Design, Synthesis, Protein−Ligand X-ray Structure, and Biological Evaluation of a Series of Novel Macrocyclic Human Immunodeficiency Virus-1 Protease Inhibitors to Combat Drug Resistance

Abstract

The structure-based design, synthesis and biological evaluation of a series of nonpeptidic macrocyclic HIV protease inhibitors are described. The inhibitors are designed to effectively fill in the hydrophobic pocket in the S1′ S2′ subsites and retain all major hydrogen bonding with the protein backbone similar to darunavir (1) or inhibitor 2. The ring size, the effect of methyl substitution and unsaturation within the macrocyclic ring structure were assessed. In general, cyclic inhibitors were significantly more potent than their acyclic homologues, saturated rings were less active than their unsaturated analogs and a preference for 10 and 13-membered macrocylic rings was revealed. The addition of methyl substituents resulted in the reduction of potency. Both inhibitors 14b and 14c exhibited marked enzyme inhibitory and antiviral activity and they exerted potent activity against multi-drug resistant HIV-1 variants. Protein-ligand X-ray structures of inhibitors 2 and 14c provided critical molecular insights into the ligand-binding site interactions.

Insights into the structural function of the complex of HIV-1 protease with TMC-126: molecular dynamics simulations and free-energy calculations

“…The crystal structure of the HIV protease bound to the mutant resistant inhibitor UIC-98038 was obtained from the Protein Data Bank (PDB; entry: 3I7E) [10]. The starting structures and force field parameters for the inhibitor were obtained as follows.…”

“…1). Its structure is largely based on that of darunavir (TMC-114) [9], which contains a bistetrahydrofuranyl (bis-THF) urethane and an isostere of sulfonamide [10].…”

Novel Protease Inhibitors (PIs) Containing Macrocyclic Components and 3( R ),3a( S ),6a( R )- bis -Tetrahydrofuranylurethane That Are Potent against Multi-PI-Resistant HIV-1 Variants In Vitro

“…Antiviral agents. In this work, 40 novel nonpeptidic PIs which contained 3(R),3a(S),6a(R)-bis-tetrahydrofuranylurethane (bis-THF) (14,15,24) and a macrocyclic ring (16) were designed and synthesized. Among them, four PIs, GRL-216, GRL-246, GRL-286, and GRL-396 ( Fig.…”

“…1), with molecular weights of 630.8, 644.8, 632.8, and 616.7, respectively, were chosen for detailed analysis, primarily on the basis of their potent antiviral activity. The method of the synthesis of these four PIs has been described elsewhere by Ghosh and coworkers (16). Saquinavir (SQV) and ritonavir (RTV) were kindly provided by Roche Products, Ltd. (Welwyn Garden City, United Kingdom) and Abbott Laboratories (Abbott Park, IL), respectively.…”

“…We identified a group of novel potent macrocyclic PIs (16). GRL-216, which possesses a dual anti-HIV-1 mechanism, inhibits the catalytic activity and dimerization of HIV-1 pro-tease and exerts potent activity against wild-type HIV-1 as well as a wide spectrum of PI-resistant HIV-1 variants in vitro.…”