Quinolone-Pyrazinamide Derivatives: synthesis, characterisation, in silico ADME analysis and in vitro biological evaluation against Mycobacterium tuberculosis
- Authors: Rukweza, Kudakwashe Gerald
- Date: 2023-10-13
- Subjects: Quinolone antibacterial agents , Mycobacterium tuberculosis , Antitubercular agents , Tuberculosis Chemotherapy , Drug resistance , Moxifloxacin , Isoniazid
- Language: English
- Type: Academic theses , Master's theses , text
- Identifier: http://hdl.handle.net/10962/390901 , vital:68596
- Description: Tuberculosis is one of the leading causes of death worldwide caused by an infectious species, Mycobacterium tuberculosis (Mtb). Some of the factors that contribute to the prevalence of this disease include the complexity of diagnosis, prolonged period of therapy, side effects associated with current TB drugs, the prevalence of resistance against the current treatment options and a high incidence of co-infection with HIV/AIDS. Thus, there is a need for new alternative drugs to provide safer and shorter treatment therapy options that are not susceptible to the development of drug resistance. In this project, we focus our attention on the quinolone pharmacophore. Quinolones are currently used as alternative options in the treatment of resistant strains of Mtb. Previous work pertaining to quinolone-isoniazid hybrid compounds showed promising in vitro activity against the H37Rv strain of Mtb and served as the inspiration to pursue this project. The journey commenced with the synthesis of quinolone-pyrazinamide hybrid compounds (Figure 3.1). These compounds were synthesised, through the attachment of the quinolone and the pyrazinamide entity through a hydrazine linker. The synthesised compounds were purified, and their structural identity confirmed using common spectroscopic techniques including 1H and 13C NMR, infra-red (IR) and mass spectrometry. In vitro biological assays were performed by testing for the activity against the H37RvMA strain of Mtb. The bioassays were performed in triplicates to ensure the accuracy of the results. Moxifloxacin and isoniazid were tested as control compounds. Finally, the resultant compounds were profiled in silico for physicochemical and ADMET properties using open access software SwissADME. All the synthesised compounds 3.8a-f showed no activity against H37RvMA. In most cases, the resulting compounds showed minimal to no activity (MICs ≥ 57.3 μM) in all three media. During the in vitro studies, the compounds showed significant precipitation in the media over time suggesting poor aqueous solubility. The SwissADME analysis of these compounds indicated poor solubility in aqueous media, which is likely linked to their molecular size and complexity. Despite poor aqueous solubility, compounds 3.8a-f showed acceptable physicochemical properties and ADME parameters. No PAINs (Pan-assay interference compounds) were observed. Minimal to no interaction with CYP enzymes were predicted. Most of the compounds were compatible with the Lipinski’s rules of five. , Thesis (MSc) -- Faculty of Science, Pharmacy, 2023
- Full Text:
- Date Issued: 2023-10-13
- Authors: Rukweza, Kudakwashe Gerald
- Date: 2023-10-13
- Subjects: Quinolone antibacterial agents , Mycobacterium tuberculosis , Antitubercular agents , Tuberculosis Chemotherapy , Drug resistance , Moxifloxacin , Isoniazid
- Language: English
- Type: Academic theses , Master's theses , text
- Identifier: http://hdl.handle.net/10962/390901 , vital:68596
- Description: Tuberculosis is one of the leading causes of death worldwide caused by an infectious species, Mycobacterium tuberculosis (Mtb). Some of the factors that contribute to the prevalence of this disease include the complexity of diagnosis, prolonged period of therapy, side effects associated with current TB drugs, the prevalence of resistance against the current treatment options and a high incidence of co-infection with HIV/AIDS. Thus, there is a need for new alternative drugs to provide safer and shorter treatment therapy options that are not susceptible to the development of drug resistance. In this project, we focus our attention on the quinolone pharmacophore. Quinolones are currently used as alternative options in the treatment of resistant strains of Mtb. Previous work pertaining to quinolone-isoniazid hybrid compounds showed promising in vitro activity against the H37Rv strain of Mtb and served as the inspiration to pursue this project. The journey commenced with the synthesis of quinolone-pyrazinamide hybrid compounds (Figure 3.1). These compounds were synthesised, through the attachment of the quinolone and the pyrazinamide entity through a hydrazine linker. The synthesised compounds were purified, and their structural identity confirmed using common spectroscopic techniques including 1H and 13C NMR, infra-red (IR) and mass spectrometry. In vitro biological assays were performed by testing for the activity against the H37RvMA strain of Mtb. The bioassays were performed in triplicates to ensure the accuracy of the results. Moxifloxacin and isoniazid were tested as control compounds. Finally, the resultant compounds were profiled in silico for physicochemical and ADMET properties using open access software SwissADME. All the synthesised compounds 3.8a-f showed no activity against H37RvMA. In most cases, the resulting compounds showed minimal to no activity (MICs ≥ 57.3 μM) in all three media. During the in vitro studies, the compounds showed significant precipitation in the media over time suggesting poor aqueous solubility. The SwissADME analysis of these compounds indicated poor solubility in aqueous media, which is likely linked to their molecular size and complexity. Despite poor aqueous solubility, compounds 3.8a-f showed acceptable physicochemical properties and ADME parameters. No PAINs (Pan-assay interference compounds) were observed. Minimal to no interaction with CYP enzymes were predicted. Most of the compounds were compatible with the Lipinski’s rules of five. , Thesis (MSc) -- Faculty of Science, Pharmacy, 2023
- Full Text:
- Date Issued: 2023-10-13
An in vitro investigation of novel quinolone derivatives on selected pharmacological targets for diabetes mellitus and associated complications
- Authors: Ayodele, Omobolanle Opeyemi
- Date: 2023-03-29
- Subjects: Diabetes , Hyperglycemia , Quinolone antibacterial agents , Cardiovascular system Diseases , Diabetes Alternative treatment , In vitro experiment
- Language: English
- Type: Academic theses , Master's theses , text
- Identifier: http://hdl.handle.net/10962/409813 , vital:70632
- Description: Diabetes mellitus (DM) is a group of endocrine and metabolic disorders characterised and identified by the presence of hyperglycaemia over a long period and, to an extent, accompanied by hyperlipidaemia. CVD has been reported to be the leading cause of mortality in patients with DM. Several antidiabetic agents are available for managing DM, but these agents are not for curative therapy and present with undesirable side effects. In addition, these agents become less effective as the patient's condition progresses to complete beta-cell failure. Therefore, developing newer antidiabetic agents with minimal undesirable side effects, prolonged efficacy and protection against the development of DM complications are necessary. This study was conducted to identify potential novel antidiabetic agents with cardiovascular-protective activity. The compounds of interest for the study were quinolone derivatives since quinolones have been reported to have an antihyperglycaemic effect. , Thesis (MSc) -- Faculty of Pharmacy, 2023
- Full Text:
- Date Issued: 2023-03-29
- Authors: Ayodele, Omobolanle Opeyemi
- Date: 2023-03-29
- Subjects: Diabetes , Hyperglycemia , Quinolone antibacterial agents , Cardiovascular system Diseases , Diabetes Alternative treatment , In vitro experiment
- Language: English
- Type: Academic theses , Master's theses , text
- Identifier: http://hdl.handle.net/10962/409813 , vital:70632
- Description: Diabetes mellitus (DM) is a group of endocrine and metabolic disorders characterised and identified by the presence of hyperglycaemia over a long period and, to an extent, accompanied by hyperlipidaemia. CVD has been reported to be the leading cause of mortality in patients with DM. Several antidiabetic agents are available for managing DM, but these agents are not for curative therapy and present with undesirable side effects. In addition, these agents become less effective as the patient's condition progresses to complete beta-cell failure. Therefore, developing newer antidiabetic agents with minimal undesirable side effects, prolonged efficacy and protection against the development of DM complications are necessary. This study was conducted to identify potential novel antidiabetic agents with cardiovascular-protective activity. The compounds of interest for the study were quinolone derivatives since quinolones have been reported to have an antihyperglycaemic effect. , Thesis (MSc) -- Faculty of Pharmacy, 2023
- Full Text:
- Date Issued: 2023-03-29
Fabrication and characterization of ciprofloxacin loaded niosomes for transtympanic delivery
- Authors: Mhlanga, Asavela
- Date: 2022-04-06
- Subjects: Drug delivery systems , Liposomes , Ciprofloxacin , Quinolone antibacterial agents , Drug carriers (Pharmacy) , Drug stability , Lamellarity , Niosomes
- Language: English
- Type: Academic theses , Master's theses , text
- Identifier: http://hdl.handle.net/10962/290715 , vital:56777
- Description: Ciprofloxacin (CPH) is a broad-spectrum antibiotic used to treat bone, joint, and skin infections. It is commercially available as an extended-release tablet and as a cream dosage form. CPH is a bactericidal active pharmaceutical ingredient (API) of the fluoroquinolone drug class. It inhibits deoxyribonucleic acid (DNA) replication by inhibiting bacterial DNA topoisomerase and DNA gyrase enzymes. Common adverse effects include nausea, vomiting, unusual fatigue, pale skin, and may increase the risk of tendinitis, which could be a major concern. CPH is, according to the Biopharmaceutics Classification System (BCS), classified as a BCS class IV drug exhibiting low oral bioavailability, low solubility, and intestinal permeability. CPH was chosen as a good candidate for the study because of its stability in solutions, its low molecular weight (331.4 g/mol), and its moderate lipophilicity (log P = 0.28) [16]. The use of conventional ear drops in the ear is effective, avoids hepatic first metabolism and extensive protein binding and may reduce adverse effects as a low dose may be used to achieve a therapeutic effect. However, conventional ear drops and oral antibiotics have a long onset of action and have to be taken/applied in short intervals. For convenience and assurance of a long residence time in the ear, CPH may be delivered by using a niosomal formulation, a liquid at room temperature, to allow administration into the ear without the need to constantly apply the ear drops for long periods of time. A simple, rapid, precise, accurate, reproducible, and specific reversed-phase high-performance liquid chromatography (RP-HPLC) method using ultraviolet (UV) detection for the quantitation of CPH was developed and optimized using a central composite design (CCD). The method was validated using International Conference on Harmonisation (ICH) guidelines and was found to be linear, precise, accurate, and specific for the analysis of CPH. Since the method is specific, it was used to quantify CPH in commercial and experimental formulations and monitor CPH released during in-vitro release testing. The compatibility of CPH and potential excipients was investigated during preformulation studies using Fourier transform infrared spectroscopy (FT-IR) and differential scanning calorimetry (DSC) to identify and select suitable excipients for use during formulation development activities. No apparent interactions were evident between CPH, and the excipients tested. The probe sonication method was used to manufacture CPH loaded niosomes using different surfactants/surfactant combinations, and a combination of Tween® 80: sodium lauryl sulfate (SLS) was found to be the best composition in terms of both entrapment efficiency and Zeta potential. The limits for the independent input variables used for the manufacture included amplitude, sonication time, and amount of cholesterol were determined. Design of experiments (DOE) was used to design the study. The input variables investigated included amplitude, amount of cholesterol, and sonication time. The output or responses monitored included Zeta potential, vesicle size, polydispersity index (PDI), and entrapment efficiency. Non-ionic surfactant systems are predominantly stabilized by steric stabilization, and there is only a minor electrostatic element from adsorbed hydroxyl ions. With the inclusion of SLS it is to be expected that Zeta potential will be a contributing factor. DOE using Box-Behnken design (BBD) and response surface methodology (RSM) in addition to Artificial Neural Networks (ANN) were used for the optimization of the formulation. The optimized formulation had a composition of 1 g cholesterol, 1 g of Tween® 80, 1 g of SLS and was prepared at an amplitude of 11.294 % with a sonication time of 3.304 minutes. The formulation exhibited zero-order release kinetics and had an average pH of 7.45. The formulation was stored at 4 ℃ and 25 ℃ and was assessed for vesicle size, entrapment efficiency, Zeta potential, colour, lamellarity, and PDI every 7 days for 4 weeks. The lead formulation stored at 4 ℃ was more stable than the formulation at 25 ℃ in terms of entrapment efficiency, PDI and vesicle size during the 4-week period. CPH loaded niosomes for transtympanic delivery in the treatment of otitis media were developed and optimized. The technology exhibits sustained release of CPH and has the potential for further development and optimization. , Thesis (MSc) -- Faculty of Pharmacy, Pharmacy, 2022
- Full Text:
- Date Issued: 2022-04-06
- Authors: Mhlanga, Asavela
- Date: 2022-04-06
- Subjects: Drug delivery systems , Liposomes , Ciprofloxacin , Quinolone antibacterial agents , Drug carriers (Pharmacy) , Drug stability , Lamellarity , Niosomes
- Language: English
- Type: Academic theses , Master's theses , text
- Identifier: http://hdl.handle.net/10962/290715 , vital:56777
- Description: Ciprofloxacin (CPH) is a broad-spectrum antibiotic used to treat bone, joint, and skin infections. It is commercially available as an extended-release tablet and as a cream dosage form. CPH is a bactericidal active pharmaceutical ingredient (API) of the fluoroquinolone drug class. It inhibits deoxyribonucleic acid (DNA) replication by inhibiting bacterial DNA topoisomerase and DNA gyrase enzymes. Common adverse effects include nausea, vomiting, unusual fatigue, pale skin, and may increase the risk of tendinitis, which could be a major concern. CPH is, according to the Biopharmaceutics Classification System (BCS), classified as a BCS class IV drug exhibiting low oral bioavailability, low solubility, and intestinal permeability. CPH was chosen as a good candidate for the study because of its stability in solutions, its low molecular weight (331.4 g/mol), and its moderate lipophilicity (log P = 0.28) [16]. The use of conventional ear drops in the ear is effective, avoids hepatic first metabolism and extensive protein binding and may reduce adverse effects as a low dose may be used to achieve a therapeutic effect. However, conventional ear drops and oral antibiotics have a long onset of action and have to be taken/applied in short intervals. For convenience and assurance of a long residence time in the ear, CPH may be delivered by using a niosomal formulation, a liquid at room temperature, to allow administration into the ear without the need to constantly apply the ear drops for long periods of time. A simple, rapid, precise, accurate, reproducible, and specific reversed-phase high-performance liquid chromatography (RP-HPLC) method using ultraviolet (UV) detection for the quantitation of CPH was developed and optimized using a central composite design (CCD). The method was validated using International Conference on Harmonisation (ICH) guidelines and was found to be linear, precise, accurate, and specific for the analysis of CPH. Since the method is specific, it was used to quantify CPH in commercial and experimental formulations and monitor CPH released during in-vitro release testing. The compatibility of CPH and potential excipients was investigated during preformulation studies using Fourier transform infrared spectroscopy (FT-IR) and differential scanning calorimetry (DSC) to identify and select suitable excipients for use during formulation development activities. No apparent interactions were evident between CPH, and the excipients tested. The probe sonication method was used to manufacture CPH loaded niosomes using different surfactants/surfactant combinations, and a combination of Tween® 80: sodium lauryl sulfate (SLS) was found to be the best composition in terms of both entrapment efficiency and Zeta potential. The limits for the independent input variables used for the manufacture included amplitude, sonication time, and amount of cholesterol were determined. Design of experiments (DOE) was used to design the study. The input variables investigated included amplitude, amount of cholesterol, and sonication time. The output or responses monitored included Zeta potential, vesicle size, polydispersity index (PDI), and entrapment efficiency. Non-ionic surfactant systems are predominantly stabilized by steric stabilization, and there is only a minor electrostatic element from adsorbed hydroxyl ions. With the inclusion of SLS it is to be expected that Zeta potential will be a contributing factor. DOE using Box-Behnken design (BBD) and response surface methodology (RSM) in addition to Artificial Neural Networks (ANN) were used for the optimization of the formulation. The optimized formulation had a composition of 1 g cholesterol, 1 g of Tween® 80, 1 g of SLS and was prepared at an amplitude of 11.294 % with a sonication time of 3.304 minutes. The formulation exhibited zero-order release kinetics and had an average pH of 7.45. The formulation was stored at 4 ℃ and 25 ℃ and was assessed for vesicle size, entrapment efficiency, Zeta potential, colour, lamellarity, and PDI every 7 days for 4 weeks. The lead formulation stored at 4 ℃ was more stable than the formulation at 25 ℃ in terms of entrapment efficiency, PDI and vesicle size during the 4-week period. CPH loaded niosomes for transtympanic delivery in the treatment of otitis media were developed and optimized. The technology exhibits sustained release of CPH and has the potential for further development and optimization. , Thesis (MSc) -- Faculty of Pharmacy, Pharmacy, 2022
- Full Text:
- Date Issued: 2022-04-06
Effect of fluoroquinolones antibiotics on vancomycin and oxacillin resistant staphylococcus species in Eastern Cape Province
- Authors: Soyege, Oludotun
- Date: 2012
- Subjects: Staphylococcus aureus , Quinolone antibacterial agents , Fluoroquinolones
- Language: English
- Type: Master's theses , text
- Identifier: http://hdl.handle.net/10353/25349 , vital:64212
- Description: This study shows the susceptibility profile of some Staphylococcus species isolated from commensal Staphylococci in Nkonkobe municipality, South Africa. A total number of 120 Staphylococcal isolates were screened for their susceptibilities to various classes of antibiotics such as Aminoglycoside (Gentamycin), Aminoglycoside (Kanamycin), Macrolide (Erythromycin), Tetracycline (Minocycline), Anti-tuberculous (Rifampicin), Lincosamides (Clindamycin), Cephalosporin and Fluoroquinolones in general. During the study, 32 (26percent) the test organisms were susceptible to both methicillin and vancomycin, while 12 (10percent) had co-resistance to the antibiotics. Furthermore, Gentamycin (an Aminoglycoside) had a relatively high potency against the isolates with 107 (89.17percent) of the bacteria being susceptible to it, while 10 (8.33percent) were resistant. On the other hand, Erythromycin (a Macrolide) was active against 72 (60percent) of the isolates, while 5 (4.17percent) and 74 (61.67percent) of the isolates yielded intermediate and resistant responses respectively. In addition , 51 (42.5percent) of the isolates were susceptible to rifampicin, while 1 (0.83percent) and 17 (14.17percent) were intermediate and resistant respectively. Ten percent of the isolates screened for their antibiotic susceptibility pattern in this study were positive for mecA gene among the vancomycin-oxacillin resistant strains while van gene was not detected in any of the isolates. This shows how the synergy of both vancomycin and oxacillin contribute to some resistance nature of Staphylococci. In order to overcome this resistance attributes of Staphylococci, to the commonly used antibiotics as discussed under this context, various types of fluoroquinolones were tested. The result shows that less than 10percent of the isolates were generally resistant to the fluoroquinolones except against Nalidix acid to which all the isolates were resistant. Other antibiotics had relatively higher resistance patterns as observed for minocycline (39.51percent), clindamycin (12.75percent), gentamycin (12.31percent) and vancomycin (12.3percent). The new generation fluoroquinolones including Gatifloxacin, Levofloxacin, Moxifloxacin and Ciprofloxacin to which less than 5percent of the bacteria are resistant gives some clinical advantage over the Methicillin and Vancomycin resistant strains. About 31percent of the isolates had multiple antibiotic resistance index of ≥1 and suggests animals in the community as potential reservoirs of antibiotic resistance determinants in the environment. Data obtained in this study is of epidemiological importance and valuable for disease control. , Thesis (MSc) -- Faculty of Science and Agriculture, 2012
- Full Text:
- Date Issued: 2012
- Authors: Soyege, Oludotun
- Date: 2012
- Subjects: Staphylococcus aureus , Quinolone antibacterial agents , Fluoroquinolones
- Language: English
- Type: Master's theses , text
- Identifier: http://hdl.handle.net/10353/25349 , vital:64212
- Description: This study shows the susceptibility profile of some Staphylococcus species isolated from commensal Staphylococci in Nkonkobe municipality, South Africa. A total number of 120 Staphylococcal isolates were screened for their susceptibilities to various classes of antibiotics such as Aminoglycoside (Gentamycin), Aminoglycoside (Kanamycin), Macrolide (Erythromycin), Tetracycline (Minocycline), Anti-tuberculous (Rifampicin), Lincosamides (Clindamycin), Cephalosporin and Fluoroquinolones in general. During the study, 32 (26percent) the test organisms were susceptible to both methicillin and vancomycin, while 12 (10percent) had co-resistance to the antibiotics. Furthermore, Gentamycin (an Aminoglycoside) had a relatively high potency against the isolates with 107 (89.17percent) of the bacteria being susceptible to it, while 10 (8.33percent) were resistant. On the other hand, Erythromycin (a Macrolide) was active against 72 (60percent) of the isolates, while 5 (4.17percent) and 74 (61.67percent) of the isolates yielded intermediate and resistant responses respectively. In addition , 51 (42.5percent) of the isolates were susceptible to rifampicin, while 1 (0.83percent) and 17 (14.17percent) were intermediate and resistant respectively. Ten percent of the isolates screened for their antibiotic susceptibility pattern in this study were positive for mecA gene among the vancomycin-oxacillin resistant strains while van gene was not detected in any of the isolates. This shows how the synergy of both vancomycin and oxacillin contribute to some resistance nature of Staphylococci. In order to overcome this resistance attributes of Staphylococci, to the commonly used antibiotics as discussed under this context, various types of fluoroquinolones were tested. The result shows that less than 10percent of the isolates were generally resistant to the fluoroquinolones except against Nalidix acid to which all the isolates were resistant. Other antibiotics had relatively higher resistance patterns as observed for minocycline (39.51percent), clindamycin (12.75percent), gentamycin (12.31percent) and vancomycin (12.3percent). The new generation fluoroquinolones including Gatifloxacin, Levofloxacin, Moxifloxacin and Ciprofloxacin to which less than 5percent of the bacteria are resistant gives some clinical advantage over the Methicillin and Vancomycin resistant strains. About 31percent of the isolates had multiple antibiotic resistance index of ≥1 and suggests animals in the community as potential reservoirs of antibiotic resistance determinants in the environment. Data obtained in this study is of epidemiological importance and valuable for disease control. , Thesis (MSc) -- Faculty of Science and Agriculture, 2012
- Full Text:
- Date Issued: 2012
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