Studies towards the synthesis of novel, coumarin-based HIV-1 protease inhibitors

Rashamuse, T. J. (2008) Studies towards the synthesis of novel, coumarin-based HIV-1 protease inhibitors. Masters thesis, Rhodes University.




A series of the Baylis-Hillman adducts have been obtained by reacting protected O-benzylated and unprotected substituted salicylaldehydes with methyl acrylate or tertbutyl acrylate, respectively, using DABCO as catalyst. Treatment of the Baylis-Hillman adducts with HCl in a mixture of acetic acid and acetic anhydride afforded the corresponding 3-(chloromethyl)coumarin derivatives with yields of up to 94%. Similar use of HI afforded the corresponding 3-(iodomethyl)coumarins but, depending on the reaction time, the reduced 3-methyl analogues could also be obtained. Arbuzov reactions of the 3-(halomethyl)coumarin derivatives have been undertaken to afford 4-phosphorylated and 1’-phosphorylated derivatives, regioselectivity being dependent on the halide-leaving group. The 3-(chloromethyl)coumarin derivatives have been subjected to nucleophilic (SN) attack by benzylamine to give the corresponding 3- [(benzylamino)methyl]coumarin derivatives in yields of up to 74%. Further treatment of the 3-[(benzylamino)methyl]coumarin derivatives with chloroacetyl chloride afforded the chloroacetamide derivatives, which exhibit hindered rotation about the amine C(O)-N bond. The acetamide derivatives have also been subjected to Arbuzov reaction conditions to afford the phosphorylated derivatives in yields of up to 86%. In a preliminary modelling study, hydrolysed analogues of the synthesized phosphorylated derivatives have been docked into the active site of the HIV-1 protease enzyme using the Cerius-2 Ligandfit software module to provide an insight into potential receptor-ligand hydrogen bonding interactions.

Item Type:Thesis (Masters)
Additional Information:M.Sc. (Chemistry)
Uncontrolled Keywords:Coumarins; Protease Inhibitors; HIV infections; HIV (Viruses); AIDS (Disease); Heterocyclic compounds; Treatments; Derivatives; HIV-1 Protease inhibitors
Subjects:Y Unknown > Subjects to be assigned
Divisions:Faculty > Faculty of Science > Chemistry
Supervisors:Kaye, P.T. (Prof.)
ID Code:1332
Deposited By: Ms Michelle Booysen
Deposited On:04 Jun 2009
Last Modified:06 Jan 2012 16:20
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