Cocrystals, salts and eutectics of anti-tuberculosis medicines
- Authors: Matlapeng, Tsebang Alice
- Date: 2024-10-11
- Subjects: Cocrystal , Tuberculosis , 4-aminosalicylic acid , Isoniazid , Pyrazinamide , Pyrazinoic acid
- Language: English
- Type: Academic theses , Master's theses , text
- Identifier: http://hdl.handle.net/10962/464521 , vital:76518
- Description: Tuberculosis remains as a prominent cause of death worldwide. This infectious disease is treated with first and second line drugs. However, challenges of multi drug resistant tuberculosis and adverse side effects such as depletion of essential B group vitamins in the body by first line drugs, as well as poor physicochemical properties of second line drugs persist. Cocrystallisation of anti-tubercular drugs with various coformers has therefore been used as an alternative method to improve the physicochemical properties of active pharmaceutical ingredients (API) while maintaining their efficacy. The main objective of this study was to carry out cocrystal screening of anti-tubercular API and vitamin B coformers to make drug-drug or drug-vitamin multicomponent complexes. Preparation of the multicomponent complexes was carried out by mechanochemical grinding (neat grinding (NG), liquid assisted grinding (LAG) and slow evaporation. All complexes were characterised using Fourier-transform infrared spectroscopy (FTIR), powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and crystal structures were elucidated using single-crystal X-ray diffraction (SCXRD). The cocrystal screening resulted in the formation of various solid forms, which included cocrystals, salts and eutectic products. Two cocrystals of 4-aminosalicylic acid (PAS) were isolated and characterised. The cocrystal of PAS with isoniazid (INH) demonstrated similar characteristics for both the bulk crystalline material and milled materials. The cocrystal of PAS and pyrazinamide (PYR) prepared using mechanochemical synthesis was met with challenges, while difficulties were also encountered in obtaining suitable crystals for SCXRD analysis. The ground and recrystallised samples of the PAS and pyrazinecarboxylic acid (PCBA) showed distinct differences in their thermal behaviour, with SCXRD revealing the decomposition product phenolammonium-pyrazinecarboxylate salt ‘sans’ the CO2 moiety. Salt formation involving pyridoxine (PN) yielded a salt hydrate with PAS (PN-PAS) and an anhydrous salt with PCBA (PN-PCBA). Both salts exhibited very complex packing arrangements with equally complex thermal behaviour depending on the solvent used during preparation, and the method of preparation. Three eutectic systems involving INH with PYR, PN and pyridoxine hydrochloride (PNꞏHCl) were identified, and their phase diagrams were constructed from DSC data. The eutectic compositions obtained were 1:1 for INH:PYR, 1:1 for INH:PN and 6:4 for INH:PNꞏHCl. Finally, a total of eight multicomponent complexes were prepared using selected API and vitamin B6 components. The results presented here provide motivation for further investigation and evaluation of the pharmacochemical properties of these API. , Thesis (MSc) -- Faculty of Science, Chemistry, 2024
- Full Text:
- Date Issued: 2024-10-11
- Authors: Matlapeng, Tsebang Alice
- Date: 2024-10-11
- Subjects: Cocrystal , Tuberculosis , 4-aminosalicylic acid , Isoniazid , Pyrazinamide , Pyrazinoic acid
- Language: English
- Type: Academic theses , Master's theses , text
- Identifier: http://hdl.handle.net/10962/464521 , vital:76518
- Description: Tuberculosis remains as a prominent cause of death worldwide. This infectious disease is treated with first and second line drugs. However, challenges of multi drug resistant tuberculosis and adverse side effects such as depletion of essential B group vitamins in the body by first line drugs, as well as poor physicochemical properties of second line drugs persist. Cocrystallisation of anti-tubercular drugs with various coformers has therefore been used as an alternative method to improve the physicochemical properties of active pharmaceutical ingredients (API) while maintaining their efficacy. The main objective of this study was to carry out cocrystal screening of anti-tubercular API and vitamin B coformers to make drug-drug or drug-vitamin multicomponent complexes. Preparation of the multicomponent complexes was carried out by mechanochemical grinding (neat grinding (NG), liquid assisted grinding (LAG) and slow evaporation. All complexes were characterised using Fourier-transform infrared spectroscopy (FTIR), powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and crystal structures were elucidated using single-crystal X-ray diffraction (SCXRD). The cocrystal screening resulted in the formation of various solid forms, which included cocrystals, salts and eutectic products. Two cocrystals of 4-aminosalicylic acid (PAS) were isolated and characterised. The cocrystal of PAS with isoniazid (INH) demonstrated similar characteristics for both the bulk crystalline material and milled materials. The cocrystal of PAS and pyrazinamide (PYR) prepared using mechanochemical synthesis was met with challenges, while difficulties were also encountered in obtaining suitable crystals for SCXRD analysis. The ground and recrystallised samples of the PAS and pyrazinecarboxylic acid (PCBA) showed distinct differences in their thermal behaviour, with SCXRD revealing the decomposition product phenolammonium-pyrazinecarboxylate salt ‘sans’ the CO2 moiety. Salt formation involving pyridoxine (PN) yielded a salt hydrate with PAS (PN-PAS) and an anhydrous salt with PCBA (PN-PCBA). Both salts exhibited very complex packing arrangements with equally complex thermal behaviour depending on the solvent used during preparation, and the method of preparation. Three eutectic systems involving INH with PYR, PN and pyridoxine hydrochloride (PNꞏHCl) were identified, and their phase diagrams were constructed from DSC data. The eutectic compositions obtained were 1:1 for INH:PYR, 1:1 for INH:PN and 6:4 for INH:PNꞏHCl. Finally, a total of eight multicomponent complexes were prepared using selected API and vitamin B6 components. The results presented here provide motivation for further investigation and evaluation of the pharmacochemical properties of these API. , Thesis (MSc) -- Faculty of Science, Chemistry, 2024
- Full Text:
- Date Issued: 2024-10-11
In silico identification of natural inhibitory compounds against the Mycobacterium tuberculosis Enzyme Pyrazinamidase using high-throughput virtual screening techniques
- Authors: Kenyon, Thomas
- Date: 2021-10-29
- Subjects: Mycobacterium tuberculosis , Pyrazinamide , Molecular dynamics , High throughput screening (Drug development) , Mutagenesis , South African Natural Compounds database (SANCDB)
- Language: English
- Type: Master's theses , text
- Identifier: http://hdl.handle.net/10962/192074 , vital:45193
- Description: Tuberculosis (TB) is most commonly a pulmonary infection caused by the bacterium Mycobacterium tuberculosis. With the exception of the COVID-19 pandemic, TB was the most common cause of death due to an infectious disease for a number of years up until 2020. In 2019, 10 million people fell ill with TB worldwide and 1.4 million people died (WHO, 2020a). Additionally, multidrug-resistant TB (MDR-TB) remains a public health crisis and a health security threat. A global total of 206 030 people with multidrug- or rifampicin-resistant TB (MDR/RR-TB) were reported in 2019, a 10% increase from 186 883 in 2018. South Africa is ranked among the 48 high TB burden countries, with an estimated 360 000 people falling ill in 2019, resulting in 58 000 deaths, the majority of which being among people living with HIV. Unlike HIV, however, TB is a curable disease when managed correctly with long durations of antitubercular chemotherapy. Pyrazinamide (PZA) is an important first-line tuberculosis drug unique for its activity against latent TB. PZA is a prodrug, being converted into its active form, pyrazinoic acid (POA) by the Mtb gene pncA, coding for the pyrazinamidase enzyme (PZase). TB resistance to first-line drugs such as PZA is commonly associated with mutations in the pncA/PZase enzyme. This study aimed to identify potential novel inhibitors that bind to the active site of PZase. By making use of molecular docking studies and molecular dynamics (MD) simulations, high throughput virtual screening was performed on 623 compounds from the South African Natural Compounds database (SANCDB; https://sancdb.rubi.ru.ac.za). Ligands that selectively bound to the PZase active site were identified using docking studies, followed by MD simulations to assess ligand-PZase complex stability, Finally, hit compounds identified from the first round of MD simulations were screened again against PZase structures with high confidence point mutations known to infer PZA resistance in order to identify any novel compounds which had inhibitory potential against both WT and mutant forms of the PZase enzyme. , Thesis (MSc) -- Faculty of Science, Biochemistry and Microbiology, 2021
- Full Text:
- Date Issued: 2021-10-29
- Authors: Kenyon, Thomas
- Date: 2021-10-29
- Subjects: Mycobacterium tuberculosis , Pyrazinamide , Molecular dynamics , High throughput screening (Drug development) , Mutagenesis , South African Natural Compounds database (SANCDB)
- Language: English
- Type: Master's theses , text
- Identifier: http://hdl.handle.net/10962/192074 , vital:45193
- Description: Tuberculosis (TB) is most commonly a pulmonary infection caused by the bacterium Mycobacterium tuberculosis. With the exception of the COVID-19 pandemic, TB was the most common cause of death due to an infectious disease for a number of years up until 2020. In 2019, 10 million people fell ill with TB worldwide and 1.4 million people died (WHO, 2020a). Additionally, multidrug-resistant TB (MDR-TB) remains a public health crisis and a health security threat. A global total of 206 030 people with multidrug- or rifampicin-resistant TB (MDR/RR-TB) were reported in 2019, a 10% increase from 186 883 in 2018. South Africa is ranked among the 48 high TB burden countries, with an estimated 360 000 people falling ill in 2019, resulting in 58 000 deaths, the majority of which being among people living with HIV. Unlike HIV, however, TB is a curable disease when managed correctly with long durations of antitubercular chemotherapy. Pyrazinamide (PZA) is an important first-line tuberculosis drug unique for its activity against latent TB. PZA is a prodrug, being converted into its active form, pyrazinoic acid (POA) by the Mtb gene pncA, coding for the pyrazinamidase enzyme (PZase). TB resistance to first-line drugs such as PZA is commonly associated with mutations in the pncA/PZase enzyme. This study aimed to identify potential novel inhibitors that bind to the active site of PZase. By making use of molecular docking studies and molecular dynamics (MD) simulations, high throughput virtual screening was performed on 623 compounds from the South African Natural Compounds database (SANCDB; https://sancdb.rubi.ru.ac.za). Ligands that selectively bound to the PZase active site were identified using docking studies, followed by MD simulations to assess ligand-PZase complex stability, Finally, hit compounds identified from the first round of MD simulations were screened again against PZase structures with high confidence point mutations known to infer PZA resistance in order to identify any novel compounds which had inhibitory potential against both WT and mutant forms of the PZase enzyme. , Thesis (MSc) -- Faculty of Science, Biochemistry and Microbiology, 2021
- Full Text:
- Date Issued: 2021-10-29
In silico identification of selective novel hits against the active site of wild type mycobacterium tuberculosis pyrazinamidase and its mutants
- Authors: Gowo, Prudence
- Date: 2021-04
- Subjects: Mycobacterium tuberculosis , Pyrazinamide , Multidrug resistance , Antitubercular agents , Molecular dynamics , Hydrogen bonding , Ligand binding (Biochemistry) , Dynamic Residue Network
- Language: English
- Type: thesis , text , Masters , MSc
- Identifier: http://hdl.handle.net/10962/178007 , vital:42898
- Description: The World Health Organization declared Tuberculosis a global health emergency and has set a goal to eradicate it by 2035. However, effective treatment and control of the disease is being hindered by the emerging Multi-Drug Resistant and Extensively Drug Resistant strains on the most effective first line prodrug, Pyrazinamide (PZA). Studies have shown that the main cause of PZA resistance is due to mutations in the pncA gene that codes for the target protein Pyrazinamidase (PZase). Therefore, this study aimed to identify novel drug compounds that bind to the active site of wild type PZase and study the dynamics of these potential anti-TB drugs in the mutant systems of PZase. This approach will aid in identifying drugs that may be repurposed for TB therapy and/or designed to counteract PZA resistance. This was achieved by screening 2089 DrugBank compounds against the whole wild type (WT) PZase protein in molecular docking using AutoDOCK4.2. Compound screening based on docking binding energy, hydrogen bonds, molecular weight and active site proximity identified 47 compounds meeting all the set selection criteria. The stability of these compounds were analysed in Molecular Dynamic (MD) simulations and were further studied in PZase mutant systems of A3P, A134V, A146V, D8G, D49A, D49G, D63G, H51P, H137R, L85R, L116R, Q10P, R140S, T61P, V139M and Y103S. Generally, mutant-ligand systems displayed little deviation from the WT systems. The compound systems remained compact, with less fluctuations and more hydrogen bond interactions throughout the simulation (DB00255, DB00655, DB00672, DB00782, DB00977, DB01196, DB04573, DB06414, DB08981, DB11181, DB11760, DB13867, DB13952). From this research study, potential drugs that may be repurposed for TB therapy were identified. Majority of these drugs are currently used in the treatment of hypertension, menopause disorders and inflammation. To further understand the mutant-ligand dynamic systems, calculations such as Dynamic Residue Network (DRN) may be done. Also, the bioactivity of these drugs on Mycobacterium tuberculosis may be studied in wet laboratory, to understand their clinical impart in vivo experiments. , Thesis (MSc) -- Faculty of Science, Biochemistry and Microbiology, 2021
- Full Text:
- Date Issued: 2021-04
- Authors: Gowo, Prudence
- Date: 2021-04
- Subjects: Mycobacterium tuberculosis , Pyrazinamide , Multidrug resistance , Antitubercular agents , Molecular dynamics , Hydrogen bonding , Ligand binding (Biochemistry) , Dynamic Residue Network
- Language: English
- Type: thesis , text , Masters , MSc
- Identifier: http://hdl.handle.net/10962/178007 , vital:42898
- Description: The World Health Organization declared Tuberculosis a global health emergency and has set a goal to eradicate it by 2035. However, effective treatment and control of the disease is being hindered by the emerging Multi-Drug Resistant and Extensively Drug Resistant strains on the most effective first line prodrug, Pyrazinamide (PZA). Studies have shown that the main cause of PZA resistance is due to mutations in the pncA gene that codes for the target protein Pyrazinamidase (PZase). Therefore, this study aimed to identify novel drug compounds that bind to the active site of wild type PZase and study the dynamics of these potential anti-TB drugs in the mutant systems of PZase. This approach will aid in identifying drugs that may be repurposed for TB therapy and/or designed to counteract PZA resistance. This was achieved by screening 2089 DrugBank compounds against the whole wild type (WT) PZase protein in molecular docking using AutoDOCK4.2. Compound screening based on docking binding energy, hydrogen bonds, molecular weight and active site proximity identified 47 compounds meeting all the set selection criteria. The stability of these compounds were analysed in Molecular Dynamic (MD) simulations and were further studied in PZase mutant systems of A3P, A134V, A146V, D8G, D49A, D49G, D63G, H51P, H137R, L85R, L116R, Q10P, R140S, T61P, V139M and Y103S. Generally, mutant-ligand systems displayed little deviation from the WT systems. The compound systems remained compact, with less fluctuations and more hydrogen bond interactions throughout the simulation (DB00255, DB00655, DB00672, DB00782, DB00977, DB01196, DB04573, DB06414, DB08981, DB11181, DB11760, DB13867, DB13952). From this research study, potential drugs that may be repurposed for TB therapy were identified. Majority of these drugs are currently used in the treatment of hypertension, menopause disorders and inflammation. To further understand the mutant-ligand dynamic systems, calculations such as Dynamic Residue Network (DRN) may be done. Also, the bioactivity of these drugs on Mycobacterium tuberculosis may be studied in wet laboratory, to understand their clinical impart in vivo experiments. , Thesis (MSc) -- Faculty of Science, Biochemistry and Microbiology, 2021
- Full Text:
- Date Issued: 2021-04
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