- Title
- Thiazole derivatives as potential hiv-1 protease inhibitors
- Creator
- Hlongwe, Zola
- Subject
- Gqeberha (South Africa)
- Subject
- Eastern Cape (South Africa)
- Subject
- Enzyme kinetics
- Date Issued
- 2021-04
- Date
- 2021-04
- Type
- Master's theses
- Type
- text
- Identifier
- http://hdl.handle.net/10948/52116
- Identifier
- vital:43427
- Description
- Series of compounds were screened using Schrodinger suite (Maestro). The DFT calculations were used for geometry optimization of the ligands using the B3YLYP functional and 6-31G basis set, and these structures were used for docking studies. Maestro was used to predict the activity of thiazole derivatives against HIV-1 protease. The range of estimated inhibition constants for these thiazole derivatives (65 nM-5 μM) indicate moderate to weak activity against HIV-1 protease, given that the activity of current protease inhibitors is typically found have experimental inhibition constants around 0.1-2.0 nM. Twenty compounds were selected based on the docking results and they were synthesized and characterized by NMR, FT-IR and elemental analysis. The cytotoxicity studies were done at two different concentrations (100 μM and 10 μM), using the brine shrimp bioassay. All compounds were highly toxic at 100 μM, with the percentage mortality between 20 to 75%. Eight compounds were selected for the enzyme bioassay based on the results obtained from lower concentration (10 μM). In the enzyme inhibition studies, the profile of HIV-1 activity was done at different inhibitor concentrations (800 μM – 10 μM) by measuring the cleavage of the synthetic substrate (Abz-Thr-lle-PNO2Phe=Gln-Arg-NH2) at excitation wavelength of 345/490 nm using fluorescence. Ligands 5 (unsubstituted derivative), 7 (4-nitro derivative) and 16 (4-methoxy derivative) gave percentage inhibition of 39, 45 and 42%, and this activity was very low compared to the activity of the positive control ritonavir (85% enzyme inhibition). Ligands 8 (4-methoxy derivative) and 12 (4-methoxy derivative) gave enzyme inhibition of 70% and 75%. These results suggest that the presence of the methoxy substituents ii increases activity of these compounds against HIV-1 protease. Most of the compounds gave good IC50 values between 12.5-42.7 nM. The bromo-substituted ligand 7 gave the lowest IC50 (12.5 nM). Ligand 11 also gave a good IC50 value of 14.86 nM. The bromo-substituted derivatives showed to be very active compared to other types of thiazole derivatives. Enzyme kinetics were carried out to compare the inhibition constants obtained via computational modelling. Ligand 7 (4-methoxy derivatives) binds better in the active site of HIV-1 protease than other compounds in Class B, with Ki = 50 nM, Km = 23.8 Nm and Vmax = 83.3 nM/min. The unsubstituted (L5), 4-bromo (L7) and 4-nitro (L8) substituted compounds gave inhibition constants of 100 to 112 nM. The in vitro testing yielded higher activity than that determined in silico.
- Description
- Thesis (MSc) -- Faculty of Science, School of Biomolecular and Chemical Sciences, 2021
- Format
- computer
- Format
- online resource
- Format
- application/pdf
- Format
- 1 online resource (xv, 148 pages)
- Format
- Publisher
- Nelson Mandela University
- Publisher
- Faculty of Science
- Language
- English
- Rights
- Nelson Mandela University
- Rights
- All Rights Reserved
- Rights
- Open Access
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