Synthesis of dihydropyrimidine α,γ-diketobutanoic acid derivatives targeting HIV integrase

Abstract

The synthesis and antiviral evaluation of a series of dihydropyrimidinone and thiopyrimidine derivatives bearing aryl α,γ-diketobutanoic acid moiety are described using the Biginelli multicomponent reaction as key step. The most active among 20 synthesized novel compounds were 4c, 4d and 5b, which possess nanomolar HIV-1 integrase (IN) stand transfer (ST) inhibition activities. In order to understand their mode of interactions within the IN active site, we docked all the compounds into the previously reported X-ray crystal structure of IN. We observed that compounds 4c, 4d and 5b occupied an area close to the two catalytic Mg2+ ions surrounded by their chelating triad (E221, D128 and D185), DC16, Y212 and the β-diketo acid moiety of 4c, 4d and 5b chelating Mg2+. As those compounds lack anti-HIV activities in cell, their prodrugs were synthetized. The prodrug 4c′ exhibited an anti-HIV activity of 0.19 μM in primary human lymphocytes with some cytotoxicity. All together, these results indicate that the new analogs potentially interact within the catalytic site with highly conserved residues important for IN catalytic activity.

Highly Efficient Synthesis of Substituted 3,4-Dihydropyrimidin-2-(1H)-ones (DHPMs) Catalyzed by Hf(OTf)4: Mechanistic Insights into Reaction Pathways under Metal Lewis Acid Catalysis and Solvent-Free Conditions

“…However, the preparation of these specific catalysts greatly limits their value in practical applications. In most of recent medicinal research, DHPMs were synthesized with easily accessible metal Lewis acid catalysts [39,40,41,42]. Therefore, the identification of highly potent, commercially available, affordable, and non-toxic metal Lewis acid catalysts for Biginelli reaction are still awaiting exploration.…”

Therapeutic potential of heterocyclic pyrimidine scaffolds

“…Among the series, compound c10 (( Z )-ethyl-4-benzyl-1-(4-(3-hydroxy-4-isopropoxy-4-oxobut-2-enoyl)benzyl)-6-methyl-2-oxo-1,2-dihydro pyrimidine-5-carboxylate) was found to be most active anti-HIV agent (Table 32 , Fig. 8 ) [ 42 ].…”

FeCl3∙6H2O/TMSBr-Catalyzed Rapid Synthesis of Dihydropyrimidinones and Dihydropyrimidinethiones under Microwave Irradiation

“…Dihydropyrimidinones and dihydropyrimidinethiones have received great attention in synthetic organic chemistry because of their ubiquitous presence in a large number of natural products and pharmaceutical agents [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 ]. For example, they act as key components in natural marine alkaloids such as batzelladine A-I [ 11 , 12 , 13 ], ptilocaulin [ 14 ], and saxitoxin [ 15 ].…”