Application of computational methods in elucidating the isomerization step in the biosynthesis of coumarins
- Authors: Tshiwawa, Tendamudzimu
- Date: 2019
- Subjects: Coumarins , Isomerization , Biosynthesis , Organic compounds -- Synthesis , Cinnamic acid
- Language: English
- Type: text , Thesis , Doctoral , PhD
- Identifier: http://hdl.handle.net/10962/67646 , vital:29124
- Description: The identity of the enzyme(s) responsible for the biosynthetic transformation of cinnamic acid derivatives to important, naturally occurring coumarins has yet to be established. This study constitutes a high-level theoretical analysis of the possibility that a recently reported molecular mechanism of the synthesis of coumarins from Baylis-Hillman adducts, may provide a viable model for three critical phases in the biosynthetic pathway Particular attention has been given to the first of these phases: i) E→Z isomerisation of the cinnamic acid precursor; ii) Cyclisation (lactonisation) to the hemi-acetal intermediate; and ii) Dehydration to afford the coumarin derivative. In order to accomplish this analysis, an enzyme capable, theoretically, of effecting this E→Z isomerisation required identification, and its potential involvement in the transformation mechanism explored. Combined Molecular Mechanics and high-level Quantum Mechanical/DFT calculations were used to access complementary models of appropriate complexes and relevant processes within the enzyme active sites of a range of eleven Chalcone Isomerase (CHI) enzyme candidates, the structures of which were downloaded from the Protein Data Bank. Detailed B3LYP/6-31+G(d,p) calculations have provided pictures of the relative populations of conformations within the ensemble of conformations available at normal temperatures. Conformations of several protonation states of cinnamic acid derivatives have been studied in this way, and the results obtained showed that coupled protonation and deprotonation of (E)-o-coumaric acid provides a viable approach to achieve the E→Z isomerization. In silico docking of the B3LYP/6-31+G(d,p) optimized (E)-o-coumaric acid derivatives in the active sites of each of the candidate CHI enzymes (CHI) revealed that (E)-o-coumaric acid fits well within the active sites of Medicago Sativa CHI crystallographic structures with 1FM8 showing best potential for not only accommodating (E)-o-coumaric acid , but also providing appropriate protein active site residues to effect the simultaneous protonation and deprotonation of the substrate , two residues being optimally placed to facilitate these critical processes. Further exploration of the chemical properties and qualities of selected CHI enzymes, undertaken using High Throughput Virtual Screening (HTVS), confirmed 1FM8 as a viable choice for further studies of the enzyme-catalysed E→Z isomerization of (E)-o-coumaric acid. A molecular dynamics study, performed to further evaluate the evolution of (E)-o-coumaric acid in the CHI active site over time, showed that the ligand in the 1FM8 active site is not only stable, but also that the desired protein-ligand interactions persist throughout the simulation period to facilitate the E→Z isomerization. An integrated molecular orbital and molecular mechanics (ONIOM) study of the 1FM8-(E)-o-coumaric acid complex, involving the direct protonation and deprotonation of the ligand by protein residues; has provided a plausible mechanism for the E → Z isomerization of (E)-o-coumaric acid within the 1FM8 active site; a transition state complex (with an activation energy of ca. 50 kCal.mol-1) has been located and its connection with both the (E)- and (Z)-o-coumaric acid isomer has been confirmed by Intrinsic Reaction Coordinate (IRC) calculations. More realistic models of the 1FM8-(E)-o-coumaric acid complex, with the inclusion of water solvent molecules, have been obtained at both the QM/MM and adaptive QM/MM levels which simulate the dynamic active site at the QM level. The results indicate that the simultaneous protonation and deprotonation of (E)-o-coumaric acid within the CHI enzyme is a water-mediated process – a conclusion consistent with similar reported processes. Visual inspection of the 1FM8-(Z)-o-coumaric acid complex reveals both the necessary orientation of the phenolic and carboxylic acid moieties of the (Z)-o-coumaric acid and the presence of appropriate, proximal active site residues with the potential to permit catalysis of the subsequent lactonisation and dehydration steps required to generate coumarin.
- Full Text:
- Date Issued: 2019
Arylquinolinecarboxamides: Synthesis, in vitro and in silico studies against Mycobacterium tuberculosis
- Authors: Bokosi, Fostino R B , Beteck, Richard M , Jordaan, Audrey , Seldon, Ronnett , Warner, Digby F , Tshiwawa, Tendamudzimu , Lobb, Kevin A , Khanye, Setshaba D
- Date: 2021
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/451064 , vital:75015 , xlink:href="https://doi.org/10.1002/jhet.4340"
- Description: A series of fourteen 6-substituted-2-(methoxyquinolin-3-yl) methyl)-N-(pyridin-3-ylmethyl) benzamides was prepared from commercially available anilines infive simple and convenient synthetic steps. The structures of all new productswere confirmed by routine spectroscopic methods: IR,1Hand13 CNMR,andHRMS (electrospray ionization). The resulting arylquinolinecarboxamides weresubjected to biological screening assay forin vitroinhibitory activity againstMyco-bacterium tuberculosis (Mtb) H37Rv strain. Several compounds exhibited modestantitubercular activity with compounds8–11,15and19exhibiting MIC90valuesin the range of 32–85μM. The antitubercular data suggested that inhibition ofMtbcan be imparted by the introduction of a non-polar substituent on C-6 of thequinoline scaffold. Further, to understandthepossiblemodeofactionoftheseries, the reported compounds and bedaquiline were subjected toin silicodock-ing studies againstMtbATPase to determine their potential to interfere with themycobacterial adenosine triphosphate (ATP) synthase. The results showed thatthese compounds have the potential toserve as antimycobacterial agents.In silicoADME pharmacokinetic prediction results showed the ability of thesearylquinolinecarcboxamides to be absorbed, distributed, metabolized andexcreted efficiently.
- Full Text:
- Date Issued: 2021
Synthesis and biological evaluation of bis-N2, N2′-(4-hydroxycoumarin-3-yl) ethylidene]-2, 3-dihydroxysuccinodihydrazides
- Authors: Manyeruke, Meloddy H , Tshiwawa, Tendamudzimu , Hoppe, Heinrich C , Isaacs, Michelle , Seldon, Ronnett , Warner, Digby F , Krause, Rui W M , Kaye, Perry T
- Date: 2020
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/193430 , vital:45331 , xlink:href="https://doi.org/10.1016/j.bmcl.2019.126911"
- Description: A series of N2,N2′-bis[4-hydroxycoumarin-3-yl)ethylidene]-2,3-dihydroxysuccino-hydrazides, containing 4-hydroxycoumarin, hydrazine and tartaric acid moieties, have been prepared and examined for possible biological activity. Several of these compounds exhibit promising HIV-1 integrase inhibition (IC50 = 3.5 μM), and anti-T. brucei (32% viability) and anti-mycobacterial (Visual MIC90 = 15.63 μM) activity.
- Full Text:
- Date Issued: 2020
Synthesis and conformational studies of 5-bromo-1-[(N-substituted-carbamoyl) methyl]-7-azabenzimidazoles
- Authors: Oluwafemi, Kola A , Klein, Rosalyn , Lobb, Kevin A , Tshiwawa, Tendamudzimu , Isaacs, Michelle , Hoppe, Heinrich C , Kaye, Perry T
- Date: 2022
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/452800 , vital:75171 , xlink:href="https://doi.org/10.1016/j.molstruc.2022.133811"
- Description: The Cs2CO3-catalysed condensation of 5-bromo-7-azabenzimidazole with a series of bromomethyl ketones has afforded a small library of ten, novel 5-bromo-1-[(N-substututed-carbamoyl)methyl]-7-azabenzimidazoles. Rotamerism in the products, as evidenced by the splitting of 1H- and 13C-NMR signals, is attributed to hindered internal rotation about the amide N-C(=O) bond, and has been explored using dynamic NMR (DNMR) analysis and computational methods at the GIAO B3LYP/6-311+G(2d,p) level of theory. Coalescence temperatures have been obtained for representative examples and rotational barriers determined experimentally and theoretically. A detailed theoretical analysis has been undertaken to explore conformations which may contribute to the relative populations of the s-cis and s-trans rotamers. The products have also been screened for cytotoxicity and activity against two parasitic protozoan strains (Plasmodium falciparum and Trypanosoma brucei).
- Full Text:
- Date Issued: 2022
Synthesis, stereochemistry and in vitro STD NMR and in silico HIV-1 PR enzyme-binding potential of MBH-derived inhibitors
- 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:
- Date Issued: 2022
Theoretical and photodynamic therapy characteristics of heteroatom doped detonation nanodiamonds linked to asymmetrical phthalocyanine for eradication of breast cancer cells
- Authors: Matshitse, Refilwe , Tshiwawa, Tendamudzimu , Managa, Muthumuni , Nwaji, Njemuwa , Lobb, Kevin A , Nyokong, Tebello
- Date: 2020
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/186089 , vital:44462 , xlink:href="https://doi.org/10.1016/j.jlumin.2020.117465"
- Description: An amide mono substituted benzothiozole phthalocyanine: zinc(II) 3-(4-((3,17,23-tris(4-(benzo [d]thiazol-2-yl)phenoxy)-9-yl)oxy) phenyl)amide phthalocyanine (NH2BzPc) was covalently linked to undoped and heteroatom doped detonation nanodiamonds (DNDs): B@DNDs, P@DNDs, S@DNDs, N@DNDs, and SandN@DNDs There is a drastic decrease in highest occupied molecular orbital (HOMO) – lowest unoccupied molecular orbital (LUMO) energy gaps for nanoconjugates compared to DNDs alone. B@DNDs-NH2BzPc, SandN@DNDs-NH2BzPc, and P@DNDs-NH2BzPc showed superior photodynamic therapy (PDT) effects. DNDs-NH2BzPc also had a small HOMO-LUMO gap, but did not show improved PDT activity compared to the Pc alone, suggesting doping of DNDs is important. This study shows improved PDT effect on Michigan Cancer Foundation-7 breast cancer lines at 7.63%, 7.62% and 6.5% cell viability for P@DNDs-NH2BzPc, SandN@DNDs-NH2BzPc and B@DNDs-NH2BzPc, respectively.
- Full Text:
- Date Issued: 2020