Baylis-Hillman adducts as scaffolds for the construction of novel compounds with medicinal potential

Idahosa, Kenudi Christiana (2012) Baylis-Hillman adducts as scaffolds for the construction of novel compounds with medicinal potential. PhD thesis, Rhodes University.




This project has focused on exploring the application of Baylis-Hillman (BH){a.k.a.Morita-Baylis-Hillman (MBH)} scaffolds in the construction of various compounds with medicinal potential. A series of 2-nitrobenzaldehydes has been treated under BH conditions, with two different activated alkenes, viz., (MVK) and methyl acrylate, using (DABCO) or (3-HQ) as catalyst. While most of the BH reactions were carried out at room temperature, some reactions were conducted using microwave irradiation. The resulting BH adducts have been subjected to dehydration, conjugate addition and allylic substitution to obtain appropriate intermediates, which have been used in turn, to synthesize possible lead compounds, viz., cinnamate esters as HIV-1 integrase inhibitors, 3-(aminomethyl)quinolines and quinolones as anti-malarials and cinnamate ester-AZT conjugates as dual-action HIV-1 integrase-reverse transcriptase (IN-RT) inhibitors. Conjugate addition reactions of methyl acrylate-derived BH β-hydroxy esters with the amines, piperidine, propargylamine and 2-amino-5-(diethylamino)pentane, has afforded a range of products as diastereomeric mixtures in moderate to excellent yields. Catalytic hydrogenation of the aminomethy β-hydroxy esters derivatives, using a palladium-oncarbon (Pd-C) catalyst, has afforded the corresponding, novel 3-aminomethyl-2-quinolone derivatives in moderate yields. Effective allylic substitution reactions of the MVK-derived BH β-hydroxy ketones (via a conjugate addition-elimination pathway) using in situ-generated HCl has afforded the corresponding α-chloromethyl derivatives, which have been reacted with various amines, including piperidine, piperazine, propargylamine and -amino--(diethylamino)pentane, to yield α-aminomethyl derivatives. Catalytic hydrogenation of selected α-aminomethyl derivatives, using a Pd-C catalyst, has afforded the corresponding, novel 3-(aminomethyl)-2-methylquinoline derivatives in low to moderate yields. A bioassay, conducted on a 6-hydroxy-2-methyl-3-[(piperidin-1-yl)methyl]quinoline isolated early in the study indicated anti-malarial activity and prompted further efforts in the synthesis of analogous compounds. Reaction of the methyl acrylate-derived BH adducts with POCl3 has provided access to α-(chloromethyl)cinnamate ester derivatives, which have been aminated to afford α-(aminomethyl)cinnamate ester derivatives as potential HIV-1 integrase inhibitors. The α- (propargylaminomethyl)cinnamates were used, in turn, as substrates for the “click chemistry” reaction with 3'-azido-3'-deoxythymidine (AZT– an azide and an established reverse transcriptase HIV-1 inhibitor) to afford cinnamate ester-AZT conjugates as potential dual-action HIV-1 integrase-reverse transcriptase (IN-RT) inhibitors. Computer modelling and docking studies of a cinnamate ester-AZT conjugate into the HIV-1 integrase and reverse transcriptase active-sites revealed potential hydrogen-bonding interactions with amino acid residues within the receptor cavities. The isolated products have been appropriately characterized using IR, 1- and 2-D NMR and HRMS techniques, while elucidation of the stereochemistry of the double bond in the BH-derived halomethyl derivatives has been assigned on the basis of NOE, computer modelling and X-ray crystallographic data.

Item Type:Thesis (PhD)
Uncontrolled Keywords:Baylis-Hillman scaffolds, BH, Morita-Baylis-Hillman scaffolds, MBH, Dehydration, Conjugate addition, Allylic substitution, Medicinal Compounds, Construction, 2-nitrobenzaldehydes, Activated alkenes, Methyl acrylate, Catalyst, Lead compounds, HIV-1 integrase inhibitors, Anti-malarials
Subjects:Q Science > QD Chemistry
Divisions:Faculty > Faculty of Science > Chemistry
Supervisors:Kaye, Perry Theodore
ID Code:3109
Deposited By: Philip Clarke
Deposited On:11 Jul 2012 06:08
Last Modified:11 Jul 2012 06:08
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