György Szász

Lipophilicity of antibacterial fluoroquinolones

Abstract The octanol/water partition coefficients of nine antibacterial fluoroquinolones and nalidixic and oxolinic acids were investigated. The pH-partition profile of amphoteric fluoroquinolones obtained between pH 4 and 10 showed maximum partitioning at the isoelectric point. From the two microspecies (zwitterionic and nonionic forms) which exist predominantly at this pH, the nonionic form is assumed to be transferred into the octanol phase. A relationship is derived between the apparent and true partition coefficients, valid for ampholyte compounds capable of forming zwitterions and having nonionic microspecies present in significant amounts. On the bases of true partition coefficients, three groups of examined fluoroquinolones are distinguished: lipophilic compounds (e.g., pefloxacin and amifloxacin), molecules of intermediate lipophilicity (such as ciprofloxacin and ofloxacin, etc.) and hydrophilic derivatives (e.g., norfloxacin and lomefloxacin, etc.). The influence of structural modification on the lipophilicity of these drugs is discussed.

Lipophilicity of amphoteric molecules expressed by the true partition coefficient

The octanol/water partition coefficients of six amphoteric drugs were investigated. Nitrazepam, albendazole and sulfadimidine are ordinary ampholytes, while pyridoxine, niflumic acid and terbutaline belong to the zwitterionic amphoteric compounds. The pH-partition profile of compounds showed maximum (parabolic) curve. Analyses of the UV spectra in aqueous and octanol phases at different pH values after partitioning equilibrium had been achieved proved the transfer of the neutral species into the octanol phase. The true partition coefficients were calculated from log Papp values using macroprotonation constants for ordinary ampholytes and microprotonation constants in the case of zwitterionic molecules. The results emphasize that only the true partition coefficient closely represents the intrinsic lipophilicity of zwitterionic amphoteric compounds.

Determination of protonation macro- and microconstants and octanol/water partition coefficient of the antiinflammatory drug niflumic acid

The drug niflumic acid is an amphoteric substance with overlapping pKa values. The acid-base chemistry of the molecule has been characterized in terms of protonation macroconstants (with reference to stoichiometric ionizations) and microconstants (with reference to ionizations of individual species). The proton-binding sites were assigned using 1H and 13C NMR spectroscopy. Due to the very poor water solubility of niflumic acid, the aqueous pKa values were determined from the apparent ionization constants in methanol-water solutions of various proportions by extrapolation to zero co-solvent using the Yasuda-Shedlovsky procedure. The kz tautomerization microconstant of the equilibrium unionized form<-->zwitterionic form was determined from mixtures of organic solvent (dioxane or methanol) with aqueous buffer (at the pH of isoelectric point) by UV spectroscopy, and used for calculation of the other protonation microconstants. The zwitterionic form of the molecule predominates over the uncharged form, the concentration being maximal at the isoelectric pH. The apparent partition coefficients (Papp) of niflumic acid were measured in octanol/water solution by the shake-flask method over a wide pH range. The lipophilicity profile (logPapp vs pH) shows a parabolic shape near its maximum at the isoelectric point. A relationship derived between Papp, PXH0(micropartition coefficient of the uncharged microspecies) and PX-(partition coefficient of the anion) is valid for amphoteric drugs, in cases where the partition of the unionized form and the ion-pair partition of anion can be confirmed. The logP values of microspecies indicate the high lipophilicity of niflumic acid, which is consistent with its good skin penetration and absorption.

Ion-pair partition of quaternary ammonium drugs: The influence of counter ions of different lipophilicity, size, and flexibility

AbstractPurpose. The ion-pair partition of quaternary ammonium (QA) pharmacons with organic counter ions of different lipophilicity, size, shape and flexibility was studied to elucidate relationships between ion-pair formation and chemical structure. Methods. The apparent partition coefficient (P′) of 4 QAs was measured in octanol/pH 7.4 phosphate buffer system by the shake-flask method as a function of molar excess of ten counter ions (Y), namely: mesylate (MES), acetate (AC), pyruvate (PYRU), nicotinate (NIC), hydrogenfumarate (HFUM), hydrogenmaleate (HMAL), p-toluenesulfonate (PTS), caproate (CPR), deoxycholate (DOC) and prostaglandin E1 anion (PGE1). Results. Based on 118 of highly precise logP′ values (SD< 0.05), the intrinsic lipophilicity (without external counter ions) and the ion-pair partition of QAs (with different counter ions) were characterized. Linear correlation was found between the logP′ of ion-pairs and the size of the counter ions described by the solvent accessible surface area (SASA). The lipophilicity increasing effect of the counter ions were quantified and the following order was established: DOC ~ PGE1≫ CPR ~ PTS ≫ NIC ~ HMAL ≫ PYRU ~ AC ~ MES ~ HFUM. Analyzing the lipophilicity/molar ratio (QA:Y) profile, the differences in the ion-pair formation were shown and attributed to the differences in the flexibility/rigidity and size both of QA and Y. Conclusions. Since the largest (in average, 300 ×) lipophilicity enhancement was found by the influence of DOC and PGE1 and considerable (on average 40×) increase was observed by CPR and PTS, it was concluded that bile acids and prostaglandin anions may play a significant role in the ion-pair transport of quaternary ammonium drugs and caproic acid and p-toluenesulfonic acid may be useful salt forming agents to improve the pharmacokinetics of hydrophilic drugs.

Acid-base properties and proton-speciation of vancomycin

Abstract The protonation-deprotonation equilibria of the glycopolypeptide antibiotic vancomycin are characterized in terms of protonation macroconstants, isoelectric point and diagram of pH-dependent species distribution. Vancomycin contains two basic and four acidic groups. Of these, dissociation of the C-terminal carboxyl group takes place separately at low pH, whereas proton binding of the two amino sites and deprotonation of the three phenolic hydroxyl groups occur between pH 5 and 13, in a highly overlapping fashion. Our study indicates for an isoelectric point of 8.30 the vancomycin molecule and an average charge of + 0.67, with the predominant existence of penta- and tetraprotonated species at physiological pH.

Nitrogen bridgehead compounds part 16. Facile total synthesis of 7,8-dihydro-13H-indolo[2′,3′:3,4]pyrido[2,1-b]quinazolin-5-one (Rutecarpine).☆

Rutecarpine 1 has been synthetised from hydrazone 2, in high yield by Fischer indole synthesis, Hydrazone 2 has been prepared from 3 with benzenediazonium chloride or 5 with phenylhydrazine. 2 Shows a solvent dependent E-Z isomerism.

An alternative total synthesis of rutaecarpine and vasicolinone alkaloids

Abstract Rutaecarpine ( 6 ) and vasicolinone ( 9 ) alkaloids were alternatively prepared by Fischer indolization of 3-(phenylhydrazonomethyl)pyrroloquinazoline ( 4 ) under thermal and acidic conditions, respectively.

Syntheses of indolyl-4(3H)-quinazolinones

2-(1H-Indol-2-yl)-4(3H)-quinazolinones (10, 11) and 2-(2-ethoxy-carbo- nyl-1H-indol-3-yl)-4(3H)-quinazolin-4-one (15) are prepared by the Fis- cher indolization of 2-(1-phenylhydrazonoalkyl)- (8, 9) and 2-(2-phenyl- hydrazono-2-ethoxycarbonylethyl)-4(3H)-quinazolinones (14), respecti- vely, by heating in PPA. When 2-phenylhydrazone derivative (14) is hea- ted in 85% phosphoric acid at 180°C, besides indolization ester hydro lysis and decarboxylation also occurred to yield 2-(1H-indol-3-yl)-4(3H) -quinazolinone (16). The 3-(1H-indol-3-yl)-4(3H)-quinazolinone (24) is prepared either from the isomeric 3-indolyl derivatives of anthranila- mide (21, 23) by heating in 98% formic acid, or in «one pot» procedure from 2-[1-(N-methyl-N-phenylamino)ethyl]-4(3H)-quinazolinone (17) by heating in 98% formic acid in the presence of a few drops of conc. hy- drochloric acid. The reaction mechanism is discussed

Acid‐base Properties of Terbutaline in Terms of Protonation Macro‐ and Microconstants

The acid/base chemistry of terbutaline was characterized at the molecular level in terms of protonation macroconstants and microconstants. The macroconstants were measured by potentiometry and calculated by standard evaluation methods.

Nitrogen bridgehead compounds. Part 45 [1]. Synthesis of 6-arylhydrazono-6,7,8,9-tetrahydro-11H-pyrido-[2,1-b]quinazolin-11-ones

Die Herstellung zahlreicher 6-Arylhydrazono-6,7,8,9-tetrahydro-11H-pyrido[2,1-b]chinazolin-11-one der allgemeinen Formel (III) erfolgt nach verschiedenen Wegen.