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Title: Synthesis of bicyclic analogues of p-aminosalicylate as potential anti-tuberculosis agents
Author: Ere, Diepreye
ISNI:       0000 0004 2741 0499
Awarding Body: University of Hull
Current Institution: University of Hull
Date of Award: 2007
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Para-Aminosalicylic acid (PAS) is a well known anti mycobacterial agent and its mode action is believed to be linked to interference of the biosynthesis of the siderophore mycobactin. Certain bicyclic aromatics, in which one of the aromatic rings bears hydroxyl and carboxylic acid groups ortho to one another have recently been found also to possess antimycobacterial activity (unpublished work) and this is thought to be due to similarities in their structures compared with salicylic acid, a constituent building block in mycobactin. We have therefore used the term bicyclic salicylates to describe such compounds. We propose that "bicyclic salicylates", which are hybrids of PAS and the bicyclic systems previously discovered, could be obtained from the reaction between PAS and other reagents and that these would possess greater antimycobacterial activity and less of the gastrointestinal side effects that are associated with PAS. For example, such compounds could be benzopyridines, benzimidazoles and benzothiazoles and related compounds, in which a nitrogen heterocyclic ring is fused to a benzo ring bearing a hydroxy and a carboxylic acid ortho to one another. In our investigations of such "bicyclic salicylates" we were able to synthesize ~/ quinoline derivatives by reacting PAS, or its methyl ester derivative, with selected c.s-unsanrateo carbonyl compounds following the Doebner von- Miller quinoline synthesis. We were also able to synthesize both kinetic and thermodynamic products of quinolone salicylate derivatives using a modified Conrad-Limpach synthesis, obtaining the 4-quinolones and 2-quinolones. Lastly "bicyclic salicylates" based on benzothiazoles were also synthesized from PAS methyl ester following a modified Jacobson synthesis. In all of our studies we observed that the orientation of the cyclisation reactions often favoured the position ortho to the phenolic group of the rr aminosalicylate. In the case of the benzothiazole preparations we often obtained brominated benzothiazoles (from bromination of the product) and so in these heavily substituted products we could not make a final confirmatory statement, in these cases, with respect to the orientation of cyclisation involving the aminosalicylate precursor. 11
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available