Małgorzata Szczesio

Design, synthesis, and anticonvulsant activity of new N-Mannich bases derived from spirosuccinimides and spirohydantoins.

The synthesis and anticonvulsant properties of new N-Mannich bases of [7,8-f]benzo-2-aza-spiro[4.5]decane-1,3-diones (5a-h) and [7,8-f]benzo-1,3-diaza-spiro[4.5]decane-2,4-diones (7a-h) were described. Initial anticonvulsant screening was performed using intraperitoneal (ip) maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizures tests. The neurotoxicity was determined applying the rotarod test. The majority of compounds were effective in the MES or/and scPTZ screen. The quantitative studies showed that several molecules were more potent than phenytoin, used as reference drug. Selected derivatives were screened in the 6-Hz test and also assessed for potential activity against nerve agents using the Pilocarpine Induced Status Prevention model. To explain the possible mechanism of anticonvulsant action, for chosen active derivatives, their influence on voltage-dependent Na(+) channel were tested in vitro.

Intramolecular hydrogen bond between 4-oxo and 3-carboxylic groups in quinolones and their analogs. Crystal structures of 7-methyl- and 6-fluoro-1,4-dihydro-4-oxocinnoline-3-carboxylic acids

Abstract Crystal structures of two cinnoline analogs of quinolones and statistics on quinolones molecular forms observed in the crystal state have been determined. It has been shown that common quinolones may be divided into two main types, depending on presence of proton acceptor, usually aliphatic amine group, capable of protonation under mild conditions. Quinolones lacking amine group or having one(s) bound to an aromatic system exist at physiological pH mainly in a free acid form, in which acidic hydrogen atom is locked into an intramolecular hydrogen bond. The phenomenon enhances permeability of quinolones through lipophilic cell membranes but decreases the concentration of carboxylate form capable of specific binding with bacterial DNA. Molecular (neutral) form was observed exclusively in the crystalline state for these quinolones. The dominant forms seem different for quinolones having amine substituents with unconjugated lone pair electrons at N atom. Even in the crystalline state, they may exist also in a zwitterionic form, which was found to dominate in secondary amines crystallised at neutral pH. Our limited data suggest that position and order of amine group may play important role in controlling quinolones absorption, transport and concentration and thus their biological profile.

Synthesis and biological activity of cyclolinopeptide A analogues modified with γ 4 -bis(homo-phenylalanine)

Cyclolinopeptide A (CLA), an immunosuppressive nonapeptide derived from linen seeds, was modified with S or R-γ4-bis(homo-phenylalanine) in positions 3 or 4, or both 3 and 4. These modifications changed the flexibility of new analogues and distribution of intramolecular hydrogen bonds. Analogues 11 c(Pro1-Pro2-Phe3-S-γ4-hhPhe4-Leu5-Ile6-Ile7-Leu8-Val9), 13 c(Pro1-Pro2-S-γ4-hhPhe3-R-γ4-hhPhe4-Leu5-Ile6-Ile7-Leu8-Val9) and 15 c(Pro1-Pro2-R-γ4-hhPhe3-Phe4-Leu5-Ile6-Ile7-Leu8-Val9) existed as a mixture of stable cis/trans isomers of Pro-Pro peptide bond. The comparison of the relative spatial orientations in crystal state of the two carbonyl groups, neighboring γ-amino acids, revealed conformational similarities to α-peptides. The addition of two -CH2- groups in γ-amino acids led to a more rigid conformation, although a more flexible one was expected. A significant difference in the relative orientation of the carbonyl groups was found for cyclic γ-peptides with a dominance of an antiparallel arrangement. As carbonyl groups may be engaged in the interactions with plausible receptors through hydrogen bonds, a similar biological activity of the modified peptides was expected. Our biological studies showed that certain cyclic, but not the corresponding linear peptides, lowered the viability of peripheral blood mononuclear cells (PBMC) at 100μg/mL concentration. The proliferation of PBMC induced by phytohemagglutinin A (PHA) was strongly inhibited by cyclic peptides only, in a dose-dependant manner. On the other hand, lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNF-α) production in whole blood cell cultures was inhibited by both linear and cyclic peptides. Peptide 15 c(Pro1-Pro2-R-γ4-hhPhe3-Phe4-Leu5-Ile6-Ile7-Leu8-Val9) blocked the expression of caspase-3, inhibited the expression of caspases-8 and -9 in 24h culture of Jurkat cells, and caused DNA fragmentation in these cells, as an indicator of apoptosis. Thus, we revealed a new mechanism of immunosuppressive action of a nonapeptide.

Planarity of benzoylthiocarbazate tuberculostatics. III. Diesters of 3-(2-hydroxybenzoyl)dithiocarbazic acid

Searches for new tuberculostatic agents are important considering the occurrence of drug-resistant strains of Mycobacterium tuberculosis. The structures of three new potentially tuberculostatic compounds, namely isopropyl methyl (2-hydroxybenzoyl)carbonohydrazonodithioate, C12H16N2O2S2, (Z)-benzyl methyl (2-hydroxybenzoyl)carbonohydrazonodithioate, C16H16N2O2S2, and dibenzyl (2-hydroxybenzoyl)carbonohydrazonodithioate propan-2-ol monosolvate, C22H20N2O2S2·C3H8O, were determined by X-ray diffraction. The mutual orientation of the three main fragments of the compounds, namely an aromatic ring, a dithioester group and a hydrazide group, can influence the biological activity of the compounds. In all three of the structures studied, the C(=O)NH group is in the anti conformation. In addition, the presence of the hydroxy group in the ortho position of the aromatic ring in all three structures leads to the formation of an intramolecular hydrogen bond stabilizing the planarity of the molecules.

Crystal structure of (3R)-3-benzyl-4-[(tert-but­oxy­carbon­yl)amino]­butanoic acid

The characteristic feature of the title molecule, C16H23NO4, is the syn configuration of the partially double amide C—N bond [C—N—C—O torsion angle = −14.8 (2)°]. The crystal packing is determined by intermolecular O—H⋯O and N—H⋯O hydrogen bonds, which link the molecules into a double-chain structure extending along [010].

Synthesis and Tuberculostatic Activity Evaluation of Novel Benzazoles with Alkyl, Cycloalkyl or Pyridine Moiety

Compounds possessing benzimidazole system exhibit significant antituberculous activity. In order to examine how structure modifications affect tuberculostatic activity, a series of benzazole derivatives were synthesized and screened for their antitubercular activity. The compounds 1⁻20 were obtained by the reaction between o-diamine, o-aminophenol, or o-aminothiophenol with carboxylic acids or thioamides. The newly synthesized compounds were characterized by IR, ¹H-NMR, 13C-NMR spectra, and elemental analysis. Synthesized benzazoles were evaluated for their tuberculostatic activity toward Mycobacterium tuberculosis strains. Quantum chemical calculations were performed to study the molecular geometry and the electronic structure of benzimidazoles GK-151B, 4, 6, and benzoxazole 11, using the Gaussian 03W software (Gaussian, Inc., Wallingford, CT, USA). Three-dimensional structure of benzimidazoles 1⁻3, MC-9, and GK-151B was determined by ab initio calculation using Gamess-US software. The activity of the received benzimidazoles was moderate or good. All of the benzoxazoles and benzothiazoles demonstrated much lower activity. Benzoxazoles were less active by about 50 times, and benzothiazole by 100 times than the benzimidazole analogs. Quantum chemical calculations showed differences in the distribution of electrostatic potential in the benzazole system of benzimidazoles and benzoxazoles. Three-dimensional structure calculations revealed how the parity of the alkyl substituent at the C2 position impacts the activity. Benzimidazole system is essential for the antituberculosis activity that is associated with the presence of the imine nitrogen atom in N-1 position. Its replacement by an oxygen or sulfur atom results in a decrease of the activity. The parity of the alkyl substituent at the C-2 position also modifies the activity.

Crystallographic approach to determination of active conformations of LCAPs

Long-Chain Aryl-Piperazines (LCAPs) are well known serotonin receptor ligands used in several marketed antidepressant drugs. LCAPs consist of three structural units: a terminal group, an arylpiperazine at one N atom and an aliphatic chain (spacer) at the other N atom joining the two former units. Both the arylpiperazine and the terminal groups have rather rigid structures and thus their conformational freedom is limited. The opposite is true for the aliphatic spacer, which allows practically any orientation of the terminal group. The resulting diversity of conformations observed in the crystals of LCAPs is significant, which explains their affinity to many serotonin receptors. There is a vast literature on the subject and some qualitative observations were developed. However, due to the flexible spacer and diversity of the terminal groups, their usefulness is limited. Our X-ray (16 crystal structures) and affinity studies on almost sixty new LCAPs [1], together with the data from CSD, enable us to determine the common conformations of LCAPs and the relationships between structure, affinity and conformation. In the analysis, the following features were considered: (i) axial/equatorial orientations of the substituents of the piperazine ring; (ii) –N1 protonation possible in the physiological environment; (iii) a twist of the aryl ring; (iv) –the parity and the number of atoms in the spacer; (v) – the presence of heteroatoms or groups in the spacer; (vi) – the spatial position of the terminal group in relation to the piperazine ring.

Planarity of tuberculostatic (aryl)heteroaroyl- and heteroarocarbonimidoyl-dithiocarbazonic acid esters

A rise of the mortality rates and spread of tuberculosis also in developed countries, attributed to the emergence of multi-drug resistant strains, resulted in a search for new lead compounds. Several dithiocarbazonic acid esters obtained by Foks [1-3] have shown high activity against standard and resistant strains of Mycobacterium tuberculosis. Our early crystallographic studies on type A structures (Scheme, X=N,CH) showed all of them to maintain planarity in the crystal state due to two intramolecular hydrogen bonds and extensive conjugation. Therefore we have assumed that their planarity is a prerequisite for tuberculostatic activity [46]. At that time the question could not be answered by inspection of CSD, as structures incapable of adopting planar conformation, for example N’-substituted, were not known.