ABSTRACT
Novel hydroxypyrazoline derivatives of tetracycline and minocycline have been synthesized through the reaction of these tetracyclines with hydrazine. The formation of a new chiral center at C12 is stereospecific to give 12S-12-hydroxy-1,12-pyrazolinotetracycline. A reaction mechanism for the formation of these novel tetracycline derivatives has been proposed. Hydroxypyrazolinotetracyclines exhibit no binding to Mg2+ and Zn2+, features that are required for antibiotic activity and matrix metalloproteinase (MMP) inhibitions, respectively. The modification toward their hydroxypyrazolino derivatives significantly improved the antioxidant activities of tetracycline and minocycline, as shown by three commonly used assays (DPPH, ABTS+, and superoxide scavenging). 12S-Hydroxy-1,12-pyrazolinominocycline is a promising tetracycline-based antioxidant devoid of antibiotic properties and MMP inhibitory activity, which could be beneficial in the treatment of complications related to oxidative stress.
Subject(s)
Antioxidants/chemistry , Antioxidants/pharmacology , Tetracyclines/chemistry , Tetracyclines/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Antioxidants/chemical synthesis , Antioxidants/metabolism , Crystallization , Escherichia coli/drug effects , Hydroxylation , Molecular Structure , Pyrazoles/chemistry , Spectrum Analysis , Structure-Activity Relationship , Tetracyclines/chemical synthesis , Tetracyclines/metabolism , Zinc/metabolismABSTRACT
Brucinium L-glycerate 4.75-hydrate, C23H27N2O4+.C3H5O4-.4.75H2O, was obtained by racemic resolution of DL-glyceric acid. This is the first report of triclinic crystals containing brucine. The water and L-glycerate anions form tapes built up of pentamers formed by water and carboxy O atoms, and this appears to be the reason for the low symmetry of the crystal.
ABSTRACT
The crystal structure of the title compound, K+.C6H4NO6S-, is built up from p-nitrophenyl sulfate anions and potassium cations. Adjacent anions form dimers, which are linked together in a three-dimensional network via short C-H...O contacts. The coordination sphere of the K+ ions may be described as a distorted square antiprism. The crystal structure is further stabilized by pi-pi stacking interactions between the aryl rings.
Subject(s)
Nitrobenzenes/chemistry , Crystallography, X-Ray , Molecular StructureABSTRACT
The core or the building block is an important component in drug development. In this article, we propose and review p-aminobenzoic acid (PABA) as a building block used in the design of drugs or drug candidates. PABA is frequently found as a structure moiety in drugs. For example, in a database of 12,111 commercial drugs, 1.5% (184 drugs) were found to contain the PABA moiety. These drugs have a wide range of therapeutic uses, such as: sun-screening, antibacterial, antineoplastic, local anesthetic, anticonvulsant, anti-arrhythmic, anti-emetic, gastrokinetic, antipsychotic, neuroleptic, and migraine prophylactic. This article reviews the molecular targets and the mechanisms of these activities. Drugs containing PABA also show a wide range of structural diversity. Of the 184 PABA containing drugs identified, 95 different substitutions were found at the carboxylic group and 61 were found at the amino group of the building block. Substitution on the aromatic ring was also diverse. 13, 3, and 13 different side chains were found to modify positions 2, 3 and 5 of the aromatic ring respectively. In some drugs, the amino group is further substituted to form tertiary amine (4 different side chains). Substitutions at the carboxyl and amino groups of PABA are particularly suitable for the generation of combinatorial libraries. Just by reshuffling the identified side chains of the 184 PABA containing drugs, 4.5 million compounds can be generated. Consequently, PABA fits well as a building block for a general chemical library of "drug-like" molecules with a wide range of functional and structural diversity.
Subject(s)
4-Aminobenzoic Acid/chemistry , 4-Aminobenzoic Acid/pharmacology , 4-Aminobenzoic Acid/metabolism , Alkylating Agents/chemical synthesis , Alkylating Agents/pharmacology , Animals , Chemical Phenomena , Chemistry, Physical , Combinatorial Chemistry Techniques , Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Folic Acid Antagonists/chemical synthesis , Folic Acid Antagonists/pharmacology , Humans , Ion Channels/drug effects , Receptors, Neurotransmitter/drug effectsABSTRACT
2,3:4,5-Di-O-isopropylidene-beta-D-fructopyranose 1-sulfate have been synthesized by treatment of 2,3:4,5-di-O-isopropylidene-beta-D-fructopyranose with pyridine-sulfur trioxide complex. Direct hydrolysis of the isopropylidene group at C-4, C-5 gave 2,3-O-isopropylidene-beta-D-fructopyranose 1-sulfate. The crystal and molecular structures of ammonium (1a) and potassium (1b) salts of diisopropylidene derivative and ammonium (2) salt of monoisopropylidene derivative were determined by X-ray crystallography. Data for 1a and 1b were collected in 120 K and in 150 K for 2. All salts crystallized in P2(1)2(1)2(1) space group. There are three independent anions in asymmetric unit in 1b. Pyranose rings in the diisopropylidene derivative salts studied adopt 2S(0) twist boat conformation, whereas in the monoisopropylidene exists in a slightly distorted chair conformation (4C(1)). A staggered conformation is preferred by the sulfate group as indicated by values of C-(ester)-S-O(terminal) torsion angles: -173.2(4) degrees in 1a, 175.1(6) degrees in anion A of 1b, 170.8(6) degrees in anion C of 1b and 177.9(2) degrees in 2. However, strong interactions such as potassium-oxygen and H-bonds may affect the geometry: in anion B of 1b the value of the torsion angle is 139.4(6) degrees.
