Synthesis of 5,6-Dihydro-4-hydroxy-2- pyrones as HIV-1 Protease Inhibitors:  The Profound Effect of Polarity on Antiviral Activity (original) (raw)

4-Hydroxy-5,6-dihydropyrones. 2. Potent Non-Peptide Inhibitors of HIV Protease

Journal of Medicinal Chemistry, 1997

The 4-hydroxy-5,6-dihydropyrone template was utilized as a flexible scaffolding from which to build potent active site inhibitors of HIV protease. Dihydropyrone 1c (5,6-dihydro-4-hydroxy-6-phenyl-3-[(2-phenylethyl)thio]-2H-pyran-2-one) was modeled in the active site of HIV protease utilizing a similar binding mode found for the previously reported 4-hydroxybenzopyran-2ones. Our model led us to pursue the synthesis of 6,6-disubstituted dihydropyrones with the aim of filling S 1 and S 2 and thereby increasing the potency of the parent dihydropyrone 1c which did not fill S 2. Toward this end we attached various hydrophobic and hydrophilic side chains at the 6-position of the dihydropyrone to mimic the natural and unnatural amino acids known to be effective substrates at P 2 and P 2 ′. Parent dihydropyrone 1c (IC 50) 2100 nM) was elaborated into compounds with greater than a 100-fold increase in potency [18c, IC 50) 5 nM, 5-(3,6-dihydro-4-hydroxy-6-oxo-2-phenyl-5-[2-phenylethyl)thio]-2H-pyran-2-yl)pentanoic acid and 12c, IC 50) 51 nM, 5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-3-[(2-phenylethyl)thio]-2H-pyran-2-one]. Optimization of the 3-position fragment to fill S 1 ′ and S 2 ′ afforded potent HIV protease inhibitor 49 [IC 50) 10 nM, 3-[(2-tert-butyl-5-methylphenyl)sulfanyl]-5,6dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one]. The resulting low molecular weight compounds (<475) have one or no chiral centers and are readily synthesized.

Structure-Based Design of HIV Protease Inhibitors: Sulfonamide-Containing 5,6-Dihydro-4-hydroxy-2-pyrones as Non-Peptidic Inhibitors

Journal of Medicinal Chemistry, 1996

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-2pyrone 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 S 1 ′ and S 2 ′ 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 (K i) 15 nM) and showed antiviral activity (IC 50) 5 µM) 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.

Novel inhibitors of HIV protease

Bioorganic & Medicinal Chemistry Letters, 2000

novel series of HIV protease inhibitors containing cyclic P1/P2 scaolds has been synthesized and evaluated for biological activity. The trans 3,5-dibenzyl-2-oxo pyrrolidinone ring system resulted in a 50 pM enzyme inhibitor against HIV protease in vitro when combined with an indanolamine derived P H-backbone. This compound also shows comparable activity to currently marketed drugs in the MT-4 cell-based antiviral assay.

Inhibitors of HIV Protease: Unique Non‐peptide Active Site Templates

Journal of Molecular Recognition, 1996

New templates were designed and prepared which straddle the active site of HIV-1 protease. These templates were designed to be 'flexible scaffolds' upon which substituents could be appended to fill the pockets of HIV protease. The new templates prepared and analysed were 4-hydroxy-5H-furan-2-ones, 4-hydroxy-5,6-dihydropyrones, 3-hydroxy-cyclohex-2-enones, and 4-hydroxy-2(lH)-pyridinones, of which the 4-hydroxy-5,6-dihydropyrones were found to be the most potent inhibitors of HIV-1 protease.

Diastereoselective synthesis and molecular docking studies of novel fused tetrahydropyridine derivatives as new inhibitors of HIV protease

Journal of Molecular Structure, 2017

An efficient one-pot, catalyst-free, and four-components procedure for the synthesis of novel 10b-hydroxy-4-nitro-5-phenyl-2,3,5,5a-tetrahydro-1H-imidazo[1,2-a]indeno[2,1-e]pyridin-6(10bH)one derivatives from corresponding diamine, nitro ketene dithioacetal, aldehydes and 1,3-indandione in ethanol has been achieved upon a Knoevenagel condensation-Michael addition-tautomerismcyclisation sequence. All the newly synthesized compounds were screened for molecular docking studies. Molecular docking studies were carried out using the crystal structure of HIV protease enzyme. Some of the compounds obtain minimum binding energy and good affinity toward the active pocket of HIV protease enzyme in compare with Saquinavir as a standard HIV protease inhibitor.

Discovery and optimization of nonpeptide HIV-1 protease inhibitors

Bioorganic & Medicinal Chemistry, 1996

Several small, achiral nonpeptide inhibitors of H1V-I protease with low micromolar activity were identified by mass screening of the Parke-Davis compound library. Two of the compounds, structurally similar, were both found to be competitive and reversible inhibitors [compound 1, 4-hydroxy-3-(3-phenoxypropyl)-l-benzopyran-2-one: K, = 1.0 p.M; compound 2, 4-hydroxy-6-phenyl-3-(phenylthio)-pyran-2-one: K~ = 1.1 ~tM]. These inhibitors were chosen as initial leads for optimization of in vitro inhibitory activity based on molecular modeling and X-ray crystallographic structural data. While improvements in inhibitory potency were small with analogues of compound 1, important X-ray crystallographic structural information of the enzyme-inhibitor complex was gained. When bound, 1 was found to displace H20301 in the active site while hydrogen bonding to the catalytic Asps and Ile50 and Ilel50. "[he pyranone group of compound 2 was found to bind at the active site in the same manner, with the 6-phenyl and the 3-phenylthio occupying P1 and PI', respectively. The structural information was used to develop design strategies to reach three or four of the internal pockets, P2-P2'. This work led to analogues of diverse structure with high potency (IC50 < 10 nM) that contain either one or no chiral centers and remain nonpeptidic. The highly potent compounds possess less anti-HIV activity in cellular assays than expected, and current optimization now focuses on increasing cellular activity. The value of the HIV-1 protease inhibitors described is their potential as better pharmacological agents with a different,pattern of viral resistance development, relative to the peptidic inhibitors in human clinical trials.