Design and Synthesis of Piperazine Sulfonamide Cores Leading to Highly Potent HIV-1 Protease Inhibitors

Bungard, Christopher J.; Williams, Peter; Schulz, Jürgen; Wiscount, Catherine M.; Holloway, M. Katharine; Loughran, Marie; Manikowski, Jesse J.; Su, Hua-Poo; Bennett, David Jonathan; Chang, Lehua; Chu, Xin‐Jie; Crespo, Alejandro; Dwyer, Michael P.; Keertikar, Kartik M.; Morriello, Gregori J.; Stamford, Andrew W.; Waddell, Sherman T.; Zhong, Bin; Hu, Bin; Ji, Tao; Diamond, Tracy L.; Bahnck-Teets, Carolyn; Carroll, Steven S.; Fay, John F.; Xu, Min; Morris, William; Ballard, Jeanine; Miller, Michael D.; McCauley, John A.

doi:10.1021/acsmedchemlett.7b00386

Cited by 41 publications

(30 citation statements)

References 16 publications

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“…Although these compounds have received some attention in the previous reviews (especially in the papers by Majumdar and Mondal, as well as Sokolov and co‐workers cited above), they have never been at the central focus of the discussion. Meanwhile, they have great potential for medicinal chemistry projects, which is confirmed by discoveries of highly potent γ‐secretase inhibitor 1 , casein kinase II inhibitor 2 , protease‐activated receptor 1 (PAR‐1) antagonist 3 , retinoic acid receptor‐related orphan receptor γ (RORγ) antagonist 4 , or human immunodeficiency virus (HIV)‐1 protease inhibitor 5 (Figure ). Unlike in most previous reviews, we have categorized the literature data on saturated bicyclic sultams by their structural subtype (i.e.…”

Section: Introductionmentioning

confidence: 99%

Saturated Bicyclic Sultams

et al. 2020

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Saturated bicyclic sultams represent a promising class of sp 3-rich three-dimensional scaffolds of outmost importance to organic and medicinal chemistry. In this review with 99 references, synthesis, properties, and applications of these compounds are surveyed. The literature data are categorized according to the structural types (i.e. fused, bridged, and spirocyclic compounds), as well as homologous series

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Section: Introductionmentioning

confidence: 99%

Saturated Bicyclic Sultams

et al. 2020

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“…Recently, Bungard and colleagues reported an outstanding optimization of HIV‐1 protease inhibitor by Introduction of 2‐thia‐1,6‐diazabicyclo[3.2.1]octane 2,2‐dioxide core into 2 . This modification had significant impact on compounds potency, making it comparable to that of marketed Atazanavir and Darunavir antivirals.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Functionalized Bridged Bicyclic Sulfonamides with a Bridgehead Nitrogen Atom

et al. 2020

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“…Efforts to improve potency, pharmacokinetics, and resistance profiles of HIV-1 PIs have led to the discovery of exceptionally potent compounds exhibiting a wide range of properties. 5,[10][11][12][13][14] In recent years, these efforts have focused mainly on exploring DRV analogues with similar sulfonamide-based dipeptide isosteres and P2/P2 moieties. Many analogues of DRV with modifications at P1/P1…”

Section: Introductionmentioning

confidence: 99%

Structural Analysis of Potent Hybrid HIV-1 Protease Inhibitors Containing Bis-tetrahydrofuran in a Pseudosymmetric Dipeptide Isostere

et al. 2020

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The design, synthesis, and X-ray structural analysis of hybrid HIV-1 protease inhibitors (PIs) containing bis-tetrahydrofuran (bis-THF) in a pseudo-C 2-symmetric dipeptide isostere are described. A series of PIs were synthesized by incorporating bis-THF of darunavir on either side of the Phe-Phe isostere of lopinavir in combination with hydrophobic amino acids on the opposite P2/P2 position. Structure-activity relationship studies indicated that the bis-THF moiety can be attached at either the P2 or P2 position without significantly affecting potency. However, the group on the opposite P2/P2 position had a dramatic effect on potency depending on the size and shape of the side chain. Cocrystal structures of inhibitors with wild-type HIV-1 protease revealed that the bis-THF moiety retained similar interactions as observed in the darunavir-protease complex regardless of position on the Phe-Phe isostere. Analyses of cocrystal structures and molecular dynamics simulations provide insights for optimizing HIV-1 PIs containing bis-THF in non-sulfonamide dipeptide isosteres.

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Design and Synthesis of Piperazine Sulfonamide Cores Leading to Highly Potent HIV-1 Protease Inhibitors

Cited by 41 publications

References 16 publications

Saturated Bicyclic Sultams

Saturated Bicyclic Sultams

Synthesis of Functionalized Bridged Bicyclic Sulfonamides with a Bridgehead Nitrogen Atom

Structural Analysis of Potent Hybrid HIV-1 Protease Inhibitors Containing Bis-tetrahydrofuran in a Pseudosymmetric Dipeptide Isostere

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