Browsing by Author "Kotze, Timothy J."

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    Synthesis and study of sulfonamide containing organometallic complexes as inhibitors for infectious disease
    (Stellenbosch : Stellenbosch University, 2019-12) Kotze, Timothy J.; Chellan, Prinessa; Smith, Gregory S.; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.
    ENGLISH ABSTRACT: Six imino sulfadoxine derivatised iridium complexes (C1 - C6), previously synthesized in literature, were investigated for drug like character by accessing their aqueous solubility through a turbidimetric assay and probing the potential active species by means of aquation experiments. The complexes C3, C5 and C6 had solubilities ranging between 20 μM and 160 μM, while C1, C2 and C4 had solubilities greater than 160 μM. Solubility was found to decrease with increasing addition of hydrophobic groups to the half-sandwich moiety coordinating via a centroidal bond to the iridium metal centre. Ease of hydrolysis of the chlorido ligand was found to decrease as the steric bulk around the metal centre was increased to the point that the chlorido of C3 remained in-tact under mild conditions in the presence of silver nitrate. This likely means the active species is the, as synthesized, chlorido complex. New synthetic methods were developed for the synthesis of the Schiff base ligands of these complexes to achieve a more efficient synthesis and obtain pure samples for testing. Though pure samples were not obtained, the efficiency of the synthesis was improved. Six new amido sulfadoxine derivatised iridium complexes (C7 – C12), were synthesized in moderate to good yields of 56% – 84% as yellow powders. Their ligands were synthesized through in situ generation of an acid chloride and subsequent quenching with sulfadoxine. A crystal structure was obtained for the pyridyl amido sulfadoxine ligand which crystallised in the triclinic, P1, space group as transparent needle like crystals. The drug-like character was also investigated for this series of complexes and their solubilities of C9, C11 and C12 were between 20 μM and 60 μM, while C7, C8 and C10 were greater than 160 μM. The same results were obtained for the aquation experiments as for C1 – C6. All complexes were tested against Mycobacterium tuberculosis (Mtb) strain H37Rv and Plasmodium falciparum strains, 3D7, Dd2 and HB3. Complex C6 was only tested against Mtb. The imino complexes were more active in general, with a MIC90 of 2.78 μM for C6 against strain H37Rv after 7 days and an IC50 of 13.8 μM for C5 against strain 3D7. Although the amido complexes exhibited promising activity against P. falciparum with C12 having an IC50 of 0.975 μM against strain 3D7 and IC50 of 0.766 μM against multidrug resistant strain Dd2. The activity was generally seen to increase as the solubility decreased with the addition of hydrophobic groups to the complexes.
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    Vitamin in the crosshairs : targeting pantothenate and coenzyme a biosynthesis for new antituberculosis agents
    (Frontiers Media, 2020) Butman, Hailey S.; Kotze, Timothy J.; Dowd, Cynthia S.; Strauss, Erick
    ENGLISH ABSTRACT: Despite decades of dedicated research, there remains a dire need for new drugs against tuberculosis (TB). Current therapies are generations old and problematic. Resistance to these existing therapies results in an ever-increasing burden of patients with disease that is difficult or impossible to treat. Novel chemical entities with new mechanisms of action are therefore earnestly required. The biosynthesis of coenzyme A (CoA) has long been known to be essential in Mycobacterium tuberculosis (Mtb), the causative agent of TB. The pathway has been genetically validated by seminal studies in vitro and in vivo. In Mtb, the CoA biosynthetic pathway is comprised of nine enzymes: four to synthesize pantothenate (Pan) from L-aspartate and α-ketoisovalerate; five to synthesize CoA from Pan and pantetheine (PantSH). This review gathers literature reports on the structure/mechanism, inhibitors, and vulnerability of each enzyme in the CoA pathway. In addition to traditional inhibition of a single enzyme, the CoA pathway offers an antimetabolite strategy as a promising alternative. In this review, we provide our assessment of what appear to be the best targets, and, thus, which CoA pathway enzymes present the best opportunities for antitubercular drug discovery moving forward.