New Heterocyclic Structures derived from Activated Indoles and Related Heterocycles

Abstract

The project investigated two aspects of novel structures containing indoles, benzimidazoles, and benzothiazoles. One focus was the synthesis of compounds with improved antimicrobial properties. The other focus was on the synthesis of new biheterocyclic structures and their potential conversion into novel porphyrin-like macrocycles. Novel indole-based inhibitors of bacterial RNA holoenzyme formation were investigated. The Knoevenagel condensation was found to be a convenient method for the synthesis of novel inhibitors which incorporate 2-phenyl benzimidazole, 2-phenylbenzothiazole, or 4,6-dimethoxyindole-2-carboxylate scaffolds with rhodanine analogues. The synthesised compounds have been tested for their ability to inhibit RNA polymerase – σA interactions using an enzyme-linked immunosorbent assay. Furthermore, antibacterial activities against Escherichia coli and Bacillus subtilis were also investigated. The structure-activity relationship studies of synthesised compounds revealed that biological activities were affected by the C2 modifications of the indole. The 2-thiobarbituric acid moiety was found to be necessary for the antibacterial activity and several of these novel inhibitors showed significant antibacterial activities against Bacillus subtilis at micromolar concentration. One indole-2-carboxylate -2-thiobarbituric acid hybrid was recognized as a lead compound for further investigation. IV Four different 2,7’-indolylheteroaromatic systems were investigated, including 2,7’-indolylbenzimidazole, 2,7’-indolylbenzothiazole, 2,7’-indolylbenzoxazole and 2,7’-indolylbenzofuran. Specially activated examples of 2,7’-indolylbenzimidazoles and 2,7’-indolylbenzofurans were prepared from 4,6-dimethoxyindoles, and their reactivity was investigated. The 2,7’-indolylbenzimidazoles were shown to form 2:1 complexes with zinc, copper, and nickel. The ML2 structures were confirmed by NMR and high resolution mass spectrometry data. Numerous attempts were made to convert the biheterocyclic systems into porphyrin-like macrocycles by oxidative coupling reactions. However, these were largely unsuccessful due to the relative unreactivity of the benzimidazole ring component. One centro-symmetric macrocycle containing a 2,7’-indolylbenzimidazole component was synthesised via an acid-catalysed addition reaction of a mono hydroxymethyl substituted biheterocycle, which was derived from the corresponding aldehyde by reduction. The macrocycle synthesis derived from bis(hydroxymethyl) indolylbenzimidazole was attempted under the same synthetic strategy, but the desired macrocycle could not be isolated. The synthesis of porphyrin-like macrocycles containing two benzimidazoles and two benzothiazoles via 2-7’-links using an aldehyde-amine condensation approach was investigated. Different protection and deprotection methods were systematically screened to synthesise an appropriately substituted 2-(7’- V benzimidazolyl)benzthiazole. A 4,6-dimethoxy-2-(2’,3’-diaminophenyl)benzthiaz-ole was successfully synthesised and converted into a benzimidazolone derivative. However, initial attempts to dimerize this derivative into a porphyrin-like macrocycle were unsuccessful.