Degree Name

Doctor of Philosophy


Department of Chemistry - Faculty of Science


Multidrug resistance (MDR) mediated by a drug efflux mechanism is one of the major drug resistance problems not only in bacteria but also in other microorganisms. NorA MDR efflux protein is a well characterized and major efflux pump in the pathogenic Gram-positive bacterium, Staphylococcus aureus. It contributes to the resistance to berberine and ciprofloxacin antibiotics by extrusion of these drugs from the cells of S. aureus. In order to overcome this type of drug resistance by dual action agents incorporating efflux pump inhibitor properties and antibacterial activity, a variety of new, aryl group-substituted 2-aryl-5-nitro-1H-indole efflux pump inhibitors were synthesized. In the synthesis of these 2-aryl-5-nitro-1H-indoles, a new procedure for the N-acylation of indoles was developed based on DCC/DMAP coupling with carboxylic acids. This method was particularly effective with 5-nitro-1H-indole. The activity of these indole derivatives as inhibitors of the NorA MDR pump in S. aureus was assessed. It was found that some of the 2-aryl-5-nitro-1H-indole derivatives potentiated the activity of the antibacterial agents berberine and ciprofloxacin against the resistant strain, K2361, of S. aureus. The new 2-aryl-5-nitro-1H-indole inhibitors were particularly effective in potentiating the antibacterial activity of berberine. The compound [4-benzyloxy-2-(5-nitro-1H-2-yl)-phenyl]-methanol (43) was the most potent NorA pump inhibitor found in this work. A number of dual action antibacterial agents were designed and synthesized. These included dual action prodrugs, in which the MDR pump inhibitor and berberine were attached in the same molecule with enzymatically cleavable linkages (ester or amide groups), and dual action drugs with a non-cleavable linkage (methylene group). In the synthesis of the dual action agents, a direct new approach to 13-substituted berberine derivatives was found. This approach involved alkylation of 8-allyldihydroberberine followed by the elimination of propene. The antimicrobial activity of these indole-berberine compounds was assessed against a variety of pathogenic microorganisms. One of the dual action drugs, 9,10-dimethoxy-13-[2-(5-nitro-1H-indol-2-yl)benzyl]-5,6-dihydrobenzo[g]-1,3-benzodioxolo[5,6-a]quinolizinium bromide (64), was a potent antimicrobial agent at a clinically viable concentration against various bacteria in vitro, including Staphylococcus aureus K2361, Enterococcus faecalis V583, and Salmonella enterica Serovar Typhimurium SL1344R2. This compound also had good activity against the protozoan, Plasmodium falciparum K1 (in vitro). In the case of the dual action prodrugs, the amide prodrugs were more active than the ester prodrugs against the Gram-positive bacterium S. aureus and vice versa against the Gram-negative bacterium S. enterica Serovar Typhimurium. However, minimum inhibitory concentrations for all the dual action drugs and dual action prodrugs were near or at clinically useful concentrations (ca. 1��g/mL or less) as antibacterial agents against S. enterica Serovar Typhimurium SL1344R2, and they showed 400- to 1600-fold higher activity than the parent antibacterial agent berberine. The design principle of having in the one molecule an MDR inhibitor moiety and an antibacterial moiety was established as a viable one, which potentially could be extended to other types of antimicrobial agents.

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