Design and synthesis of human immunodeficiency virus entry inhibitors: Sulfonamide as an isostere for the α-ketoamide group

Rong Jian Lu; John A. Tucker; Tatiana Zinevitch; Olga Kirichenko; Vitalii Konoplev; Svetlana Kuznetsova; Sergey Sviridov; Jason Pickens; Sagun Tandel; Enugurthi Brahmachary; Yang Yang; Jian Wang; Stephanie Freel; Shelly Fisher; Alana Sullivan; Jiying Zhou; Sherry Stanfield-Oakley; Michael Greenberg; Dani Bolognesi; Brian Bray; Barney Koszalka; Peter Jeffs; Alisher Khasanov; You An Ma; Cynthia Jeffries; Changhui Liu; Tatiana Proskurina; Tong Zhu; Alexander Chucholowski; Rongshi Li; Connie Sexton

doi:10.1021/jm070650e

Design and synthesis of human immunodeficiency virus entry inhibitors: Sulfonamide as an isostere for the α-ketoamide group

Rong Jian Lu, John A. Tucker, Tatiana Zinevitch, Olga Kirichenko, Vitalii Konoplev, Svetlana Kuznetsova, Sergey Sviridov, Jason Pickens, Sagun Tandel, Enugurthi Brahmachary, Yang Yang, Jian Wang, Stephanie Freel, Shelly Fisher, Alana Sullivan, Jiying Zhou, Sherry Stanfield-Oakley, Michael Greenberg, Dani Bolognesi, Brian BrayBarney Koszalka, Peter Jeffs, Alisher Khasanov, You An Ma, Cynthia Jeffries, Changhui Liu, Tatiana Proskurina, Tong Zhu, Alexander Chucholowski, Rongshi Li, Connie Sexton

Research output: Contribution to journal › Article › peer-review

67 Scopus citations

Abstract

The crystal structures of many tertiary α-ketoamides reveal an orthogonal arrangement of the two carbonyl groups. Based on the hypothesis that the α-ketoamide HIV attachment inhibitor BMS 806 (formally BMS378806, 26) might bind to its gp120 target via a similar conformation, we designed and synthesized a series of analogs in which the ketoamide group is replaced by an isosteric sulfonamide group. The most potent of these analogs, 14i, demonstrated antiviral potency comparable to 26 in the M33 pseudotyped antiviral assay. Flexible overlay calculations of a ketoamide inhibitor with a sulfonamide inhibitor revealed a single conformation of each that gave significantly better overlap of key pharmacophore features than other conformations and thus suggest a possible binding conformation for each class.

Original language	English (US)
Pages (from-to)	6535-6544
Number of pages	10
Journal	Journal of Medicinal Chemistry
Volume	50
Issue number	26
DOIs	https://doi.org/10.1021/jm070650e
State	Published - Dec 27 2007
Externally published	Yes

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

Access to Document

10.1021/jm070650e

Cite this

Lu, R. J., Tucker, J. A., Zinevitch, T., Kirichenko, O., Konoplev, V., Kuznetsova, S., Sviridov, S., Pickens, J., Tandel, S., Brahmachary, E., Yang, Y., Wang, J., Freel, S., Fisher, S., Sullivan, A., Zhou, J., Stanfield-Oakley, S., Greenberg, M., Bolognesi, D., ... Sexton, C. (2007). Design and synthesis of human immunodeficiency virus entry inhibitors: Sulfonamide as an isostere for the α-ketoamide group. Journal of Medicinal Chemistry, 50(26), 6535-6544. https://doi.org/10.1021/jm070650e

Lu, RJ, Tucker, JA, Zinevitch, T, Kirichenko, O, Konoplev, V, Kuznetsova, S, Sviridov, S, Pickens, J, Tandel, S, Brahmachary, E, Yang, Y, Wang, J, Freel, S, Fisher, S, Sullivan, A, Zhou, J, Stanfield-Oakley, S, Greenberg, M, Bolognesi, D, Bray, B, Koszalka, B, Jeffs, P, Khasanov, A, Ma, YA, Jeffries, C, Liu, C, Proskurina, T, Zhu, T, Chucholowski, A, Li, R & Sexton, C 2007, 'Design and synthesis of human immunodeficiency virus entry inhibitors: Sulfonamide as an isostere for the α-ketoamide group', Journal of Medicinal Chemistry, vol. 50, no. 26, pp. 6535-6544. https://doi.org/10.1021/jm070650e

@article{4f1a04dbb4f14cb2a02b133843e831c8,

title = "Design and synthesis of human immunodeficiency virus entry inhibitors: Sulfonamide as an isostere for the α-ketoamide group",

abstract = "The crystal structures of many tertiary α-ketoamides reveal an orthogonal arrangement of the two carbonyl groups. Based on the hypothesis that the α-ketoamide HIV attachment inhibitor BMS 806 (formally BMS378806, 26) might bind to its gp120 target via a similar conformation, we designed and synthesized a series of analogs in which the ketoamide group is replaced by an isosteric sulfonamide group. The most potent of these analogs, 14i, demonstrated antiviral potency comparable to 26 in the M33 pseudotyped antiviral assay. Flexible overlay calculations of a ketoamide inhibitor with a sulfonamide inhibitor revealed a single conformation of each that gave significantly better overlap of key pharmacophore features than other conformations and thus suggest a possible binding conformation for each class.",

author = "Lu, {Rong Jian} and Tucker, {John A.} and Tatiana Zinevitch and Olga Kirichenko and Vitalii Konoplev and Svetlana Kuznetsova and Sergey Sviridov and Jason Pickens and Sagun Tandel and Enugurthi Brahmachary and Yang Yang and Jian Wang and Stephanie Freel and Shelly Fisher and Alana Sullivan and Jiying Zhou and Sherry Stanfield-Oakley and Michael Greenberg and Dani Bolognesi and Brian Bray and Barney Koszalka and Peter Jeffs and Alisher Khasanov and Ma, {You An} and Cynthia Jeffries and Changhui Liu and Tatiana Proskurina and Tong Zhu and Alexander Chucholowski and Rongshi Li and Connie Sexton",

year = "2007",

month = dec,

day = "27",

doi = "10.1021/jm070650e",

language = "English (US)",

volume = "50",

pages = "6535--6544",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "26",

}

TY - JOUR

T1 - Design and synthesis of human immunodeficiency virus entry inhibitors

T2 - Sulfonamide as an isostere for the α-ketoamide group

AU - Lu, Rong Jian

AU - Tucker, John A.

AU - Zinevitch, Tatiana

AU - Kirichenko, Olga

AU - Konoplev, Vitalii

AU - Kuznetsova, Svetlana

AU - Sviridov, Sergey

AU - Pickens, Jason

AU - Tandel, Sagun

AU - Brahmachary, Enugurthi

AU - Yang, Yang

AU - Wang, Jian

AU - Freel, Stephanie

AU - Fisher, Shelly

AU - Sullivan, Alana

AU - Zhou, Jiying

AU - Stanfield-Oakley, Sherry

AU - Greenberg, Michael

AU - Bolognesi, Dani

AU - Bray, Brian

AU - Koszalka, Barney

AU - Jeffs, Peter

AU - Khasanov, Alisher

AU - Ma, You An

AU - Jeffries, Cynthia

AU - Liu, Changhui

AU - Proskurina, Tatiana

AU - Zhu, Tong

AU - Chucholowski, Alexander

AU - Li, Rongshi

AU - Sexton, Connie

PY - 2007/12/27

Y1 - 2007/12/27

N2 - The crystal structures of many tertiary α-ketoamides reveal an orthogonal arrangement of the two carbonyl groups. Based on the hypothesis that the α-ketoamide HIV attachment inhibitor BMS 806 (formally BMS378806, 26) might bind to its gp120 target via a similar conformation, we designed and synthesized a series of analogs in which the ketoamide group is replaced by an isosteric sulfonamide group. The most potent of these analogs, 14i, demonstrated antiviral potency comparable to 26 in the M33 pseudotyped antiviral assay. Flexible overlay calculations of a ketoamide inhibitor with a sulfonamide inhibitor revealed a single conformation of each that gave significantly better overlap of key pharmacophore features than other conformations and thus suggest a possible binding conformation for each class.

AB - The crystal structures of many tertiary α-ketoamides reveal an orthogonal arrangement of the two carbonyl groups. Based on the hypothesis that the α-ketoamide HIV attachment inhibitor BMS 806 (formally BMS378806, 26) might bind to its gp120 target via a similar conformation, we designed and synthesized a series of analogs in which the ketoamide group is replaced by an isosteric sulfonamide group. The most potent of these analogs, 14i, demonstrated antiviral potency comparable to 26 in the M33 pseudotyped antiviral assay. Flexible overlay calculations of a ketoamide inhibitor with a sulfonamide inhibitor revealed a single conformation of each that gave significantly better overlap of key pharmacophore features than other conformations and thus suggest a possible binding conformation for each class.

UR - http://www.scopus.com/inward/record.url?scp=37349002730&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=37349002730&partnerID=8YFLogxK

U2 - 10.1021/jm070650e

DO - 10.1021/jm070650e

M3 - Article

C2 - 18052117

AN - SCOPUS:37349002730

SN - 0022-2623

VL - 50

SP - 6535

EP - 6544

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 26

ER -

Design and synthesis of human immunodeficiency virus entry inhibitors: Sulfonamide as an isostere for the α-ketoamide group

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this