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. 2017 Nov 13;8(12):1292-1297.
doi: 10.1021/acsmedchemlett.7b00386. eCollection 2017 Dec 14.

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

Christopher J Bungard  1 , Peter D Williams  1 , Jurgen Schulz  1 , Catherine M Wiscount  1 , M Katharine Holloway  1 , H Marie Loughran  1 , Jesse J Manikowski  1 , Hua-Poo Su  1 , David J Bennett  1 , Lehua Chang  2 , Xin-Jie Chu  2 , Alejandro Crespo  2 , Michael P Dwyer  2 , Kartik Keertikar  2 , Gregori J Morriello  2 , Andrew W Stamford  2 , Sherman T Waddell  2 , Bin Zhong  3 , Bin Hu  3 , Tao Ji  3 , Tracy L Diamond  1 , Carolyn Bahnck-Teets  1 , Steven S Carroll  1 , John F Fay  1 , Xu Min  1 , William Morris  2 , Jeanine E Ballard  1 , Michael D Miller  1 , John A McCauley  1
Affiliations

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

Christopher J Bungard et al. ACS Med Chem Lett. .

Abstract

Using the HIV-1 protease binding mode of MK-8718 and PL-100 as inspiration, a novel aspartate binding bicyclic piperazine sulfonamide core was designed and synthesized. The resulting HIV-1 protease inhibitor containing this core showed an 60-fold increase in enzyme binding affinity and a 10-fold increase in antiviral activity relative to MK-8718.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Hybrid design concept based on the binding modes of MK-8718 and PL-100 (PDB codes 5IVT and 2QMP).
Scheme 1
Scheme 1
Reagents and conditions: (a) PhSO2Cl, Hunig’s base, CH2Cl2, −78 °C to RT; (b) Dess–Martin periodinane, CH2Cl2, 0 °C; (c) K2CO3, 18-crown-6, (2-nitrobenzyl)triphenylphosphonium bromide, DME, RT; (d) Pearlman’s catalyst, H2 balloon, CF3CH2OH, RT; (e) 3,3-Bis(4-fluorophenyl)propanoic acid, T3P, Hunig’s base, EtOAc, RT; (f) TFA, CH2Cl2, RT, then Chiralpak AD.
Figure 2
Figure 2
X-ray crystal structure of 7 bound to HIV-1 protease showing hydrogen bonding to Ile50A and Ile50B residues.
Scheme 2
Scheme 2
Reagents and conditions: (a) LiAlH4, 2-Me-THF, 0 °C; (b) K2CO3, 18-crown-6, (2-nitrobenzyl)triphenylphosphonium bromide, DME, RT; (c) Pearlman’s catalyst, 50 psi H2, EtOAc/MeOH, RT; (d) 3,3-Bis(4-fluorophenyl)propanoic acid, T3P, Hunig’s base, EtOAc, RT; (e) TFA, H2O, CH2Cl2; RT; (f) (i) PhSO2Cl, NEt3, DMF, 0 °C; (ii) diazene-1,2-diylbismorpholinomethanone, PBu3, THF, RT; (g) (R)-2-aminopropan-1-ol, 1,2-DCE, 40 °C; (h) (i) Boc2O, NEt3, CH2Cl2, RT; (ii) diazene-1,2-diylbismorpholinomethanone, PBu3, THF, RT; (i) TFA, CH2Cl2, RT.
Figure 3
Figure 3
Antiviral activity (EC50) of analogues 18–21 formed via amino alcohol opening of aziridine 15.
Figure 4
Figure 4
X-ray crystal structure of 18 bound to HIV-1 protease, showing steric clash and leading to design of a bicyclic piperazine.
Scheme 3
Scheme 3
(a) (i) PhSO2Cl, NEt3, DMF, 0 °C; (ii) DIAD, PBu3, THF, 0 °C; (b) (i) (R)-2-aminopent-4-en-1-ol, THF, 45 °C; (ii) Boc2O, NEt3, CH3CN, 45 °C; (c) DIAD, PBu3, THF, RT; (d) Mg, MeOH, sonication, RT; (e) 2-chloroethanesulfonyl chloride, NEt3, CH2Cl2, RT; (f) Zhan Catalyst-1B, 1,2-DCE, 50 °C; (g) Pearlman’s catalyst, H2 balloon, EtOAc, RT; (h) Dess–Martin periodinane, CH2Cl2, RT; (i) PPh3, CBr4, CH2Cl2, RT; (j) EtMgBr, THF, 0 °C; (k) 3-fluoro-2-iodoaniline, (PPh3)2PdCl2, CuI, NEt3, CH3CN, 70 °C; (l) Pearlman’s catalyst, H2 balloon, EtOH, RT; (m) (i) 3,3-Bis(4-fluorophenyl)propanoic acid, T3P, Hunig’s base, EtOAc, RT; (ii) HCl, dioxane, RT.
Figure 5
Figure 5
Antiviral activity (EC50) and X-ray crystal structure of 35 bound to HIV-1 protease.
Scheme 4
Scheme 4
Reagents and conditions: (a) (i) 5-fluoro-4-iodopyridin-3-amine, (PPh3)2PdCl2, CuI, NEt3, CH3CN, 70 °C; (ii) Pearlman’s catalyst, H2 balloon, EtOH, RT; (b) (2S,3S)-2-azido-3-(4-chlorophenyl)-3-(3,5-difluorophenyl)propanoic acid, POCl3, pyridine, 0 °C; (c) (i) PMe3, THF/H2O, 0 °C; (ii) HCl, dioxane/CH2Cl2, RT.
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