxepins. XIII. (E)/(Z) Configurational Assignment of 4,7-Dihydro-4-hydroxyimino-6-nitro-1,3-dioxepins

The configuration of oximes 1a and 1b was investigated by chemical and spectroscopic methods. Under the Beckmann rearrangement conditions, using sulfonyl chlorides as reagents, the sulfonic esters 2a-c were obtained. Under more drastic conditions, using PCl5 or P2O5, the only isolated product was 4-nitro-5H-furan-2-on (3). It was also formed as the sole product by hydrolysis of oximes 1a-b, as well as sulfonic ester 2a. The structure of all compounds was determined by one- and twodimensional homo- and hetero-nuclear 1H and 13C NMR correlated spectra: COSY, NOESY, HETCOR and HMBC. Gradient selected differential NOE measurements confirmed that, in dimethylsulfoxide solution, oximes 1a and 1b exist in E-configuration, irrespective of the route of their formation

The Novel Ketoprofenamides: Synthesis and Spectroscopic Characterization

Synthesis of a series of new ketoprofenamides (3a-h) is described. Amide formation was achieved by aminolysis of ketoprofen benzotriazolide (2) with various amines: primary, secondary, hydroxylamine and amino acid β-alanine. The structures of synthesized compounds were characterized by means of IR, 1H and 13C NMR spectroscopies and elemental analysis. The synthesized compounds are potential prodrugs of a well-known NSAID ketoprofen