Synthesis, stereochemistry and in vitro STD NMR and in silico HIV-1 PR enzyme-binding potential of MBH-derived inhibitors
- Tukulula, Matshawandile, Olasupo, Idris A, Mugumbate, Grace C, Lobb, Kevin A, Klein, Rosalyn, Sayed, Yasien, Tshiwawa, Tendamudzimu, Kaye, Perry T
- Authors: Tukulula, Matshawandile , Olasupo, Idris A , Mugumbate, Grace C , Lobb, Kevin A , Klein, Rosalyn , Sayed, Yasien , Tshiwawa, Tendamudzimu , Kaye, Perry T
- Date: 2022
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/452813 , vital:75172 , xlink:href="https://doi.org/10.1016/j.molstruc.2022.133716"
- Description: Aza-Michael reactions of a pyridine-3-carbaldehyde-derived Morita-Baylis-Hillman (MBH) adduct with various amines have afforded a series of 10 diastereomeric products, stereochemical analysis of which has been achieved using a combination of NMR (1D, 2D and NOESY) and computer modelling methods. Saturation Transfer Difference (STD) 1H NMR spectroscopy and in silico molecular docking studies have been used to explore the HIV-1 protease sub-type C enzyme binding potential of these compounds in five different HIV-1 PR enzyme receptors.
- Full Text:
- Authors: Tukulula, Matshawandile , Olasupo, Idris A , Mugumbate, Grace C , Lobb, Kevin A , Klein, Rosalyn , Sayed, Yasien , Tshiwawa, Tendamudzimu , Kaye, Perry T
- Date: 2022
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/452813 , vital:75172 , xlink:href="https://doi.org/10.1016/j.molstruc.2022.133716"
- Description: Aza-Michael reactions of a pyridine-3-carbaldehyde-derived Morita-Baylis-Hillman (MBH) adduct with various amines have afforded a series of 10 diastereomeric products, stereochemical analysis of which has been achieved using a combination of NMR (1D, 2D and NOESY) and computer modelling methods. Saturation Transfer Difference (STD) 1H NMR spectroscopy and in silico molecular docking studies have been used to explore the HIV-1 protease sub-type C enzyme binding potential of these compounds in five different HIV-1 PR enzyme receptors.
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New thiazolidine-2,4-dione derivatives combined with organometallic ferrocene: Synthesis, structure and antiparasitic activity
- Oderinlo, Ogunyemi O, Tukulula, Matshawandile, Isaacs, Michelle, Taylor, Dale, Smith, Vincent J, Khanye, Setshaba D, Hoppe, Heinrich C
- Authors: Oderinlo, Ogunyemi O , Tukulula, Matshawandile , Isaacs, Michelle , Taylor, Dale , Smith, Vincent J , Khanye, Setshaba D , Hoppe, Heinrich C
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/122978 , vital:35382 , https://doi.org/10.1002/aoc.4385
- Description: Favourable physicochemical properties of an organometallic ferrocene and antiplasmodial potency of compounds containing the thiazolidine‐2,4‐dione framework (TZD‐4) prompted us to explore compounds containing both the thiazolidine‐2,4‐dione core and the ferrocenyl unit with the primary aim of identifying compounds with promising antiprotozoal activities. Thus, a new series of rationally designed ferrocene‐based thiazolidine‐2,4‐dione derivatives, containing a selection of secondary cyclic amines, was synthesised and fully characterised using standard spectroscopic techniques. The resulting compounds were screened for their antiplasmodial and antitrypanosomal activities against both the chloroquine‐resistant (Dd2) strain of Plasmodium falciparum and the Nagana Trypanosoma brucei brucei 427. The general trend that emerged indicated that the target compounds were more selective towards T. b. brucei compared to the P. falciparum parasite. Moreover, the analogues bearing methylpiperazine (8a) and piperidine (8b) rings were more active against T. b. brucei compared to hit compound TZD‐4. Except compound 8b, which appeared promising, none of the synthesised compounds showed better activity than TZD‐4 against the P. falciparum parasite. All the synthesised compounds were non‐toxic and often showed >90% viability of the HeLa cell line screened.
- Full Text:
- Authors: Oderinlo, Ogunyemi O , Tukulula, Matshawandile , Isaacs, Michelle , Taylor, Dale , Smith, Vincent J , Khanye, Setshaba D , Hoppe, Heinrich C
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/122978 , vital:35382 , https://doi.org/10.1002/aoc.4385
- Description: Favourable physicochemical properties of an organometallic ferrocene and antiplasmodial potency of compounds containing the thiazolidine‐2,4‐dione framework (TZD‐4) prompted us to explore compounds containing both the thiazolidine‐2,4‐dione core and the ferrocenyl unit with the primary aim of identifying compounds with promising antiprotozoal activities. Thus, a new series of rationally designed ferrocene‐based thiazolidine‐2,4‐dione derivatives, containing a selection of secondary cyclic amines, was synthesised and fully characterised using standard spectroscopic techniques. The resulting compounds were screened for their antiplasmodial and antitrypanosomal activities against both the chloroquine‐resistant (Dd2) strain of Plasmodium falciparum and the Nagana Trypanosoma brucei brucei 427. The general trend that emerged indicated that the target compounds were more selective towards T. b. brucei compared to the P. falciparum parasite. Moreover, the analogues bearing methylpiperazine (8a) and piperidine (8b) rings were more active against T. b. brucei compared to hit compound TZD‐4. Except compound 8b, which appeared promising, none of the synthesised compounds showed better activity than TZD‐4 against the P. falciparum parasite. All the synthesised compounds were non‐toxic and often showed >90% viability of the HeLa cell line screened.
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The design and synthesis of novel HIV-1 protease inhibitors
- Authors: Tukulula, Matshawandile
- Date: 2009
- Subjects: Protease Inhibitors HIV infections -- Treatment AIDS (Disease) -- Treatment HIV (Viruses) Indolizine -- Derivatives Heterocyclic compounds -- Derivatives Nuclear magnetic resonance Quinoline
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4305 , http://hdl.handle.net/10962/d1004963
- Description: This study has focused on the synthesis of truncated analogues of the hydroxyethylene dipeptide isosteres, such as Ritonavir®, currently in clinical use as HIV-1 protease inhibitors. The reactions of pyridine-2- and quinoline-2-carbaldehydes with methyl acrylate, in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) or 3- hydroxyquinuclidine (3-HQ) as nucleophilic catalysts, have afforded a series of Baylis- Hillman adducts, acetylation and cyclisation of which have provided access to a series of indolizine-2-carboxylate esters. The carboxylic acids, obtained by base-catalyzed hydrolysis of these esters, have been coupled with various protected (and unprotected) amino compounds using the peptide coupling agent, 1,1’-carbonyldiimidazole (CDI), to afford a series of indolizine-2-carboxamides as indolizine-based truncated Ritonavir® analogues in quantitative yield. Aza-Michael reactions of pyridine-3-carbaldehydederived Baylis-Hillman adducts with various amino compounds have provided access to a range of pyridine-based products as mixtures of diastereomeric aza-Michael products. The assignment of the relative stereochemistry of the aza-Michael products has been established using 1-D and 2-NOESY experiments and computer modelling techniques. Computer modelling studies have also been conducted on selected aza-Michael products using ACCELRYS Cerius2 software, followed by interactive docking into the HIV-1 protease receptor site, using AUTODOCK 4.0. The docking studies have revealed hydrogen-bonding interactions between the enzyme and the synthetic ligands. Saturation Transfer Difference (STD) NMR experiments have also indicated binding of some of the aza-Michael products to the HIV-1 protease subtype C enzyme, thus indicating their binding and possible inhibitory potential.
- Full Text:
- Authors: Tukulula, Matshawandile
- Date: 2009
- Subjects: Protease Inhibitors HIV infections -- Treatment AIDS (Disease) -- Treatment HIV (Viruses) Indolizine -- Derivatives Heterocyclic compounds -- Derivatives Nuclear magnetic resonance Quinoline
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4305 , http://hdl.handle.net/10962/d1004963
- Description: This study has focused on the synthesis of truncated analogues of the hydroxyethylene dipeptide isosteres, such as Ritonavir®, currently in clinical use as HIV-1 protease inhibitors. The reactions of pyridine-2- and quinoline-2-carbaldehydes with methyl acrylate, in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) or 3- hydroxyquinuclidine (3-HQ) as nucleophilic catalysts, have afforded a series of Baylis- Hillman adducts, acetylation and cyclisation of which have provided access to a series of indolizine-2-carboxylate esters. The carboxylic acids, obtained by base-catalyzed hydrolysis of these esters, have been coupled with various protected (and unprotected) amino compounds using the peptide coupling agent, 1,1’-carbonyldiimidazole (CDI), to afford a series of indolizine-2-carboxamides as indolizine-based truncated Ritonavir® analogues in quantitative yield. Aza-Michael reactions of pyridine-3-carbaldehydederived Baylis-Hillman adducts with various amino compounds have provided access to a range of pyridine-based products as mixtures of diastereomeric aza-Michael products. The assignment of the relative stereochemistry of the aza-Michael products has been established using 1-D and 2-NOESY experiments and computer modelling techniques. Computer modelling studies have also been conducted on selected aza-Michael products using ACCELRYS Cerius2 software, followed by interactive docking into the HIV-1 protease receptor site, using AUTODOCK 4.0. The docking studies have revealed hydrogen-bonding interactions between the enzyme and the synthetic ligands. Saturation Transfer Difference (STD) NMR experiments have also indicated binding of some of the aza-Michael products to the HIV-1 protease subtype C enzyme, thus indicating their binding and possible inhibitory potential.
- Full Text:
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