Design and Development of Highly Potent HIV-1 Protease Inhibitors with a Crown-Like Oxotricyclic Core as the P2-Ligand To Combat Multidrug-Resistant HIV Variants

Abstract

Design, synthesis, and evaluation of a new class of exceptionally potent HIV-1 protease inhibitors is reported. Inhibitor 5 displayed superior antiviral activity and drug-resistance profiles. In fact, this inhibitor showed several orders of magnitude improved antiviral activity over the FDA approved drug, darunavir. This inhibitor incorporates an unprecedented 6-5-5 ring-fused crown-like tetrahydropyranofuran as the P2 ligand and an aminobenzothiazole as the P2′ ligand with the (R)-hydroxyethylsulfonamide isostere. The crown-like P2 ligand for this inhibitor has been synthesized efficiently in an optically active form using a chiral Diels-Alder catalyst providing a key intermediate in high enantiomeric purity. Two high resolution X-ray structures of inhibitor-bound HIV-1 protease revealed extensive interactions with the backbone atoms of HIV-1 protease and provided molecular insight into the binding properties of these new inhibitors.

Design of Highly Potent, Dual‐Acting and Central‐Nervous‐System‐Penetrating HIV‐1 Protease Inhibitors with Excellent Potency against Multidrug‐Resistant HIV‐1 Variants

“…[27] In this class of compounds we were able to demonstrate how the replacement of a bis -THF with a crn -THF P2-ligand led to enhanced van der Waals interactions in the S2 site. These increased hydrophobic interactions, in addition to the robust hydrogen bond interaction pattern of a cyclopropylaminobenzothiazole-based P2′-ligand, led to inhibitor 3 , which exhibited unprecedented potency, particularly against multidrug-resistant HIV-1 strains.…”

“…Based on our examination of the X-ray crystal structure of DRV and HIV-1 protease complex as well as our crn -THF-derived inhibitor 3 -bound HIV-1 protease, we planned further modifications to improve ligand-binding site interactions. [27, 37] In particular, we speculated that the insertion of a fluorine atom on the P1-phenyl ring may lead to effective van der Waals interactions with Pro81′ and Val82′ residues in the active site. To test this hypothesis, we designed and synthesized inhibitors 4 and 5 with 3,5-difluoro derivatives.…”

“…Recently, we reported the design and synthesis of a new class of PIs incorporating an unprecedented 6-5-5-ring-fused crown-like tetrahydropyranofuran ( crn -THF) as the P2-ligand and cyclopropylamino-benzothiazole (Cp-Abt) as the P2′-ligand on an ( R )-hydroxyethylsulfonamide isostere as the transition-state mimic. [23, 27] Inhibitor 3 showed superior antiviral activity and drug resistance over DRV ( 1 ). Our detailed structural analysis also provided molecular insight into its exceptional drug-resistance profiles.…”

“…[35] Amino alcohol 12a was converted into cyclopropylaminobenzothiazole derivatives as follows: treatment of amino alcohol 12a with sulfonyl chloride 14 in the presence of Et 3 N at 23°C for 12 h furnished sulfonamide derivative 15a in excellent yield. [27] This was subjected to Staudinger reduction [36] with Ph 3 P in aqueous THF at 23°C for 24 h to provide the corresponding amine. The resulting amine was reacted with (Boc) 2 O in the presence of NaHCO 3 to provide Boc derivative 16a in very good yield.…”

“…Synthesis of optically active crn -THF alcohol and its corresponding activated carbonate 20 was described recently. [27] Reaction of 4-aminobenzenesulfonamide derivative 13 with 3,5-difluorophenylmethyl as the P1-ligand and activated carbonate 20 in the presence of diisopropylethylamine (DIPEA) in CH 3 CN at 23°C for 72 h furnished inhibitor 4 in 88% yield. Similarly, reaction of activated carbonate 20 with fluoroisostere 17 in CH 3 CN under similar conditions afforded inhibitor 5 in 99% yield.…”