Synthesis and study of sulfonamide containing organometallic complexes as inhibitors for infectious disease

Kotze, Timothy J. (2019-12)

Thesis (MSc)--Stellenbosch University, 2019.

Thesis

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.

AFRIKAANSE OPSOMMING: Ses imino sulfadoksien-afgeleide iridium komplekse (C1 - C6), wat voorheen in die literatuur gesintetiseer is, is ondersoek vir dwelmagtige karakter deur hul wateroplosbaarheid deur middel van 'n turbidimetriese toetsing te verkry, sowel as die potensiële aktiewe spesie deur middel van hidrolise van die chloriedligand te ondersoek. Die komplekse C3, C5 en C6 het oplosbaarheid tussen 20 μM en 160 μM getoon, terwyl C1, C2 en C4 oplosbaarheid groter as 160 μM getoon het. Oplosbaarheid is gevind om af te neem met toevoeging van hidrofobiese groepe tot die ‘half-sandwich’ groep wat koördineer via 'n sentroïedebinding na die iridium metaal sentrum. Die gemak waarmee die chloriedligand gehidroliseer het, het afgeneem soos die steriese massa rondom die metaalsentrum verhoog is tot en met die punt dat die chloriedligand van C3 onder matige toestande in die teenwoordigheid van silwernitraat onverander gebly het. Dit beteken waarskynlik dat die aktiewe spesie die onveranderde chloriedkompleks is. Nuwe sintetiese metodes is ontwikkel vir die sintese van die Schiff-basisligande van hierdie komplekse om 'n meer doeltreffende sintese te ontdek en suiwer monsters vir biologiese toetse te verkry. Alhoewel suiwer monsters nie verkry is nie, is die doeltreffendheid van die sintese verbeter. 'n Tweede stel van ses amido sulfadoksien afgeleide iridium komplekse (C7 - C12), wat nie voorheen gemaak is nie, is met goeie opbrengste van 56% - 84% as geel poeiers gesintetiseer. Hul ligande is gesintetiseer deur in situ generasie van 'n suurchloried en daaropvolgende substitusie met sulfadoksien. 'n Kristalstruktuur is verkry vir die piridielamido-sulfadoksienligand wat in die P1 ruimtegroep as deursigtige naaldagtige kristalle gekristalliseer het. Die dwelmagtige karakter is ook ondersoek vir hierdie reeks komplekse en die oplosbaarheid van C9, C11 en C12 was tussen 20 μM en 60 μM, terwyl C7, C8 en C10 oplosbaarheid groter as 160 μM getoon het. Dieselfde resultate is verkry vir die hidrolise van die chloriedligand van C7 – C12 as die van C1 - C6. Alle komplekse is getoets teen Mycobacterium tuberculosis (Mtb) stam H37Rv en Plasmodium falciparum stamme, 3D7, Dd2 en HB3. Kompleks C6 is slegs teen Mtb getoets. Oor die algemeen was die imino-komplekse meer aktief as die amido komplekse, met 'n MIK90 na sewe dae van 2.78 μM vir C6 teen stam H37Rv en 'n IK50 van 13.8 μM vir C5 teen stam 3D7. Die amido-komplekse het wel belowende aktiwiteit teen P. falciparum vertoon met C12 wat 'n IK50 waarde van 0.975 μM teen stam 3D7 en ‘n IK50 waarde van 0.766 μM teen die multidwelmweerstandige stam Dd2 betoon het. Dit is waargeneem dat die toename van die aktiwiteit oor die algemeen gepaardgaande gegaan het met die afname van die oplosbaarheid, soos wat hidrofobiese groepe aan die komplekse bygevoeg is.

Please refer to this item in SUNScholar by using the following persistent URL: http://hdl.handle.net/10019.1/107321
This item appears in the following collections: