Probing Lipophilic Adamantyl Group as the P1-Ligand for HIV-1 Protease Inhibitors: Design, Synthesis, Protein X-ray Structural Studies, and Biological Evaluation

Abstract

A series of potent HIV-1 protease inhibitors with a lipophilic adamantyl P1 ligand have been designed, synthesized and evaluated. We have developed an enantioselective synthesis of adamantane-derived hydroxyethylamine isostere utilizing Sharpless asymmetric epoxidation as the key step. Various inhibitors incorporating P1-adamanylmethyl in combination with P2-ligands such as 3-(R)-THF, 3-(S)-THF, bis-THF and THF-THP were examined. The S1′ pocket was also probed with phenyl and phenylmethyl ligands. Inhibitor 15d, with an isobutyl P1′ ligand and a bis-THF P2 ligand proved to be the most potent of the series. The cLogP value of inhibitor 15d is impoved compared to inhibitor 2 with a phenylmethyl P1-ligand. X-ray structural studies of 15d, 15h and 15i with HIV-1 protease complexes revealed molecular insight into the inhibitor-protein interaction.

Catalytic Asymmetric Synthesis of Hexahydro-furofuran-3-ol and Its Pyran Derivatives

“…Experimental details, spectral data, and 1 H and 13 C NMR spectra of all new compounds (PDF) FAIR data, including the primary NMR FID files, for compounds [3][4][5][6][7][8][9][11][12][13][14][15][16][18][19][20][21][22][23]…”

“…A number of multidrug-resistant PIs, such as Darunavir, a new front-line therapy for HIV/AIDS, possess a unique (3 R ,3a S ,6a R )-hexahydro-furo-[2,3- b ]­furan-3-ol ( bis -THF) fragment (structure A, Figure ). SAR (Structure–activity relationship) studies revealed that synthetic analogs possessing THF-THP (structure B, Figure ) or a THP-THF bicyclic ring (structure C, Figure ) also exhibited interesting inhibitory effects …”

“…2 SAR (Structure− activity relationship) studies revealed that synthetic analogs possessing THF-THP (structure B, Figure 1) or a THP-THF bicyclic ring (structure C, Figure 1) also exhibited interesting inhibitory effects. 3 The unique structure of these bicyclic compounds and their excellent biological activities have drawn significant attention from the synthetic community. Most studies aimed at the synthesis of the bis-THF ring rely on chiral pool approaches, which generally require lengthy sequences and the extensive use of protective groups.…”

Multiple Molecular Dynamics Simulations and Free-Energy Predictions Uncover the Susceptibility of Variants of HIV-1 Protease against Inhibitors Darunavir and KNI-1657

“…Resistance to PR inhibitors mainly results from residue substitutions. Among these mutated residues, single mutations of certain conserved residues can reduce the binding of inhibitors to PR, while most double-mutant and multiple-mutant PRs bring about strong resistance toward inhibitors. , Therefore, there is an increasing need to develop new anti-AIDS inhibitors that can effectively reduce the resistance of mutants. , …”

Novel HIV-1 Protease Inhibitors with Morpholine as the P2 Ligand to Enhance Activity against DRV-Resistant Variants

“…Thus far, HIV-1 protease inhibitors (PIs) approved by the FDA have increased the life expectancy significantly and reduced the mortality dramatically. − However, the emergence of drug-resistant HIV-1 variants posed a threat to further treatment. And what’s worse, Darunavir (DRV, 1 , Figure ), with a high genetic barrier to many multidrug-resistant (MDR) protease variants, has emerged highly DRV-resistant HIV-1 variants in treatment-experienced patients. , Notably, DRV was incapable of combating the identified mutations. , Although great effort has been made to explore potent PIs, none of them were found to inhibit DRV-resistant HIV-1 variants effectively. − Hence, the discovery of novel PIs with high genetic barrier against DRV-resistant HIV-1 variants is highly urgent.…”