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Title: Novel dimeric aporphine alkaloids from the West African medicinal plant, Enantia chlorantha are potent anti-trypanosomal agents
Author: Adesokan, Adedapo
ISNI:       0000 0004 5354 0203
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 2015
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This thesis describes the isolation, structure elucidation, anti-trypanosomal activity and molecular modelling of the aporphine alkaloids obtained from Enantia chlorantha. Phytochemical studies on the Enantia chlorantha stem bark yielded six dimeric and one monomeric aporphine alkaloid along with one protoberberine type alkaloid, palmatine. Three dimeric aporphine alkaloids were novel namely: 1,1',2,2',3-pentamethoxy-6-methyl-5,5',6,6'-tetrahydro-4H,4'H-7,7'-bidibenzo[de,g]quinoline, ECP-19 (89),8-(1,2,3-trimethoxy-5,6-dihydro-4H-dibenzo[de,g]quinolin-7-yl)-6,7-dihydro-5H-[1,3]dioxolo[4',5':4,5]benzo[1,2,3-de]benzo[g]quinoline, ECHE-45 (90), and 7-methyl-8-(1,2,3-trimethoxyl-5,6-dihydro-4H-dibenzo(de,g)quinolin-7-yl)-6,7-dihydro-5H-(1,3)dioxolo(4'5':4,5)benzo(1,2,3-de) benzo(g)quinoline ECH-56 (91). The structures of the alkaloids were determined using 2D NMR experiments and their masses confirmed using ESI Mass Spectrome-ter. Anti-trypanosomal screening of these alkaloids for activity against the non-virulent bloodstream form of T.brucei brucei ,carried out using a modified microplate Alamar blue™ assay revealed that these alkaloids had excellent anti-trypanosomal activity, with MICs 1.27 to 10.96 nanomolar compared to the positive control Suramin with MIC of 9.6 nanomolar. Of the three novel dimeric alkaloids, ECP-19 (89) was the most active with MIC of 1.27 nanomolar. Molecular modelling was carried out for all of these alkaloids as well as their derivatives monomeric aporphine alkaloids using the GRIP technique with Vlife molecular Design Suite (V life MDS 4.2) on seven validated Trypanosoma brucei protein targets from the Protein Data Bank (PDB). These protein targets were: T. brucei Glutathione Synthetase , Glutathione peroxidase-type tryparedoxin peroxidase, oxidized form ,Glutathione peroxidase-type tryparedoxin peroxidase, reduced form , Sterol 14-alpha demethylase (CYP51) from T. brucei in complex with the tipifarnib derivative 6-(4-chlorophenyl)(methoxy)(1-methyl-1H-imidazol-5-yl)methyl)-4-(2,6-difluorophenyl)-1-methylquinolin-2(1H)-one , T. brucei Ornithine Decarboxylase , Riboflavin kinase ,and Trypanothione reductase from T. brucei. The inhibition of T. brucei ornithine decarboxylase was the most significant, hence the possibility of it being a likely mechanism of action for these alkaloids. Further molecular modelling studies of the eight alkaloids whose structure were elucidated in this thesis, as well as six derivate monomeric alka-loids were carried out to pinpoint the 'best fit' alkaloids to Ornithine decarboxylase's active site Ly-sine 69 using the GOLD 5.5.2 software. This revealed the dimeric aporphine alkaloids isolated in this study had docking score as a function of GOLD.PLP.Fitness which ranged from -95.1384 to 27.8819 for dimers,which is not as good as the docking scores ranging from 26.5959 - 38.4616 for monomers isolated in this study, as well as monomeric derivatives of the dimers. Derivative monomer, Compound 95 had the best docking score of 38.4616. This set of results in terms of the novelty of the dimeric alkaloids, their excellent anti-trypanosomal activity in vitro, significant results in molecular models and the fact that anecdotal evidence of use of Enantia chlorantha extracts in vivo for treatment of ailments traditionally in rural West Africa for cen-turies may form a basis for further drug development studies. As it is the norm in drug discovery syn-thetic analogues developed from a natural product scaffold tend to provide a vast number of molecules to test and develop further, therefore future molecular modelling studies are currently being tailored to optimising the 'best fit' monomeric alkaloids to hybrid modelled synthetic analogues for further drug development studies beyond the scope of the PhD study.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: R Medicine (General)