Synthesis of peptidomimetic compounds as HIV-1 protease inhibitors
- Authors: Kayembe, Jean-Pierre
- Date: 2020
- Subjects: Protease inhibitors , HIV (Viruses) , HIV infections Treatment , Peptidomimetics
- Language: English
- Type: Doctoral theses , text
- Identifier: http://hdl.handle.net/10962/124397 , vital:35604 , DOI https://dx.doi.org/10.21504/10962/124397
- Description: This research project has involved the design, synthesis and evaluation of novel peptidomimetics compounds as HIV-1 protease inhibitors. Here is presented one-step, two-step and three-step syntheses and the in vitro bio-assay studies of a series of fully characterized peptidomimetics as HIV-1 protease inhibitors candidate using the shortest and most cost effective synthetic routes. The first series of compounds were accessed via a synthetic elaboration of Morita-Baylis-Hillman adducts by a Michael addition with benzylamine, proline or glycine esters to afford a series of β-amino-β’-hydroxycarboxylate esters in moderate to good yields. Base-catalyzed cyclization of non-benzylated aza-Michael adducts afforded a series of coumarin-3-hydroxy-2-methylenepropanoate esters in moderate yields. The uncatalyzed direct amidation of diethyl tartrate/tartaric acid and tartaric acid osazone with selected amines/amino acids afforded a series of C2-symmetrical and unsymmetrical 1,2-dihydroxycarboxylates in moderate to very high yields. All the synthesized compounds were fully characterized using spectroscopic techniques. These conjugates, designed as potential HIV-1 inhibitors, were tested against the HIV-1 protease enzyme. A number of these ligands have exhibited inhibition levels and IC50 values comparable to ritonavir, permitting, therefore, their identification as lead compounds for the development of novel inhibitors. , Thesis (PhD) -- Faculty of Science, Chemistry, 2020
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Exploring the potential of imines as antiprotozoan agents with focus on t. Brucei and p. Falciparum
- Authors: Oluwafemi, Kola Augustus
- Date: 2018
- Subjects: Protozoa , Parasites , Imines , Nuclear magnetic resonance , HeLa cells , Plasmodium falciparum , Trypanosoma brucei , Isomerism
- Language: English
- Type: Doctoral theses , text
- Identifier: http://hdl.handle.net/10962/62235 , vital:28145 , DOI 10.21504/10962/62235
- Description: This work focuses on the design, synthesis and evaluation of imine-containing heterocyclic and acyclic compounds with special focus on their bioactivity against parasitic protozoans (P. falciparum and T. brucei) - given the context of drug resistance in the treatment of malaria and Human African sleeping sickness and the fact that several bioactive organic compounds have been reported to possess the imino group. Starting from 2-aminopyridine, novel #-alkylated-5-bromo-7-azabenzimidazoles and substituted 5-bromo-1-(carbamoylmethy)-7-azabenzimidazole derivatives were prepared, and their bioactivity against parasitic protozoans was assessed. NMR spectra of the substituted 5- bromo-1-(carbamoylmethy)-7-azabenzimidazole derivatives exhibited rotational isomerism, and a dynamic NMR study was used in the estimation of the rate constants and the free- energies of activation for rotation. The free-energy differences between the two rotamers were determined and the more stable conformations were predicted. Novel 2-phenyl-7-azabenzimidazoles were also synthesised from 2-aminopyridine. A convenient method for the regioselective formylation of 2,3-diaminopyridines into 2-amino- 7-(benzylimino)pyridine analogues of 2-phenyl-7-azabenzimidazole was developed, and some of the resulting imino derivatives were hydrogenated to verify the importance of the imino moiety for bioactivity. The 2-phenyl-7-azabenzimidazoles and the 2-amino-7- (benzylimino)pyridine analogues were screened for their anti-protozoal activity and their cytotoxicity level was determined against the HeLa cell line. In order to validate the importance of the pyridine moiety, novel #-(phenyl)-2- hydroxybenzylimines, #-(benzyl)-2-hydroxybenzylimines and (±)-trans-1,2-bis[2- hydroxybenzylimino]cyclohexanes were also synthesized and screened for activity against the parasitic protozoans and for cytotoxicity against the HeLa cell line. The biological assay results indicated that these compounds are not significantly cytotoxic and a good number of them show potential as lead compounds for the development of new malaria and trypanosomiasis drugs. , Thesis (PhD) -- Faculty of Science, Chemistry, 2018
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Design, development and evaluation of novel lead compounds as HIV-1 enzyme inhibitors
- Authors: Sekgota, Khethobole Cassius
- Date: 2015
- Subjects: Enzyme inhibitors , Viruses -- Reproduction , HIV (Viruses)
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4546 , http://hdl.handle.net/10962/d1017926
- Description: This project has been concerned with the application of the Baylis-Hillman methodology to the synthesis of medicinally important diketo acid analogues (cinnamate ester-AZT conjugates and 3-hydroxy ester-AZT conjugates) as dual-action HIV-1 IN/RT inhibitors; and on exploratory studies in the preparation of 3-(amidomethyl)-(1H)-2-quinolones as PR inhibitors; and (1H)-2- quinolone-AZT conjugates as dual action IN/RT inhibitors. A series of Baylis-Hillman adducts has been prepared, typically in moderate to excellent yield, by reacting 2-nitrobenzaldehyde with methyl acrylate, ethyl acrylate and methyl vinyl ketone in the presence of 1,4- diazabicyclo[2.2.2]octane (DABCO). Subsequently, various transformations that include conjugate addition of primary and secondary amines to the α,ß-unsaturated moiety to obtain 2- (aminomethyl)-3-hydroxy-3-(2-nitrophenyl)propanoate derivatives, effective SN2´ substitution of the BH ß-hydroxy by a Vilsmeier-Haack in situ-generated chloride to afford Baylis-Hillman allyl chlorides, iron in acetic acid-catalyzed cyclisation to 3-acetoxymethyl-(1H)-2-quinolone derivatives were achieved. Thus, using the Baylis-Hillman methodology, two nuanced classes of diketo acid analogues were constructed. These involved conjugating appropriate propargylamine derivatives with AZT using the „click‟ reaction. In an exploratory study, the quinolone derivative, precisely 3-acetoxymethyl- (1H)-quinol-2-one, was transformed into 3-hydroxymethyl-(1H)-quinol-2-one using potassium carbonate in a mixture of methanol and water (1:1). Following successful hydrolysis, the resulting alcohol was transformed to the corresponding chloride, 3-chloromethyl-(1H)-quinol-2- one, using thionyl chloride. Subsequent nucleophilic substitution afforded 3-(aminomethyl)- (1H)-2-quinolone derivatives which were subsequently transformed to 3-(amidomethyl)-(1H)-2- quinolones; and 3-[(propargylamino)-methyl]-(1H)-quinol-2-one as precursors to quinolone- AZT derivatives. All compounds were characterized by NMR, IR, and where appropriate, high resolution MS
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Synthesis and evaluation of novel HIV-1 enzyme inhibitors
- Authors: Olomola, Temitope Oloruntoba
- Date: 2011
- Subjects: HIV infections -- Treatment HIV infections -- Chemotherapy HIV (Viruses) Enzyme inhibitors AZT (Drug) Reverse transcriptase Proteolytic enzymes Ligands Psoralens Resorcinol
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4369 , http://hdl.handle.net/10962/d1005034
- Description: This study has involved the design, synthesis and evaluation of novel HIV-1 enzyme inhibitors accessed by synthetic elaboration of Baylis-Hillman adducts. Several series of complex coumarin-AZT and cinnamate ester-AZT conjugates have been prepared, in high yields, by exploiting the click reaction between appropriate Baylis-Hillman derived precursors and azidothymidine (AZT), all of which have been fully characterised using spectroscopic techniques. These conjugates, designed as potential dual-action HIV-1 inhibitors, were tested against the appropriate HIV-1 enzymes, i.e. HIV-1 reverse transcriptase and protease or HIV-1 reverse transcriptase and integrase. A number of the ligands have exhibited % inhibition levels and IC50 values comparable to drugs in clinical use, permitting their identification as lead compounds for the development of novel dual-action inhibitors. In silico docking of selected ligands into the active sites of the respective enzymes has provided useful insight into binding conformations and potential hydrogen-bonding interactions with active-site amino acid residues. A series of furocoumarin carboxamide derivatives have been synthesised in four steps starting from resorcinol and these compounds have also been tested for HIV-1 integrase inhibition activity. The structures of unexpected products isolated from Aza-Baylis-Hillman reactions of N-tosylaldimines have been elucidated by spectroscopic analysis, and confirmed by single crystal X-ray analysis. A mechanism for what appears to be an unprecedented transformation has been proposed. Microwave-assisted SeO₂ oxidation of Baylis-Hillman-derived 3-methylcoumarins has provided convenient and efficient access to coumarin-3-carbaldehydes, and a pilot study has revealed the potential of these coumarin-3-carbaldehydes as scaffolds for the construction of tricyclic compounds. The HCl-catalysed reaction of tert-butyl acrylate derived Baylis-Hillman adducts has been shown to afford 3-(chloromethyl)coumarins and α-(chloromethyl)cinnamic acids, the Zstereochemistry of the latter being established by X-ray crystallography. ¹H NMR-based experimental kinetic and DFT-level theoretical studies have been undertaken to establish the reaction sequence and other mechanistic details. Base-catalysed cyclisation on the other hand, has been shown to afford 2H-chromene rather than coumarin derivatives.
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Synthesis of novel inhibitors of 1-Deoxy-D-xylulose-5-phosphate reductoisomerase as potential anti-malarial lead compounds
- Authors: Mutorwa, Marius Kudumo
- Date: 2011
- Subjects: Antimalarials -- Development Plasmodium falciparum Malaria -- Chemotherapy Drug development Lead compounds Phosphonates Phosphonic acids Ligands
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4372 , http://hdl.handle.net/10962/d1005037
- Description: This research has focused on the development of novel substrate mimics as potential DXR inhibitors of 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXR), an essential enzyme in the mevalonate-independent pathway for the biosynthesis of isoprenoids in Plasmodium falciparum. DXR mediates the isomerisation and reduction of 1-deoxy-D-xylulose-5-phosphate (DOXP) into 2C-methyl-D-erithrytol 4-phosphate (MEP) and has been validated as an attractive target for the development of novel anti-malarial chemotherapeutic agents. Reaction of various amines with specially prepared 4-phosphonated crotonic acid in the presence of the peptide coupling reagent, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), has afforded a series of amido-phosphonate esters in moderate to good yields (48% - 73%) which, using a RuCl₃/CeCl₃/NaIO₄ catalyst system, have been dihydroxylated to furnish the dihydroxy-amido phosphonate ester pro-drugs; subsequent hydrolysis under microwave irradiation has afforded the corresponding phosphonic acids. A second series of potential inhibitors viz., 3-substituted aniline-derived phosphonate esters, their corresponding phosphonic acids and mono-sodium salts, have also been successfully synthesised. In these compounds, the essential functional groups are separated by one, two, three or four methylene groups, Deprotonation of the 3-substituted aniline substrates, followed by reaction with the appropriate ω-chloroalkanoyl chloride produced the ω-chloroamide intermediates, which were subjected to the Michaelis-Arbuzov reaction to afford the diethyl phosphonate esters in moderate to good yields (48% - 74%). Microwave-assisted TMSBrmediated cleavage of the phosphonate esters furnished the phosphonic acids, neutralisation of which afforded the mono-sodium salts. Furan-derived phosphate esters and phosphonic acids have been prepared as conformationally-restricted DOXP analogues. Functionalization at C-5 of the trityl-protected furan was achieved using the Vilsmeier-Haack formylation and Friedel-Crafts acylation reactions and, following de-tritylation, phosphorylation and oximation, using hydroxylamine hydrochloride, the novel oxime derivatives have been isolated as a third series of potential DXR inhibitors in very good yields (87% - 96%). Finally, in order to exploit an additional binding pocket in the PƒDXR active site, a series of N-benzylated phosphoramidic derivatives were obtained in seven steps from the starting material, diethyl phosphoramidate. The known inhibitors, fosmidomycin and its acetyl derivative FR900098, were also successfully synthesised as standards for STD-NMR binding and inhibition assays. In all, over 200 compounds (136 novel) have been prepared and appropriately characterised using 1-and 2-D NMR and IR spectroscopic analysis and, where necessary, HRMS or combustion analysis. Saturation Transfer Difference (STD) protein-NMR experiments, undertaken using selected compounds, have revealed binding of most of the ligands examined to EcDXR. Computersimulated docking studies have also been used to explore the preferred ligand-binding conformations and interactions between the ligands and essential DXR active-site residues, while DXR-enzyme inhibition assays of selected synthesised ligands have revealed certain patterns of inhibitory activity.
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Synthesis of novel coumarin derivatives as potential inhibitors of HIV-1 protease
- Authors: Rose, Nathan Rolf
- Date: 2007 , 2013-07-01
- Subjects: Coumarins , Protease Inhibitors , Heterocyclic compounds -- Derivatives , HIV infections -- Treatment
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4430 , http://hdl.handle.net/10962/d1007220 , Coumarins , Protease Inhibitors , Heterocyclic compounds -- Derivatives , HIV infections -- Treatment
- Description: This research has focused on the development of novel coumann derivatives containing peptide-like side chains as potential HIV-1 protease inhibitors. The reaction of various salicylaldehyde derivatives with tert-butyl acrylate In the presence of 1,4- diazabicyclo[2.2.2]octane (DABCO) has afforded a series of Baylis-Hillman adducts in moderate yield. Cyclisation of the adducts in the presence of HCI afforded the corresponding 3-(chloromethyl)coumarin derivatives, which have been reacted with various amine hydrochlorides in the presence of Proton Sponge® to afford a series of novel 3- (aminomethyl)coumarin derivatives, which were fully characterised by NMR and HRMS methods. Various approaches to the introduction of hydroxyl or amino groups at the C-4 position of coumarin and the 3-(chloromethyl)coumarin derivatives have been explored; these have included dihydroxylation of the coumarin double bond, and the synthesis of 4- benzylaminocoumarin derivatives as potential intermediates. The Vilsmeier-Haack and Mannich reactions have also been investigated as possible methods of introducing the desired peptide-like functionality. Computer modelling of selected structures has indicated that some of the novel 3- (aminomethyl)coumarin derivatives may exhibit activity as inhibitors of HIV-1 protease. The planned enzyme inhibition assays were unfortunately precluded by the aqueous insolubility of the selected compounds. Three ¹³C NMR chemical shift algorithms, viz., Modgraph Neural Network, Modgraph HOSE and Chern Window, have been applied to selected compounds prepared in this study. The Modgraph Neural Network algorithm was found, in all cases, to provide the most accurate correlations with the experimentally-determined chemical shifts. , KMBT_363 , Adobe Acrobat 9.54 Paper Capture Plug-in
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