HIV-1 protease inhibitors with a P1 phosphonate modification maintain potency against drug-resistant variants by increased interactions with flap residues

FMO-guided design of darunavir analogs as HIV-1 protease inhibitors

“…Hydrogen bond (H-bond) interaction and salt bridges refer to the electrostatic ( ) and charge transfer with higher-order mixed terms energies ( ), while hydrophobic interaction can be suggested by dispersion ( ). The steric repulsion between atoms was described by the exchange-repulsion energy ( ) 21 , 69 . Our selection of substructures used at various substitution sites (P1, P2, P1′, P2′) was elucidated based on guidelines from previous studies.…”

Diastereoselective Synthesis of the HIV Protease Inhibitor Darunavir and Related Derivatives via a Titanium Tetrachloride-Mediated Asymmetric Glycolate Aldol Addition Reaction

“…The successful application of darunavir in combination therapies has inspired the pursuit of improved syntheses of darunavir − and syntheses of derivatives with the potential for even greater potency (Figure ). − In this context, the seminal efforts of Ghosh and coworkers laid the foundation for structural aspects of darunavir and the domains where the structure could be modified. In 2023, Raines and coworkers modified the structure of darunavir by modifying the P2’ region with the use of a benzoborolone group (see 2a and 2b ) and demonstrated the utility of installing such groups as pharmacophores .…”

“…11 This modification resulted in sustained potency against highly resistant HIV-1 variants. 11 Reiser and coworkers changed the P2 domain of darunavir by the use of an ethereal bicyclic cyclopentyl system resulting in low nanomolar IC 50 values. 12 Ghosh and coworkers have been leaders in this field with the development of a number of darunavir derivatives wherein the P2 domain has been changed to enhance drug efficacy.…”

“…The combined modifications led to enzyme inhibition that was markedly potent and yielded more insight into the nature of the binding properties of a series of related derivatives with the protease. The dominant synthetic pathway for the preparation of darunavir and many of its derivatives has involved the use of either β-epoxy azide 6 15 or commercially available β-epoxy carbamates 7a,b (a: R = -Boc; 7,11 b: R = -CBz. 10 An alternate pathway to the chiral structural framework of darunavir, which was developed by Funicello and coworkers, 9 involves the preparation of a suitable vinyl ester (9) obtained from a ligandfree Suzuki-Miyaura coupling reaction (Figure 2).…”

“…In 2023, Raines and coworkers modified the structure of darunavir by modifying the P2’ region with the use of a benzoborolone group (see 2a and 2b ) and demonstrated the utility of installing such groups as pharmacophores . Schiffer, Ali, and coworkers modified the P2 domain by introducing a phenolic methylene diethylphosphonate group in conjunction with the introduction of modifications of the P1’ and P2’ domains to afford darunavir derivative 3 . This modification resulted in sustained potency against highly resistant HIV-1 variants …”