ABSTRACT
Four macrolides-6-O-methyl-8a-aza-8a-homoerythromycin, clarithromycin, azithromycin and azithromycin 11,12-cyclic carbonate, have been selected for the construction of a series of new quinolone derivatives. The quinolone moiety is connected to the macrolide scaffold via a diaminoaklyl 4''-O-propionyl ester chain of varying length. At the terminus the linker is attached via one of the nitrogen atoms in the linker at C(6) or C(7) of the quinolone. Many of compounds described, particularly clarithromycin derivative 37, and azithromycin derivatives 48 and 55, exhibited excellent antibacterial activity against a wide range of clinically relevant macrolide-resistant organisms, with profiles superior to that of telithromycin, an enhanced spectrum ketolide.
Subject(s)
Anti-Bacterial Agents/pharmacology , Macrolides/chemistry , Macrolides/pharmacology , Anti-Bacterial Agents/chemistry , Bacterial Infections/drug therapy , Bacterial Infections/microbiology , Drug Resistance, Bacterial , Erythromycin/chemistry , Erythromycin/pharmacology , Humans , Microbial Sensitivity Tests , Propionates/chemistryABSTRACT
Anthryl-phenyl, phenanthryl-phenyl, and naphthyl-phenyl trans-epoxides (1, 2, and 3, respectively) having enantiomeric purities of 95%, 99%, and 96% were synthesized from a diastereo and enantiopure sulfonium salt derived from Eliel's oxathiane. The determination of their (1R,2R) absolute configurations was achieved by application of the CD exciton chirality method using a Zn-porphyrin tweezer on the corresponding alcohols obtained after opening of these epoxides with LiAlH(4). The R-configuration at C2 of these epoxides, (-)-1, (+)-2, and (-)-3, is consistent with our previous results concerning asymmetric synthesis of monoaryl epoxides, cyclopropanes, and aziridines. The (1S,2R)-configuration of the cis isomer (when present) was also confirmed. Moreover, the agreement between the negative exciton chirality for conjugates of (S)-configuration predicted by molecular modeling and the observed CD spectra helps to clarify the relative steric size of phenyl and CH(2)-aryl (phenanthryl or anthryl), which is critical when the tweezer method is applied for absolute configurational assignment (phenyl = medium group; anthacenyl CH(2) and phenanthryl CH(2) = large group).
Subject(s)
Epoxy Compounds/chemistry , Epoxy Compounds/chemical synthesis , Amino Alcohols/chemical synthesis , Amino Alcohols/chemistry , Methods , Models, Molecular , Nuclear Magnetic Resonance, Biomolecular , StereoisomerismABSTRACT
New brush-type chiral stationary phases (CSP I-IV) comprising N-3,5,6-trichloro-2,4-dicyanophenyl-L-alpha-amino acids (1-4) were prepared by binding of chiral selectors 1-4 to gamma-aminopropyl silica gel. To check the role of excess free aminopropyl groups, CSP V was prepared by binding N-3,5,6-trichloro-2,4-dicyanophenyl-L-alanyl-(3-triethoxysilyl)propylamide to unmodified silica gel. The best separation of racemic 2-aryloxypropionic acids (TR-1-13) was obtained with CSP I; the -(-)-S enantiomer were regularly eluted first, as determined by a CD detector. The mechanism of chiral recognition implies a synergistic interaction of carboxylic acid analyte with the chiral selector and achiral free gamma-aminopropyl units on silica. In fact, CSP V, which is lacking an achiral aminopropyl spacer, shows a lower separation ability for 2-aryloxypropionic acids, but a similar enantioselective discrimination of esters TR-19-20, in comparison with CSP I. CSP I-IV retain unaltered separation ability after a few months of continuous work using a large number of various mobile phases.
Subject(s)
Phenyl Ethers/chemistry , Propionates/chemistry , Chromatography, High Pressure Liquid , Circular Dichroism , Indicators and Reagents , Spectrophotometry, Ultraviolet , StereoisomerismABSTRACT
In a series of four racemic phenoxyalkyl-alkyl carbinols, 1-phenoxy-2-hydroxybutane (1) is enantioselectively acetylated by Burkholderia cepacia (formerly Pseudomonas cepacia) lipase with an E value > or = 200, whereas for the other three racemates E was found to be < or = 4. To explain the high preference of B. cepacia lipase for (R)-(+)-1, a precursor of its transition state analogue with a tetrahedral P-atom, (R(P),S(P))-O-(2R)-(1-phenoxybut-2-yl)methylphosphonic acid chloride was prepared and crystallized in complex with B. cepacia lipase. The X-ray structure of the complex was determined, allowing to compare the conformation of the inhibitor with results of molecular modelling.
Subject(s)
Burkholderia cepacia/enzymology , Lipase/chemistry , Organophosphorus Compounds/metabolism , Catalysis , Crystallography, X-Ray , Hydrogen Bonding , Lipase/antagonists & inhibitors , Lipase/metabolism , Models, Molecular , Stereoisomerism , Substrate SpecificityABSTRACT
Two new chiral stationary phases, 3-[5-chloro-1,3-dicyano-2,4-[2'-(N'-1,3-dinitrobenzoyl-D-phenylglycinyl) aminoethyl]aminophen-1-yl] aminopropyl silica (CSP-1) and 3-[5-chloro-1,3-dicyano-2,4-[2'-(N'-1,3-dinitrobenzoyl-L-leucinyl) aminoethyl] aminophen-1-yl] aminopropyl silica (CSP-2), were prepared by solid-phase synthesis. They comprise chiral unit, 3,5-dinitrobenzoyl derivative of the amino acid, D-PhGly or L-Leu, bound via spacer 1,2-diaminoethane to 2,4-positions of the persubstituted benzene ring, derived from compound 1, and possess pseudo-C2 symmetry. Preparation of model compounds 6 and 7 confirmed the structure of chiral selectors, which comprise pi-donor persubsituted aromatic ring and two strong pi-acceptor 3,5-dinitrobenzoyl amido units. CD spectra of model selectors 6 and 7, run in DMSO above 250 nm, exhibit negative exciton coupling (EC) between pi-acceptor and pi-donor chromophores, C(1) symmetric model compound 8 exhibited much weaker EC and 9, devoid of pi-donor unit, does not exhibit any significant CD. Combined pi-donor and pi-acceptor properties enable the new CSPs to separate a broad range of racemates. The columns with CSP-1 and CSP-2 were tested for the separation of 22 racemates by HPLC with two different mobile phase systems and the results are compared with those obtained by using a structurally related commercial column.
ABSTRACT
Regioselective functionalization of 2,4,5,6-tetrachloro-1, 3-dicyanobenzene (TCDCB) by nucleophilic substitution of the chlorine at C(4) with L-Ala, L-Phe or L-Pro, followed by amide-bond formation to lipophilic amines containing strong pi-donor group, and by final introduction of the spacer 3-aminopropyltriethoxysilyl (APTES), provided a number of new brush-type chiral selectors in the form of 1-2:1 mixture of 2,4 and 4,6-di(alkyl)amino regioisomers (8/9, 10/11, 12/13, 14/15, 20/21, 23/24). Linking these to silica gel (Nucleosil 100-5) gave new chiral stationary phases for HPLC columns (CSP I-CSP VI). Being strong pi-basic selectors, most of these columns exhibited good resolution properties for pi-acid test racemates (TR 1-TR 9), specifically rac 3, 5-dinitrobenzoyl-alpha-amino acid isopropyl-esters (DNB-AA). CSP V [1,3-dicyano-2,5(5,6)-dichloro-6(2)-(gamma'-silica bound propylamino)-4-N-¿[N-butyl]-N'-[(1R)-cyclohexylethyl]-N'-[napht hylmet hyl]acetamido¿-aminobenzene] and particularly the dipeptide-containing CSP VI [2,5(5,6)-dichloro-6(2)-(gamma'-silica bound propylamino)-4-N-(3', 5'-dimethylanilido)-L-alanyl-L-prolyl-aminobenzene] proved to have the highest efficiency, comparable with the best commercial brush-type columns with pi-donor properties. Further evidence revealed that multiple hydrogen bonding via the amide group in the chiral environment and pi-pi interaction play a major role in chiral recognition, whereas steric perturbations via nonbonding VDW interactions contribute substantially only to the resolution of CSP III [2,5(5,6)-dichloro-6(2)-(gamma'-silica bound propylamino)-4-N-(cyclohexylamido)-L-alanyl-aminobenzene]. This contribution is minor for the other CSPs.
Subject(s)
Cyanides/chemistry , Evaluation Studies as Topic , Magnetic Resonance Spectroscopy , Spectrophotometry, Infrared , StereoisomerismABSTRACT
Novel chiral selectors 3-5 were prepared by regioselective nucleophilic substitution of 2,4,5,6-tetrachlorobenzene-1,3-dicarbonitrile (TCBDC, 1) at C(4) by (1R,2R)-trans-diaminocyclohexane, followed by acylation of the intermediary 2 with carboxylic acids containing pi-acid or pi-basic unit. On substitution of the second chlorine atom by the spacer 3-aminopropyltriethoxysilane (APTES), a 1:1 mixture of regioisomers of N-(([3, 6-dichloro-2,4-dicyano-5-(4,4,4-triethoxy-4-silabutyl)-amino]phenyl)amino) cyclo-hexylcarboxamides and N-(5,6-dichloro-2,4-dicyano-3-(4,4,4-triethoxy-4-silabutyl)-amino]pheny) amino)cyclohexylcarboxamides (6/7, 8/9, 10/11) was obtained. Their covalent binding to Nucleosil 100-5 provided three new chiral stationary phases (CSP-1-CSP-3). NMR spectra of model compounds 12-14 and MM2 calculations on model compounds 15,16 revealed pi-pi interactions between persubstituted benzene ring and second aromatic ring. The results of the evaluation of new CSPs in the separation of 23 test racemates by HPLC are reported. CSP-2 and CSP-3, that have lower conformational freedom than CSP-1, allow for better separation. In particular, good results are obtained in the separation of some 1,4-benzodiazepines and open-chain aromatic amides by CSP-2 and CSP-3.
ABSTRACT
Chiral functionalization of 2,4,5,6-tetrachloro-1,3-dicyanobenzene (1) by regioselective nucleophilic substitution of one or two chlorine atoms by optically pure (R)-(+)-1-naphthylethylamine (NEA), or by a glycine unit as a spacer to (R)-NEA, enables the preparation of brush-type chiral selectors (2, 3, 9, 13). By the introduction of the 3-aminopropyltriethoxysilyl (APTES) group, reactive intermediates 4a/b, 5, 10a/b, and 14a/b are obtained (a/b indicate a mixture of regioisomers with APTES in 6- and 2-position). Binding of these to silica gel afforded four novel chiral stationary phases (CSPs) 6, 7, 15, and 16. HPLC columns containing CSPs with (R)-NEA directly linked to polysubstituted aromatic ring (6, 7) are not very effective in resolution of most of the 23 racemic analytes, whereas the columns with distant pi-basic subunits (15, 16) exhibited higher resolving efficacy, in particular towards the isopropyl esters of racemic N-3,5-dinitrobenzoyl-alpha-amino acids. Effective resolution of test racemates reveals the importance of the presence of the hydrogen bond donor amido group and the distance between the persubstituted benzene ring in 1 and the pi-basic naphthalene ring of (R)-NEA. Copyright 1999 Wiley-Liss, Inc.
ABSTRACT
By combining the gel filtration and circular dichroism (CD) methods in studying the binding of chiral (S)/(R)-(I) to human serum albumin (HSA) the following results were obtained: HSA affinity for (S)-(I) is about 17 times higher than for (R)-(I); there exist two independent and nonequivalent binding sites for (S)-(I), and one site of lower affinity for (R)-(I); at equimolar concentrations of (I) and HSA, (S)-enantiomer is bound up to 45%, but (R)-enantiomer binds up to 22% only; differential CD-spectra at various concentrations, in the presence of HSA at 1.45 X 10(-5) M concentration, reveals distortions of the chromophoric system i.e. of the conformation of (S)-(I). This effect, and the low affinity of both enantiomers for HSA, allows only a qualitative interpretation of CD-data.
Subject(s)
Benzodiazepines/metabolism , Serum Albumin/metabolism , Benzodiazepines/blood , Chemical Phenomena , Chemistry, Physical , Chromatography, Gel , Circular Dichroism , Humans , Protein Binding , Receptors, GABA-A/metabolism , Spectrophotometry, Ultraviolet , StereoisomerismABSTRACT
The synthesis of 11-acyl-5,11-dihydro-6H-pyrido [2,3-b]-[1,4] benzodiazepin-6-ones (III), (V-IX), is described as well as their spectroscopic characteristics, dipole moments and partition coefficients. The same properties are determined for their N-oxide analogues (X) and (XI), while pharmacological data for some of the above compounds are compared with those of pirenzepin (I), a well known antiulcer drug.
Subject(s)
Anti-Ulcer Agents/chemical synthesis , Benzodiazepinones/chemical synthesis , Acetylcholine/antagonists & inhibitors , Animals , Benzodiazepinones/pharmacology , Chemical Phenomena , Chemistry, Physical , Gastric Acid/metabolism , Guinea Pigs , In Vitro Techniques , Lethal Dose 50 , Mice , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Rats , Structure-Activity RelationshipABSTRACT
Starting from 3-hydroxy-1,4-benzodiazepin-2-ones 1--3, via 3-chloro derivatives 4--6, 13 new C(3)-substituted 1,4-benzodiazepin-2-ones were synthesized. Reaction of 4--6 with ethylene glycol yielded 3-(beta-hydroxyethyl) derivatives 7--9. Similar reaction with the isopropylidene derivative of glycerol afforded 10--12, which on hydrolysis of the isopropylidene group hielded glycerol derivatives 13--15. Reaction of trichloroacetyl chloride with oxazepam and temazepam yielded the corresponding trichloroacetyl esters 16 and 17. The beta-hydroxyethyl derivative 7 was conjugated with an acetylated glucopyranose derivative to give isomeric 18 and 19. Partition coefficients (log Poct) and central nervous system activities (in six stranded tests) were determined for 7--15 as well as several standard compounds. Most of the compounds exhibiting beneficial central nervous system activity had Poct values between 1.71 and 2.48. No correlation between lipophilicity and central nervous system activity could be discerned for these compounds.
Subject(s)
Benzodiazepinones/chemical synthesis , Central Nervous System/drug effects , Animals , Benzodiazepinones/pharmacology , Esters/chemical synthesis , Ethers/chemical synthesis , Female , Male , Mice , SolubilityABSTRACT
Cyclisation rates of some S-alpha-amino acid derivatives (I--VII) into chiral 1,4-benzodiazepin-2-ones were determined under physiological-like conditions (pH, temperature) and plotted against pKa values of the corresponding alpha-amino acids. No correlation between k, i.e. t1/2 values, of the acidic precursors, and pharmacodynamic activity, as determined by some standard tests, were observed, however. Unambiguity of cyclisation, and its t1/2 values reveal benefit for physico-chemical properties of the investigated acyclic precursors as transport-forms of the chiral 1,4-benzodiazepin-2-ones with prolonged pharmacological activity.