ABSTRACT
The thiosemicarbazones of beta-carboline-3-carboxaldehyde (compound 2) and 3-acetyl-beta-carboline (compound 3) were found to effectively inhibit the in vitro growth of the promastigote form of Leishmania donovani, 50% inhibition being obtained at concentrations of 5.0 and 2.5 microM, respectively, while irreversible growth inhibition was achieved at 40 (compound 2) and 17.5 microM (compound 3). The thiosemicarbazone of pyridine-2-carboxyaldehyde (compound 4) was considerably less active while both methyl beta-carboline-3-carboxylate (compound 1) and the thiosemicarbazone of ethyl 5-formyl-6-azaindole-2-carboxylate (compound 5) were inactive at the highest concentrations tested. At concentrations provoking approximately 50% growth inhibition of promastigotes, compound 2 was observed to preferentially block DNA rather than RNA synthesis, but for compound 3, the reverse was true. Compound 3, the most active analogue studied, may thus act, at least partially, via a novel, though as yet unelucidated, mechanism.
Subject(s)
Carbolines/pharmacology , Leishmania donovani/drug effects , Thiosemicarbazones/pharmacology , Animals , Carbolines/chemical synthesis , Carbolines/toxicity , Chemical Phenomena , Chemistry , DNA/biosynthesis , Leishmania donovani/growth & development , Leishmania donovani/metabolism , Mice , Molecular Structure , Protein Biosynthesis , RNA/biosynthesis , Structure-Activity Relationship , Thiosemicarbazones/chemical synthesis , Thiosemicarbazones/toxicityABSTRACT
Hybrid molecules incorporating pharmacologically important structural features of both 3-carboxy-beta-carbolines and 1,4-benzodiazepines were synthesized, and their affinities for the benzodiazepine receptor were determined in vitro. One of these hybrids, 8,14-dioxo-13,14-dihydro-8H-indolo[3',2':4,5]pyrido[2,1-c] [1,4]benzodiazepine (13), demonstrated high affinity for the receptor, displacing both benzodiazepines (IC50 = 23 nM) and beta-carbolines (IC50 = 47 nM) from their binding sites. Of the compounds synthesized, 13 also most closely satisfied the structural requirements that generally ensure a high affinity of both beta-carbolines and benzodiazepines for the receptor (e.g., aromaticity of the beta-carboline, presence of a carbonyl at C-3 of the beta-carboline and of a pi 2-region on the benzodiazepine). The hybrids not fulfilling these requirements had no affinity for the receptor. In vivo pharmacological properties of 13 could not be demonstrated because of its metabolic instability and/or its poor transport into the brain. The results are discussed in terms of a possible overlapping of beta-carboline binding sites with those of benzodiazepines on the receptor.
Subject(s)
Benzodiazepines/chemical synthesis , Carbolines/chemical synthesis , Ligands , Receptors, GABA-A/metabolism , Animals , Carbolines/metabolism , Flunitrazepam/metabolism , Mice , Molecular ConformationABSTRACT
The X-ray crystal structure of 3-(methoxycarbonyl) amino-beta-carboline, a selective antagonist of the sedative effects of diazepam having a high affinity for the benzodiazepine receptor, has been determined. The results were compared with structural information obtained from this compound, both in the solid state and in dilute solution, by use of Fourier transform infrared spectroscopy. Its X-ray structure was also compared with those of two other active beta-carbolines, methyl beta-carboline-3-carboxylate and N-ethyl-3-carbamoyl-beta-carboline. The crystal packing characteristics of 3-(methoxycarbonyl) amino-beta-carboline differ from those of these two beta-carbolines in both the pattern of intermolecular hydrogen bonding and the quality of their pi-pi stacking interactions. The relevance this may have to the selective activity of 3-(methoxycarbonyl) amino-beta-carboline is discussed.
Subject(s)
Carbolines , Diazepam/antagonists & inhibitors , Carbolines/pharmacology , Crystallography , Models, Molecular , Molecular Conformation , Receptors, GABA-A/drug effects , X-Ray DiffractionABSTRACT
Seven 3-N-substituted derivatives of 3-amino-beta-carboline were synthesized and their affinities for the benzodiazepine receptor were assessed in vitro. Two compounds, 3-(ethylamino)-beta-carboline and 3-[(methoxycarbonyl)amino]-beta-carboline (beta-CMC), showing IC50 values of 460 and 71 nM, respectively, were selected for in vivo studies. The former compound showed long-lasting proconvulsant activity in Papio papio baboons while beta-CMC was shown in mice to selectively antagonize the sedative effects of diazepam without exhibiting convulsant, proconvulsant, or anxiogenic activity by itself.
Subject(s)
Carbolines/chemical synthesis , Diazepam/antagonists & inhibitors , Indoles/chemical synthesis , Receptors, GABA-A/drug effects , Animals , Carbolines/pharmacology , Convulsants/pharmacology , In Vitro Techniques , Male , Mice , Papio , Rats , Rats, Inbred Strains , Structure-Activity RelationshipABSTRACT
The conformations of codlemone (8,10-dodecadienol) and of a model analog have been studied by CNDO calculations. Stable conformations are found for the folded forms when the polarity of the solvent is taken into account.
