ABSTRACT
A number of new compounds containing 3-bromo-2,5-dihydro-1H-2,5-pyrroledione and indole substructures were found to have antibacterial activity against resistant strains of Staphylococcus aureus, Mycobacterium smegmatis and some other Gram positive bacteria. The investigated compounds exhibit minimal inhibition concentrations (MIC's) lower than those of ciprofloxacin, vancomycin and doxycycline resp. A different spectrum of activity, suggests a mechanism of action different to vancomycin and doxycycline. This might be important in circumventing existing resistance mechanisms. Here we report about the synthesis and on the antibacterial activity in a structure activity relationship study.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Gram-Positive Bacteria/drug effects , Indoles/chemical synthesis , Pyrroles/chemical synthesis , Anti-Bacterial Agents/pharmacology , Ciprofloxacin/pharmacology , Doxycycline/pharmacology , Drug Resistance, Microbial , Indoles/pharmacology , Microbial Sensitivity Tests , Mycobacterium smegmatis/drug effects , Pyrroles/pharmacology , Staphylococcus aureus/drug effects , Structure-Activity Relationship , Vancomycin/pharmacologyABSTRACT
Indolo[2,3-a]pyrrolo[3,4-c]carbazoles were isolated from nature, e.g., from low plants, especially fungi, as structurally rare natural substances. Responsible for naming and also the most important representative of this type is staurosporine (1), isolated from Streptomyces staurosporeus, and its aglycon (2), also known as staurosporinone or K-252c. 3,4-Disubstituted pyrrolidin-2-ones, a group of compounds with many interesting biological properties are related to staurosporinone. The most important property is the inhibition of protein kinase C (PKC), so that this antiproliferative agent can interfere with the cell cycle. The synthetic strategy, developed by us, allows the synthesis of pyrrolidin-2-ones by an intermolecular Michael addition, starting from nitroethene derivatives and substituted acetate Michael donors. With this method also enantioselective syntheses can be carried out using chiral auxiliaries. After reduction of the nitro group and subsequent lactamization, the lactam partial structure, which is essential for the biological activity, is obtained. Besides indole substituents, which were used for the synthesis of staurosporinone, substituted indole-, phenyl-, and pyridyl- as well as enantiomerically pure (S)-proline derivatives were used. Here, considerably high diastereoselectivity and enantioselectivity ((S)-pyrrolidine) could be detected. Just like the total synthesis of staurosporinone within three steps, the easiest and shortest approach reported up to now, with good to moderate yields, this sequence allows highly diastereoselective syntheses, which open the easy access to a new family of compounds.
ABSTRACT
The construction of the ring-expanded carbazole system, forming arcyriaflavin homologues, is efficiently accomplished by the reaction of 2,2'-bridged bis-indoles with 3,4-dibromo-2,5-dihydro-1H-2,5-pyrroledione derivatives under Grignard conditions. A ring size of up to nine members in the central ring is achievable. Substitutions either at the indole system or at the imide-N are also possible. The conformation of homoarcyriaflavins as a cross-link between the rigid arcyriaflavins and the flexible arcyriarubins was investigated by NMR, X-ray, and semiempiric quantum chemical calculation methods.