Thesis (M.Sc.(Chemistry)) -- University of Limpopo, 2020 / Breast cancer is a malignant tumour that starts in the cells of the breast. Many studies
revealed aromatase (CYP19A1) and cyclin-dependent kinase 2 (CDK2) as possible
therapeutic targets regarding breast cancer treatment, because they play crucial roles in
anti-apoptotic processes during cell proliferation. Quinoxaline derivatives have attracted
a great deal of attention due to their biological activities against fungi, virus, bacteria and
cancer. Computer modelling was employed in order to reduce time and cost by searching
the library of molecules and identifying those which are likely to bind to the drug target.
A library of new one hundred (100) nitro and amino quinoxaline alkyne derivatives were
successfully designed and screened against target proteins (CYP19A1 and CDK2) using
virtual screening technique and thirteen (13) molecules were identified to be hit
compounds against both targets with the docking score ranging from -6.143 to -8.372
kcal/mol as a measure of binding affinity. The hit compounds were subjected to IFD in
order to identify tight binding through intermolecular interactions with active site residues
of the binding pocket of the target proteins.
All identified nitro and amino quinoxaline alkyne derivatives were successfully
synthesised in a multi-step reaction sequence and their spectroscopic analysis (NMR,
FTIR and MS) were in good agreement with the proposed structures in a good to
moderate yield. The newly synthesised novel amino and nitro-quinoxaline derivatives
were evaluated for anti-proliferative activity against breast cancer (MCF-7). Compound
59 showed to possess good inhibition against MCF-7 with an IC50 of 9.102 μM, whereas
compounds 34, 54, 56 and 61 showed promising activity against MCF-7 with an IC50 value
of < 50 μM. However, the MTT assay results showed that 59 was found to be toxic with
an IC50 value of 0.205 μM against Raw 264.7 cell line. The dose response investigations
showed that 31 and 34 have the promising anti-cancer activity against CYP19A and the
correlation between molecular modelling (in-silico) and CYP19A inhibition activities (in-
vitro), was established as compounds 31 and 34 were identified to bind to the drug target
(CYP19A) with the docking score of -8.372 and 7.630 kcal/mol respectively.
All the synthesized compounds were evaluated for the antitubercular activity against Mtb
H37Rv strain as a secondary study. Compounds 57-62 with nitro-quinoxaline derivatives
exhibited stronger inhibitory effects on Mtb H37Rv strain. In addition, compounds 60 and
62 were found to be most active against Mtb H37Rv with the high activity at MIC90 of
<0.65 and <0.64 μM respectively. All active compounds are currently investigated for their
cytotoxicity which have not been investigated before / National Research Foundation (NRF) and
SASOL Inzalo Foundation
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:ul/oai:ulspace.ul.ac.za:10386/3454 |
| Date | January 2021 |
| Creators | Lekgau, Karabo |
| Contributors | Nxumalo, W., Leboho, T. C., Gumede, T. C. |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | xvi, 142 leaves |
| Relation |
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