Browsing by Author "Jana, Collins Edward"

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    Synthesis and evaluation of pantothenic acid analogues as potential inhibitors of malaria parasites and bacteria
    (Stellenbosch : Stellenbosch University, 2011-12) Jana, Collins Edward; Strauss, Erick; Stellenbosch University. Faculty of Sciences. Dept. of Biochemistry.
    ENGLISH ABSTRACT: A lot of progress has been made in the development and utilization of antimalarial and antibacterial drugs. However, reports of increasing resistance to these antimicrobial agents are threatening to reduce their overall efficacy. In view of this, the need for new antimicrobials is of the paramount importance. Since pantothenate promotes the growth of microbes, analogues of this compound that may act as antimetabolites have been synthesized and tested for their inhibitory properties against microbial growth. N-substituted pantothenamides is a class of pantothenate analogues previously synthesized in our group that have shown good antibacterial activities, as well as promising inhibition of the proliferation of malaria parasites. In this study the chemical and structural diversity of these analogues were expanded by preparing N-substituted pantothenamides in which a methyl functionality was introduced on either the α- or ß-carbon of the ß-alanine moiety of pantothenate. These compounds were synthesized and purified in parallel, resulting in the production of 40 N-substituted α- and ß-methylpantothenamides which were investigated as potential antibacterial and antimalarial agents. The growth inhibitory activities of these compounds were first investigated on S. aureus, since in the previous study it was shown that N-substituted pantothenamides demonstrated remarkable inhibitory activities against this microbe. Next, the impact of these compounds on the proliferation of malaria parasites was also investigated to determine if the introduction of the methyl group could improve on the poor inhibition exhibited by the first series of pantothenamides tested against this organism. Finally pantoyltauramides, sulfonamide analogues of the pantothenamides, were also synthesized and tested for their inhibitory activities against proliferation of malaria parasites P. falciparum in vitro. The results show that additional functionalization of pantothenic acid may prove to be a viable strategy for improving the inhibitory activity of these antimetabolites.
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    Synthesis, profiling and mode of action studies of PanSulfAms as inhibitors of coenzyme a biosynthesis and utilization
    (Stellenbosch : Stellenbosch University, 2019-12) Jana, Collins Edward; Strauss, Erick; De Villiers, Marianne; Stellenbosch University. Faculty of Science. Dept. of Biochemistry.
    ENGLISH ABSTRACT: Though tremendous progress has been made in the development of antibacterial drugs, the evolution of antimicrobial resistance is a serious problem that is affecting the successful prevention and treatment of various infections caused by microbial pathogens. Taking this into consideration, the need for new antimicrobials is of paramount importance. Since the B-vitamin pantothenate promotes the growth of microbes, analogues of this compound that may act as antimetabolites have been synthesized and tested for their inhibitory properties against bacterial growth. N-substituted pantoyltauramides (PanSulfAms) are a class of pantothenate analogues previously synthesized by various research groups in the 1940s. These analogues demonstrated promising inhibition of the proliferation of avian malaria parasites as well as showing good antibacterial activities against Streptococcus pyogenes. In this study, the chemical and structural diversity of these analogues was expanded by preparing PanSulfAms in which various amide moieties were introduced to the sulfonic acid group of taurine. These compounds were subsequently used to produce fourteen PanSulfAms that were investigated for their potential as antibacterial agents. The growth inhibitory activities of the synthesized PanSulfAms were first investigated against Escherichia coli and Staphylococcus aureus both as models of Gram-negative and Gram-positive bacteria respectively, and because these compounds have never been investigated on these microbes. We also investigated the link between the organisms’ pantothenate kinase (PanK) types and the observed growth inhibition to ascertain whether this relates to the compounds’ mode of action. In this study, we have shown for the first time that PanSulfAms have the potential to inhibit S. aureus growth, but not that of E. coli. In addition, we have also performed the first detailed comparative kinetic analysis of PanSulfAms that cause S. aureus growth inhibition, demonstrating that PanK type directs the mode of action of these compounds. Finally, the PanSulfAms were studied for their ability to inhibit CoA biosynthesis. We show that their impact is compound-specific and relates to their interaction with the various CoA biosynthetic enzymes. We demonstrate for the first time that certain phosphorylated PanSulfAms act as inhibitors of the PPCS activity of the bifunctional CoaBC protein, and that, in combination with a specific interaction with the S. aureus PanK, has strong negative impact on the rate of CoA biosynthesis that likely contributes to their overall mode of action.