Year

2005

Degree Name

Doctor of Philosophy

Department

Department of Chemistry - Faculty of Science

Abstract

The overall aim of this project was to investigate the synthesis and activity of a range of compounds based on the benzo[b]thiophene-2-carboxamide structural motif as potential new antimalarial agents, and to a lesser extent as antibacterial agents. In order to subsequently explore any structure-biological activity relationships, the first part of the project involved the systematic synthesis of some 39 non-fused substituted benzo[b]thiophene amide derivatives including tetrahydroisoquinolines, tetrahydro-β-carbolines, dihydropyrroles, piperazines, piperidines and other bridged ring systems as part of the amide-nitrogen component. Methods for the synthesis of the new amide derivatives were developed based on benzo[b]thiophene acid chloride and amine reactions, or on dicyclohexylcarbodiimide-mediated carboxylic acid amine coupling reactions. Further substitution reactions were also undertaken on tetrahydro-β-carboline amides (55, 56, and 57) with the introduction of an N-benzyl group and an N-onitrobenzyl group in the case of 55. The N-boc protected piperazine amide 63 also served as a precursor for other N-substituted piperazine amide derivatives. A single crystal X-ray structure on amides 63 and 73 confirmed the amide rotamer geometry in the solid state with these compounds. The second part of the project incorporated the synthesis of fused analogues which were more conformationally restricted while still retaining the benzo[b]thiophene amide structural motif. A new free radical cyclisation approach to the benzo[b]thieno[2,3-c]pyridin-1-one system in compound 92 was developed, together with the corresponding model isoquinolinone analogue 95. The reaction was based on the use of tributyltin hydride and AIBN to produce the required free radical intermediate from an arylbromide precursor. The free radical cyclisation reaction was extended to synthesise N-benzyl and substituted N-benzyl analogues of 92. The dihydroxylation of the N-allyl substituent in 92 was achieved using potassium osmate and N-methylmorpholine-N-oxide (NMO). A further free radical cyclisation route to the N-benzo[b]thien-2-oyl derivatives 112 was also achieved. The synthesis of the novel 9-membered ring containing fused derivatives 120 and 121 was also achieved. This synthesis involved ring closing metathesis methodology using the bis-allyl amides 118 and 119 and Grubbs’ I ruthenium catalyst. The polymer supported version of this catalyst gave better yields of the cyclisation products. A single crystal X-ray structure of 120 confirmed the cis geometry of the double bond in the 9-membered ring. In the course of preparing the required precursor 119 for the 9-membered ring synthesis, a new imine allylation reagent combination was discovered involving zinc, allyltributyltin and boron trifluoride etherate. This reaction is worthy of further investigation to determine its wider synthetic utility. Ring closing metathesis reactions also afforded the dihydropyrrole amides 113 and 114 in good yields. A palladium-mediated cyclisation approach to the new benzo[b]thieno[2,3- c]pyrrolo[2,3-a]indol-11-one system in 126 was also accomplished based on the Nacylindoles 124 and 125. A number of the compounds were tested for their possible in vitro antimalarial activity against two strains of Plasmodium falciparum (K1 CB1 and TM4/ 8.2) and two active leads, the benzo[b]thienoquinolinone derivatives 95 and 102, were discovered. Some potential structure-activity trends for the tested benzo[b]thiophene derivatives were observed (Chapter 4). Antibacterial testing of a few benzo[b]thiophene compounds against Staphylococcus aureus and vancomycin-resistant Enterococcus faecium strains was also done, and the benzo[b]thienoquinolinone derivative 92 exhibited promising activity against Staphylococcus aureus.

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Unless otherwise indicated, the views expressed in this thesis are those of the author and do not necessarily represent the views of the University of Wollongong.