Synthesis of New HIV-1 Protease and Integrase Inhibitors via Baylis-Hillman Reaction
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Date
2010-10
Authors
Olasupo, I.A
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Abstract
A series of the Baylis-Hillman adducts 133 were obtained by reacting unprotected substituted and unsubstituted salicylaldehydes with tert-butyl acrylate for three to fourteen days, using 1,4-diazabicyclo[2.2.2]octane (DABCO) as nucleophilic catalysts in 25-69% yields. Oxidation of these adducts led to unexpected cyclization products: tert-butyl 6-bromochromene-3-carboxylate 149.
Another series of the Baylis-Hillman adducts were obtained by reacting protected O-benzylated salicylaldehydes with methyl acrylate and tert-butyl acrylate, using 1,4-diazabicyclo[2.2.2]octane (DABCO) or 3-hydroxyquinuclidine (3HQC) as nucleophilic catalysts with the yield range of 10-85% in twenty one days at room temperature.
Oxidation of the methyl acrylate O-benzylated Baylis-Hillman adducts using l,l,l-triacetoxy-l,l-dihydro-1,2-benxiodoxol-3(1H)-one (Dess-Martin periodinane reagent-DMP) afforded a series of new β-keto esters 152 in excellent yields of 90-100% after a series of trials.
The methyl acrylate O-benzylated Baylis-Hillman adducts was explored as substrates for aza-Michael reactions using various amines/amino acids in the presence of the tetrabutylammonium bromide (TBAB) as catalyst. The diastereomeric aza-Michael products: β-amino-β-hydroxy esters (155-159)a-d obtained in yields of 39–93% was targeted as truncated ritonavir analogues for investigation as potential HIV-1 protease inhibitors.
3-Methylamino coumarin derivatives 160a-d which are potential HIV-1 protease inhibitors were obtained in moderate yield of 12-27% from acid-catalysed deprotection and cyclization of some β-amino-β-hydroxy esters of the (S)-benzyl cysteamine derivatives 156a-d.
The O-benzylated methylamino cinnamate ester derivatives (163-5)a-d targeted as CAPE analogues for investigation as potential HIV integrase inhibitors was prepared from acid-catalysed electrophilic addition/dehydration of the O-benzylated Baylis-Hillman adducts followed by SN1 reactions with amine derivatives.
The O-benzylated methylamino cinnamate ester derivatives gave the (E) and (Z) steroisomers for the (S)-benzyl cysteamine (163a-d) and L-proline (165a-d) derivatives, which indicates that the strategy employed can be used in the synthesis of either stereoisomers.
Computer modelling of representative O-benzylated β-amino-β-hydroxy ester derivatives of the (S)-benzyl cysteamine derivatives 156a-d as potential HIV-1 protease inhibitors were done using the ACCELRYS Cerius2 platform, and interactive in silico docking into the active site of the HIV-1 protease enzyme, using the AUTODOCK 4.0 docking software, indicated the importance of hydrogen-bonding interactions between the enzyme and the ligands mediated by bridging water molecules situated in the receptor cavity.
The docking results suggest that the ligands 156a-d exhibit the potential to act as HIV-1 protease inhibitors while 5-bromo substituted derivative 156d gave better inhibition than others and their inhibition indicators were found to be comparable to FDA approved drugs even though slightly lower.
Description
A Thesis Submitted to the School of Postgraduate Studies, University of Lagos
Keywords
Baylis-Hillman , Oxidation , Cyclization products , HIV-1 protease inhibitors , Research Subject Categories::NATURAL SCIENCES::Chemistry
Citation
Olasupo, I.A (2010). Synthesis of New HIV-1 Protease and Integrase Inhibitors via Baylis-Hillman Reaction. A Thesis Submitted to University of Lagos School of Postgraduate Studies Phd Thesis and Dissertation, 227pp.