Solid Phase Synthesis of Novel Pyrrolidinedione Analogs as Potent HIV-1 Integrase Inhibitors

Abstract

A novel series of HIV-1 integrase inhibitors were identified from a 100 member (4R(1) x 5R(2) x 5R(3)) library of pyrrolidinedione amides. A solid-phase route was developed which facilitates the simultaneous variation at R(1), R(2), and R(3) of the pyrrolidinedione scaffold. The resulting library samples were assayed for HIV-1 integrase activity and analyzed to determine the R(1), R(2), and R(3) reagent contributions towards the activity.

Divergent Synthesis of Novel Five-Membered Heterocyclic Compounds by Base-Mediated Rearrangement of Acrylamides Derived from a Novel Isocyanide-Based Multicomponent Reaction

“…There are not many biological data on compounds structurally similar to 9 and 10 , for example compounds of general formula 14 have recently found biological applications as HIV-1 integrase inhibitors [ 10 ], while compounds 15 ( Figure 2 ) have shown activity as PGE 2 production inhibitors [ 11 ].…”

Past and Future. Current Drugs Targeting HIV-1 Integrase and Reverse Transcriptase-Associated Ribonuclease H Activity: Single and Dual Active Site Inhibitors

“…In particular, the compound 5-(3-chlorophenyl)-3-hydroxy-1-(4methoxyphenethyl)-4-(pyrimidine-2-carbonyl)-1H-pyrrol-2(5H)-one (11; Figure 5), presenting a pyridine substitution, inhibited the IN 3′-processing and the strand transfer reactions with an IC 50 value of 77 µM and 40 µM, respectively, and inhibited the viral replication with an unexpected EC 50 value of 0.317 µM and a selective index of 83 [65]. Other compounds with the pyrrolidinedione scaffolds were identified as potential HIV-1 INI [53,66] and a library of pyrrolidinedione derivatives was tested in in vitro assay, with the 3-(benzylcarbamoyl)-4-hydroxy-5-oxo-1H-pyrrole-1,2(2H,5H)-dicarboxylic acid derivatives (12; Figure 5), which showed an IC 50 value of 0.04 µM [66].…”

Pyrrolidine‐2,3‐diones: Synthesis, reactions and biological activity

“…1‐Benzyl‐4‐carboethoxy‐2,3‐pyrrolidinedione is reported as a highly specific aldose reductase inhibitor, 8 and a series of the 4‐arylidene derivatives have been found to be inhibitors of blood platelet aggregation 9 . A number of 4‐carboxamido‐2,3‐pyrrolidinediones have been reported as potent HIV‐1 inhibitors, 10 and a series of chiral peptide derivatives related to 2,3‐pyrrolidinedione have good anti‐inflammatory and analgesic activities 11 . In addition, the total synthesis of leopolic acid A, a natural 2,3‐pyrrolidinedione, with antimicrobial activity has been recently reported 12 .…”