László Károlyházy

Novel Antiarrhythmic Compounds with Combined Class IB and Class III Mode of Action

Cardiac arrhythmias represent a major area of cardiovascular research, and for drug therapy, a large choice of antiarrhythmic agents have been available. However, clinical trials with antiarrhythmic drugs have recently indicated that serious side effects may considerably limit the use of various antiarrhythmic agents, in particular, for preventing arrhythmia-related mortality. Amiodarone with its complex mode of action, while exerting a strong and favorable antiarrhythmic action, posseses extracardiac untoward side effects originating from its chemical structure. In this paper, we report on our attempt to develop conceptually new, therapeutically valuable antiarrhythmic compounds, in which Class I/B and Class III features were combined into single molecules bearing no structural resemblance to amiodarone. Synthesis and pharmacological screening of series of N-(phenylalkyl)-N-(phenoxyalkyl)amines led us to discover some new promising compounds with the required dual mode of action. GYKI-16638, selected for further investigation, was also found to possess a remarkable in vivo antiarrhythmic effect, and it is now considered as a safe new antiarrhythmic drug candidate.

Generation and analysis of the conformational potential energy surfaces of N-acetyl-N-methyl-L-alanine-N'-methylamide. An exploratory ab initio study

Abstract N-methylation is a naturally occurring modification in small peptides, e.g. antibiotics that can effect the conformational preferences of the molecule as well as the ease of trans to cis isomerization of the involved peptide bond. In the present exploratory study we have calculated the potential energy surface of both N -acetyl- l -alanine- N ′-methylamide and N -acetyl- N -methyl- l -alanine- N ′-methylamide at the RHF/3-21G level of theory with a cis – trans or with a trans – trans peptide conformation. With respect to the non-methylated model system our results indicate that N-methylation reduces the number of observable backbone conformers in both amide configurations. The effect of methylation on the ease of trans to cis isomerization was assessed by calculating the energetics of the corresponding transition structures. An increase in the activation energies of the trans to cis isomerization of the relevant peptide bond was observed for the N-methylated moiety.

Theoretical and experimental studies on ring closure reactions of 4(5)-chloro-5(4)-hydroxyalkylamino-6-nitro-3 (2H)-pyridazinones

Abstract Cyclization of the title compounds with sodium ethoxide may proceed in various ways to afford differently fused pyridazino ring systems. Theoretical considerations based on frontier molecular orbital (FMO) analysis of 4-chloro-5-hydroxyalkylamino-6-nitropyridazinones were in agreement with experimental results in most cases. Formation of pyridazino[3,4] annelated systems was predicted and observed from 5-hydroxyethylamines and their N-benzyl analogs. However, in the ring closure reaction of the 5-N-benzyl-N-hydroxypropylamino derivative, besides [3,4] annelation, another cyclization also occurred to form a pyridazino[4,5-b]oxazepine derivative as minor product, whereas the 5-hydroxypropylamino derivative without an N-benzyl group gave a [3,4]-fused bicyclic compound, and a 6-ethoxy monocyclic derivative. The next homologue, i.e. the 5-hydroxybutylamino derivative, underwent only an intermolecular nucleophilic substitution reaction to give 6-ethoxypyridazinone derivative. In the cases of the 4-regioisomers, the N-benzyl derivatives could only be cyclized, and pyridazino[4,5] annelated systems were obtained. Structures of new compounds were proven by spectroscopic methods and microanalytical data. For a regioisomeric pair of pyridazino[4,5-b]oxazepines, X-ray analyzes were also carried out.

Chemistry of secologanin. Part 7: Chemical fragmentation of secologanin: biomimetic transition from the aliphatic into the aromatic skeleton

Abstract Transformation of secologanin and its ethylene acetal was investigated under acidic and basic conditions. Under acidic conditions both compounds gave benzaldehyde and an undefined fragment. A primary amine was incorporated into the substrate by lactamization with or without deglucosylation. Secondary and tertiary amines catalyzed lactonization of secologanin, but piperidine cleaved the acetal into methyl 3-piperidino-acrylate and an undefined C 7 unit which proved to be a phenyl group analogous to the indole alkaloid derivatives of secologanin. The biogenetic and biomimetic significance of the fragmentation is discussed.

Chemistry of secologanin. Part 5. Graphical analysis of the acidic deglycosylation of vincoside derivatives

Acidic hydrolysis and cyclization were studied in vincoside glycosides (‘natural’ series) and their dihydro derivatives (‘dihydro’ series) in which either one or both N atoms were free or blocked by an alkyl group. For interpretation of the results, a graph was constructed in which 25 points (actually circles) represent a maximum of 81 aglycone types and 40 arrows indicate 131 possible cyclizations. The reaction matrix of the graph was under thermodynamic control and in most cases afforded the thermodynamically most stable product aglycones. In addition to the deglycosylation, two types of cyclization were observed. In azacyclizations, the preferred nucleophilic site is N-4 over N-1, and the preferred electrophilic site is C-22 in the glycosides, C-21 over C-19 and C-17 in aglycones. In oxacyclizations, the preferred nucleophilic site is O-17 over C-18 and C-21, and the preferred electrophilic site is C-19 over C-21 and C-17 in the ‘natural’ series, C-21 over C-17 in the ‘dihydro’ series. In one case, the kinetically favoured aglycone types which had been generated in the reaction mixture were trapped in a subsequent reaction (outside the graph) before thermodynamic equilibrium was attained. With the help of graphical analysis it was possible to justify the formation of the most favourable and actually isolated products and pathways out of a large number of possibilities.