Structure-Based Design of HIV Protease Inhibitors:  5,6-Dihydro-4-hydroxy-2-pyrones as Effective, Nonpeptidic Inhibitors

Abstract

From a broad screening program, the 4-hydroxycoumarin phenprocoumon (I) was previously identified as a lead template with HIV protease inhibitory activity. The crystal structure of phenprocoumon/HIV protease complex initiated a structure-based design effort that initially identified the 4-hydroxy-2-pyrone U-96988 (II) as a first-generation clinical candidate for the potential treatment of HIV infection. Based upon the crystal structure of the 4-hydroxy-2-pyrone III/HIV protease complex, a series of analogues incorporating a 5,6-dihydro-4-hydroxy-2-pyrone template were studied. It was recognized that in addition to having the required pharmacophore (the 4-hydroxy group with hydrogen-bonding interaction with the two catalytic aspartic acid residues and the lactone moiety replacing the ubiquitous water molecule in the active site), these 5,6-dihydro-4-hydroxy-2-pyrones incorporated side chains at the C-6 position that appropriately extended into the S1' and S2' subsites of the enzyme active site. The crystal structures of a number of representative 5,6-dihydro-4-hydroxy-2-pyrones complexed with the HIV protease were also determined to provide better understanding of the interaction between the enzyme and these inhibitors to aid the structure-based drug design effort. The crystal structures of the ligands in the enzyme active site did not always agree with the conformations expected from experience with previous pyrone inhibitors. This is likely due to the increased flexibility of the dihydropyrone ring. From this study, compound XIX exhibited reasonably high enzyme inhibitory activity (Ki = 15 nM) and showed antiviral activity (IC50 = 5 microM) in the cell-culture assay. This result provided a research direction which led to the discovery of active 5,6-dihydro-4-hydroxy-2-pyrones as potential agents for the treatment of HIV infection.

Structure-based discovery of tipranavir disodium (PNU-140690E): A potent, orally bioavailable, nonpeptidic HIV protease inhibitor

“…37 Most notably, the use of crystallographic overlays of the evolving nonpeptidic inhibitors with potent peptidomimetic compounds was critical to the expeditious drug design process. In the coumarin/pyrone series, inspection of the crystallographic overlays 34 suggested that the meta position on the C-3␣ phenyl ring of the coumarin lead was in close proximity to the C-␣ position of the histidine residue of peptidomimetic inhibitor 2 ( Figure 4).…”

“…Initial studies 37 were directed toward the 5,6-dihydropyrone template and mirrored efforts being advanced on the pyrone nucleus. Separate studies 42,43 in other labs have also focused on this ring system.…”

“…Separate studies 42,43 in other labs have also focused on this ring system. Simple analogues 37 such as compound 16 could be prepared that were structurally similar to the related pyrones and displayed comparable enzymatic inhibitory activity (Figure 7). Modification of the dihydropyrone's C-6 substituents had a significant effect on protease inhibition, while the influence of the C-3␣ alkyl group was less profound for the compounds studied.…”

A New 2-Pyrone Derivative, 5-Bromo-3-(3-hydroxyprop-1-ynyl)-2H-pyran-2-one, Suppresses Stemness in Glioma Stem-Like Cells

“…Accumulating evidence indicates that microbial 2-pyrones, dihydro-2-pyrones, and secondary metabolites exhibit a wide range of antifungal, cytotoxic, neurotoxic, and phytotoxic properties (Dickinson, 1993). These compounds also display antitumor and HIV-inhibitory activities (Thaisrivongs et al, 1996;Poppe et al, 1997;Turner et al, 1998), which reinforces their potential medicinal importance. In addition, an investigation of the anticancer properties of tricyclic 2-pyrones showed that these compounds prevented DNA synthesis and growth in human leukemic cells in vitro (Trachootham et al, 2008).…”

Synthesis and thermal studies of mixed ligand complexes of Cu(II), Co(II), Ni(II) and Cd(II) with mercaptotriazoles and dehydroacetic acid

“…The importance of similar pyrones as potential fungicides is reinforced by the existence of several natural fungicides possessing structures analogous to 5, 6-dihydro dehydroacetic acid, like alternaric acid, the podoblastins and lachnelluloic acid [3][4][5], studies have shown that such compounds and their complexes have very interesting biological properties [6][7][8][9][10][11][12][13]. Like dehydroacetic acid, mercaptotriazoles and their complexes have been shown to posses enhanced biological activities [14][15][16][17][18][19][20][21][22][23][24][25][26][27].…”