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 Mg(2+) ions surrounded by their chelating triad (E221, D128 and D185), DC16, Y212 and the β-diketo acid moiety of 4c, 4d and 5b chelating Mg(2+). As those compounds lack

SUBMITTER: Sari O 

PROVIDER: S-EPMC4629473 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature