Synthesis and biolgical screening of potential plasmodium falciparum DXR inhibitors
- Authors: Adeyemi, Christiana Modupe
- Date: 2017-04
- Subjects: Plasmodium falciparum , Enzyme inhibitors , Malaria , Antimalarials , Drug development , Malaria -- Chemotherapy , Isopentenoids -- Synthesis , Fosmidomycin , 1-Deoxy-D-xylulose 5-phosphate
- Language: English
- Type: Doctoral theses , text
- Identifier: http://hdl.handle.net/10962/61790 , vital:28060
- Description: The non-mevalonate isoprenoid pathway, also known as the 1-deoxy-D-xylulose-5- phosphate DXP pathway, is absent in humans, but present in the anopheles mosquito responsible for the transmission of malaria. DXP reductoisomerase - a key enzyme in the DXP pathway in Plasmodium falciparum (PfDXR) has been identified as a target for the design of novel anti-malarial drugs. Fosmidomycin and its acetyl analogue (FR900098) are known to be inhibitors of PfDXR and, in this study, synthetic variations of the fosmidomycin scaffold have led to four series of novel analogues. Particular attention has been centred on the introduction of various substituted benzyl groups in each of these series in order to occupy a recently discovered vacant pocket in the PfDXR active-site and thus enhance ligand-enzyme binding. In the process 160 ligands and precursors have been prepared, no less than 119 of them novel. Fistly, a series of C-benzylated phosphonate esters and phosphonic acids were synthesised, in which the fosmidomycin hydroxamate Mg2+- coordinating moiety was replaced by an amide funtionality and the number of methylene groups in the “hydrophobic patch” between the phosphonate and the hydroxamate moiety was decreased from two to one. Several approaches were explored for this series, the most successful involving reaction of 3- substituted anilines with a-bromo propanoic acid in the presence of the coupling agent 1,1'- carbonyldiimidazole (CDI), followed by Michaelis-Arbuzov phosphonation using triethyl phosphite. Reaction of the resulting chiral phosphonate esters with bromotrimethylsilane gave the corresponding phosphonic acids in good yields. In order to obviate chirality issues, a second series of potential “reverse” fosmidomycin analogues was synthesised by replacing the methylene group adjacent to the the phosphonate moiety with a nitrogen atom. Deprotonation, alkylation and phosphorylation of various amines gave diethyl #-benzylphosphoramidate ester intermediate. Aza-Michael addition of these intermediates, followed by hydrolysis gave the corresponding carboxylic acids which could be reacted with different hydroxylamine hydrochloride derivatives to afford the novel hydroxamic acid derivatives in good yields. Thirdly, a series of a novel #-benzylated phosphoramidate derivatives were prepared as aza- FR900098 analogues. Alkylation of different amines using bromoacetalde-hyde diethylacetal gave a series of N-benzyl-2,2-diethoxyethylamine compounds, which were then elaborated via a futher six steps to afford novel #-benzylated phosphoramidate derivatives. Finally, in order to ensure syn-orientation of the donor atoms in the Mg - coordinating group and, at the same time, introduce conformational constraints in the ligand, the hydrophobic patch and the hydroxamate moiety were replaced by cyclic systems. Several approaches towards the synthesis of such conformationally constrained phosphoramidate analogues from maleic anhydride led to the unexpected isolation of an unprecedented acyclic furfuryl compound, and 1H NMR and DFT-level theoretical studies have been initiated to explore the reaction sequence. A series of #-benzylated phosphoramidate derivatives containing dihydroxy aromatic rings (as the conformationally constrained groups) to replace the hydroxamate moiety, were successfully obtained in six steps from the starting material, 3,4-dihydroxylbenzaldehyde. While in vitro assays have been conducted on all of the synthesised compounds, and some of the ligands show promising anti-malarial inhibitory activity - most especially the conformationally constrained cyclic #-benzylated phosphoramidate series. Interestingly, a number of these compounds has also shown activity against T.brucei - the causative agent of sleeping sickness. In silico docking studies of selected compounds has revealed the capacity of some of the ligands to bind effectively in the PfDXR active-site with the newly introduced benzyl group occupying the adjacent vacant pocket. The physico-chemical properties of these ligands were also explored in order to predict the oral-bioavailability. Most of the ligands obeyed the Lipinski rule of 5, while QSAR methods have been used in an attempt to correlate structural variations and calculated molecular properties with the bioassay data. , Thesis (PhD) -- Faculty of Science, Chemistry, 2017
- Full Text:
- Authors: Adeyemi, Christiana Modupe
- Date: 2017-04
- Subjects: Plasmodium falciparum , Enzyme inhibitors , Malaria , Antimalarials , Drug development , Malaria -- Chemotherapy , Isopentenoids -- Synthesis , Fosmidomycin , 1-Deoxy-D-xylulose 5-phosphate
- Language: English
- Type: Doctoral theses , text
- Identifier: http://hdl.handle.net/10962/61790 , vital:28060
- Description: The non-mevalonate isoprenoid pathway, also known as the 1-deoxy-D-xylulose-5- phosphate DXP pathway, is absent in humans, but present in the anopheles mosquito responsible for the transmission of malaria. DXP reductoisomerase - a key enzyme in the DXP pathway in Plasmodium falciparum (PfDXR) has been identified as a target for the design of novel anti-malarial drugs. Fosmidomycin and its acetyl analogue (FR900098) are known to be inhibitors of PfDXR and, in this study, synthetic variations of the fosmidomycin scaffold have led to four series of novel analogues. Particular attention has been centred on the introduction of various substituted benzyl groups in each of these series in order to occupy a recently discovered vacant pocket in the PfDXR active-site and thus enhance ligand-enzyme binding. In the process 160 ligands and precursors have been prepared, no less than 119 of them novel. Fistly, a series of C-benzylated phosphonate esters and phosphonic acids were synthesised, in which the fosmidomycin hydroxamate Mg2+- coordinating moiety was replaced by an amide funtionality and the number of methylene groups in the “hydrophobic patch” between the phosphonate and the hydroxamate moiety was decreased from two to one. Several approaches were explored for this series, the most successful involving reaction of 3- substituted anilines with a-bromo propanoic acid in the presence of the coupling agent 1,1'- carbonyldiimidazole (CDI), followed by Michaelis-Arbuzov phosphonation using triethyl phosphite. Reaction of the resulting chiral phosphonate esters with bromotrimethylsilane gave the corresponding phosphonic acids in good yields. In order to obviate chirality issues, a second series of potential “reverse” fosmidomycin analogues was synthesised by replacing the methylene group adjacent to the the phosphonate moiety with a nitrogen atom. Deprotonation, alkylation and phosphorylation of various amines gave diethyl #-benzylphosphoramidate ester intermediate. Aza-Michael addition of these intermediates, followed by hydrolysis gave the corresponding carboxylic acids which could be reacted with different hydroxylamine hydrochloride derivatives to afford the novel hydroxamic acid derivatives in good yields. Thirdly, a series of a novel #-benzylated phosphoramidate derivatives were prepared as aza- FR900098 analogues. Alkylation of different amines using bromoacetalde-hyde diethylacetal gave a series of N-benzyl-2,2-diethoxyethylamine compounds, which were then elaborated via a futher six steps to afford novel #-benzylated phosphoramidate derivatives. Finally, in order to ensure syn-orientation of the donor atoms in the Mg - coordinating group and, at the same time, introduce conformational constraints in the ligand, the hydrophobic patch and the hydroxamate moiety were replaced by cyclic systems. Several approaches towards the synthesis of such conformationally constrained phosphoramidate analogues from maleic anhydride led to the unexpected isolation of an unprecedented acyclic furfuryl compound, and 1H NMR and DFT-level theoretical studies have been initiated to explore the reaction sequence. A series of #-benzylated phosphoramidate derivatives containing dihydroxy aromatic rings (as the conformationally constrained groups) to replace the hydroxamate moiety, were successfully obtained in six steps from the starting material, 3,4-dihydroxylbenzaldehyde. While in vitro assays have been conducted on all of the synthesised compounds, and some of the ligands show promising anti-malarial inhibitory activity - most especially the conformationally constrained cyclic #-benzylated phosphoramidate series. Interestingly, a number of these compounds has also shown activity against T.brucei - the causative agent of sleeping sickness. In silico docking studies of selected compounds has revealed the capacity of some of the ligands to bind effectively in the PfDXR active-site with the newly introduced benzyl group occupying the adjacent vacant pocket. The physico-chemical properties of these ligands were also explored in order to predict the oral-bioavailability. Most of the ligands obeyed the Lipinski rule of 5, while QSAR methods have been used in an attempt to correlate structural variations and calculated molecular properties with the bioassay data. , Thesis (PhD) -- Faculty of Science, Chemistry, 2017
- Full Text:
Studies towards the development of novel antimalarial agents
- Authors: Adeyemi, Christiana Modupe
- Date: 2015
- Subjects: Antimalarials , Malaria , Drug resistance , Drug development , Enzyme inhibitors , Plasmodium
- Language: English
- Type: text , Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/54645 , vital:26596
- Description: Considerable efforts have been made in the modification of existing antimalarial drugs, and the support of incentive programmes have led to a drastic decrease in malaria cases reported by WHO during the past 6 years. However, the development of drug resistance threatens the eradication of this deadly disease and has prompted research on the synthesis of novel antimalarial drugs. Our research has involved the design and synthesis of novel benzylated phosphonate esters as potential 1-deoxy-D-xylose-5-phosphate reductoisomerase (DXR) inhibitors. A series of amidoalkylphosphonate esters were obtained by reacting various 3-subsituted anilines and heterocyclic amines with chloroalkanoyl chlorides and reacting the resulting chloroalkanamides with triethyl phosphite using Michaelis-Arbuzov methodology. Benzylation of the phosphonate esters afforded a series of novel N-benzylated derivatives in good yields and these compounds were fully characterised by NMR and HRMS methods. Several approaches to the introduction of a benzyl group at the C-2 position of the phosphonate ester derivatives have been explored, leading unexpectedly to the isolation of unprecedented tetrahydrofuranyl derivatives. Studies towards the preparation of potential bi-functional PfDXR / HIV-1 RT inhibitors have also been initiated. Preliminary in silico docking studies of selected non-benzylated and benzylated phosphonated derivatives into the Pf-DXR active-site has provided useful insight into the binding potential of these ligands. Bioassays have revealed a very low toxicity for all the synthesised phosphonated compounds and a number of these ligands also exhibit a promising inhibitory activity against the Plasmodium parasite.
- Full Text:
- Authors: Adeyemi, Christiana Modupe
- Date: 2015
- Subjects: Antimalarials , Malaria , Drug resistance , Drug development , Enzyme inhibitors , Plasmodium
- Language: English
- Type: text , Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/54645 , vital:26596
- Description: Considerable efforts have been made in the modification of existing antimalarial drugs, and the support of incentive programmes have led to a drastic decrease in malaria cases reported by WHO during the past 6 years. However, the development of drug resistance threatens the eradication of this deadly disease and has prompted research on the synthesis of novel antimalarial drugs. Our research has involved the design and synthesis of novel benzylated phosphonate esters as potential 1-deoxy-D-xylose-5-phosphate reductoisomerase (DXR) inhibitors. A series of amidoalkylphosphonate esters were obtained by reacting various 3-subsituted anilines and heterocyclic amines with chloroalkanoyl chlorides and reacting the resulting chloroalkanamides with triethyl phosphite using Michaelis-Arbuzov methodology. Benzylation of the phosphonate esters afforded a series of novel N-benzylated derivatives in good yields and these compounds were fully characterised by NMR and HRMS methods. Several approaches to the introduction of a benzyl group at the C-2 position of the phosphonate ester derivatives have been explored, leading unexpectedly to the isolation of unprecedented tetrahydrofuranyl derivatives. Studies towards the preparation of potential bi-functional PfDXR / HIV-1 RT inhibitors have also been initiated. Preliminary in silico docking studies of selected non-benzylated and benzylated phosphonated derivatives into the Pf-DXR active-site has provided useful insight into the binding potential of these ligands. Bioassays have revealed a very low toxicity for all the synthesised phosphonated compounds and a number of these ligands also exhibit a promising inhibitory activity against the Plasmodium parasite.
- Full Text:
Synthesis and evaluation of novel heterocycles as potential HIV-1 enzyme inhibitors
- Ngnie Tuemgnie, Gaëlle Tatiana
- Authors: Ngnie Tuemgnie, Gaëlle Tatiana
- Date: 2014
- Subjects: Heterocyclic compounds , Enzyme inhibitors , Organic compounds , Green chemistry , Coumarins , HIV (Viruses) Enzymes
- Language: English
- Type: Doctoral theses , text
- Identifier: http://hdl.handle.net/10962/194293 , vital:45440 , DOI https://doi.org/10.21504/10962/194293
- Description: This project has focussed on the synthesis and the evaluation of organic compounds as potential HIV-1 enzyme inhibitors, by making use of green chemistry (microwave assisted synthesis and click chemistry), palladium catalyzed reactions (Heck and Sonogashira coupling), Baylis Hillman methodology and aldol condensation. These compounds were synthesized in good yields and fully characterised by spectroscopic techniques. Biological assay data revealed that some of the compounds possess high inhibitory activity and their effective inhibitory concentration was as good as those of drugs in clinical use. These potential drug molecules were identified by preliminary investigations carried out by molecular modelling where a trend of their inhibitory activity against different enzymes was anticipated. Benzotriazole-AZT conjugates generated by 1,3-dipolar cycloaddition of anthranilic acid derivatives with AZT showed good inhibitory activity in silico against both HIV-1 protease (PR) and HIV-1 reverse transcriptase (RT) enzymes. Still in line with our dual action strategy, cinnamate ester-AZT conjugates were synthesized in three steps starting from benzaldehyde derivatives with a click reaction at the final step. These compounds also showed some inhibitory activity against HIV-1 RT enzyme (88%). In addition, the cinnamoyl fragment attached to AZT appeared to improve the activity of AZT against HIV-1 RT. Peptide chemistry involving carbonyl diimidazole as a coupling reagent between cinnamic acid derivatives and protected amino acids was used to prepare substituted amino acid derivatives which appeared to be very active against the integrase (IN) enzyme (88%). Commercially available coumarin was iodinated and derivatized through palladium catalyzed Heck and Sonogashira reactions with activated alkenes and a terminal alkyne respectively to afford novel coumarin derivatives in good yields. Optimization studies on the Heck reaction with regards to the phosphine ligand, the palladium catalyst and the solvent were carried out to afford novel formyl substituted cinnamate esters with nonaflyl salicylaldehyde derivatives. , Thesis (PhD) -- Faculty of Science, Chemistry, 2014
- Full Text:
- Authors: Ngnie Tuemgnie, Gaëlle Tatiana
- Date: 2014
- Subjects: Heterocyclic compounds , Enzyme inhibitors , Organic compounds , Green chemistry , Coumarins , HIV (Viruses) Enzymes
- Language: English
- Type: Doctoral theses , text
- Identifier: http://hdl.handle.net/10962/194293 , vital:45440 , DOI https://doi.org/10.21504/10962/194293
- Description: This project has focussed on the synthesis and the evaluation of organic compounds as potential HIV-1 enzyme inhibitors, by making use of green chemistry (microwave assisted synthesis and click chemistry), palladium catalyzed reactions (Heck and Sonogashira coupling), Baylis Hillman methodology and aldol condensation. These compounds were synthesized in good yields and fully characterised by spectroscopic techniques. Biological assay data revealed that some of the compounds possess high inhibitory activity and their effective inhibitory concentration was as good as those of drugs in clinical use. These potential drug molecules were identified by preliminary investigations carried out by molecular modelling where a trend of their inhibitory activity against different enzymes was anticipated. Benzotriazole-AZT conjugates generated by 1,3-dipolar cycloaddition of anthranilic acid derivatives with AZT showed good inhibitory activity in silico against both HIV-1 protease (PR) and HIV-1 reverse transcriptase (RT) enzymes. Still in line with our dual action strategy, cinnamate ester-AZT conjugates were synthesized in three steps starting from benzaldehyde derivatives with a click reaction at the final step. These compounds also showed some inhibitory activity against HIV-1 RT enzyme (88%). In addition, the cinnamoyl fragment attached to AZT appeared to improve the activity of AZT against HIV-1 RT. Peptide chemistry involving carbonyl diimidazole as a coupling reagent between cinnamic acid derivatives and protected amino acids was used to prepare substituted amino acid derivatives which appeared to be very active against the integrase (IN) enzyme (88%). Commercially available coumarin was iodinated and derivatized through palladium catalyzed Heck and Sonogashira reactions with activated alkenes and a terminal alkyne respectively to afford novel coumarin derivatives in good yields. Optimization studies on the Heck reaction with regards to the phosphine ligand, the palladium catalyst and the solvent were carried out to afford novel formyl substituted cinnamate esters with nonaflyl salicylaldehyde derivatives. , Thesis (PhD) -- Faculty of Science, Chemistry, 2014
- Full Text:
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