The design and synthesis of novel HIV-1 protease inhibitors

Tukulula, M. (2009) The design and synthesis of novel HIV-1 protease inhibitors. Masters thesis, Rhodes University.

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Abstract

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.

Item Type:Thesis (Masters)
Uncontrolled Keywords:Baylis-Hillman reaction; HIV-1 protease; Indolizines; Aza-Michael reaction; HIV/AIDS
Subjects:Q Science > QD Chemistry
Divisions:Faculty > Faculty of Science > Chemistry
Supervisors:Kaye , P. T. (Prof.)
ID Code:1563
Deposited By: Nicolene Mvinjelwa
Deposited On:09 Mar 2010 13:44
Last Modified:06 Jan 2012 16:20
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