Development of (E)-2-((1,4-Dimethylpiperazin-2-ylidene)amino)-5-nitro-N-phenylbenzamide, ML336

Novel 2-Amidinophenylbenzamides as Potent Inhibitors of Venezuelan Equine Encephalitis Virus

Chad E. Schroeder, Tuanli Yao, Julie Sotsky, Robert A. Smith, Sudeshna Roy, Yong Kyu Chu, Haixun Guo, Nichole A. Tower, James W. Noah, Sara McKellip, Melinda Sosa, Lynn Rasmussen, Layton H. Smith, E. Lucile White, Jeffrey Aubé, Colleen Jonsson, Donghoon Chung, Jennifer E. Golden

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Venezuelan equine encephalitis virus (VEEV) is an emerging pathogenic alphavirus that can cause significant disease in humans. Given the absence of therapeutic options available and the significance of VEEV as a weaponized agent, an optimization effort was initiated around a quinazolinone screening hit 1 with promising cellular antiviral activity (EC50 = 0.8 μM), limited cytotoxic liability (CC50 > 50 μM), and modest in vitro efficacy in reducing viral progeny (63-fold at 5 μM). Scaffold optimization revealed a novel rearrangement affording amidines, specifically compound 45, which was found to potently inhibit several VEEV strains in the low nanomolar range without cytotoxicity (EC50 = 0.02-0.04 μM, CC50 > 50 μM) while limiting in vitro viral replication (EC90 = 0.17 μM). Brain exposure was observed in mice with 45. Significant protection was observed in VEEV-infected mice at 5 mg kg-1 day-1 and viral replication appeared to be inhibited through interference of viral nonstructural proteins.

Original languageEnglish (US)
Pages (from-to)8608-8621
Number of pages14
JournalJournal of Medicinal Chemistry
Volume57
Issue number20
DOIs
StatePublished - Oct 23 2014

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Venezuelan Equine Encephalitis Viruses
Viral Nonstructural Proteins
Quinazolinones
Amidines
Alphavirus
Antiviral Agents
2-((1,4-dimethylpiperazin-2-ylidene)amino)-5-nitro-N-phenylbenzamide
Brain

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Development of (E)-2-((1,4-Dimethylpiperazin-2-ylidene)amino)-5-nitro-N-phenylbenzamide, ML336 : Novel 2-Amidinophenylbenzamides as Potent Inhibitors of Venezuelan Equine Encephalitis Virus. / Schroeder, Chad E.; Yao, Tuanli; Sotsky, Julie; Smith, Robert A.; Roy, Sudeshna; Chu, Yong Kyu; Guo, Haixun; Tower, Nichole A.; Noah, James W.; McKellip, Sara; Sosa, Melinda; Rasmussen, Lynn; Smith, Layton H.; White, E. Lucile; Aubé, Jeffrey; Jonsson, Colleen; Chung, Donghoon; Golden, Jennifer E.

In: Journal of Medicinal Chemistry, Vol. 57, No. 20, 23.10.2014, p. 8608-8621.

Research output: Contribution to journalArticle

Schroeder, CE, Yao, T, Sotsky, J, Smith, RA, Roy, S, Chu, YK, Guo, H, Tower, NA, Noah, JW, McKellip, S, Sosa, M, Rasmussen, L, Smith, LH, White, EL, Aubé, J, Jonsson, C, Chung, D & Golden, JE 2014, 'Development of (E)-2-((1,4-Dimethylpiperazin-2-ylidene)amino)-5-nitro-N-phenylbenzamide, ML336: Novel 2-Amidinophenylbenzamides as Potent Inhibitors of Venezuelan Equine Encephalitis Virus', Journal of Medicinal Chemistry, vol. 57, no. 20, pp. 8608-8621. https://doi.org/10.1021/jm501203v
Schroeder, Chad E. ; Yao, Tuanli ; Sotsky, Julie ; Smith, Robert A. ; Roy, Sudeshna ; Chu, Yong Kyu ; Guo, Haixun ; Tower, Nichole A. ; Noah, James W. ; McKellip, Sara ; Sosa, Melinda ; Rasmussen, Lynn ; Smith, Layton H. ; White, E. Lucile ; Aubé, Jeffrey ; Jonsson, Colleen ; Chung, Donghoon ; Golden, Jennifer E. / Development of (E)-2-((1,4-Dimethylpiperazin-2-ylidene)amino)-5-nitro-N-phenylbenzamide, ML336 : Novel 2-Amidinophenylbenzamides as Potent Inhibitors of Venezuelan Equine Encephalitis Virus. In: Journal of Medicinal Chemistry. 2014 ; Vol. 57, No. 20. pp. 8608-8621.
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abstract = "Venezuelan equine encephalitis virus (VEEV) is an emerging pathogenic alphavirus that can cause significant disease in humans. Given the absence of therapeutic options available and the significance of VEEV as a weaponized agent, an optimization effort was initiated around a quinazolinone screening hit 1 with promising cellular antiviral activity (EC50 = 0.8 μM), limited cytotoxic liability (CC50 > 50 μM), and modest in vitro efficacy in reducing viral progeny (63-fold at 5 μM). Scaffold optimization revealed a novel rearrangement affording amidines, specifically compound 45, which was found to potently inhibit several VEEV strains in the low nanomolar range without cytotoxicity (EC50 = 0.02-0.04 μM, CC50 > 50 μM) while limiting in vitro viral replication (EC90 = 0.17 μM). Brain exposure was observed in mice with 45. Significant protection was observed in VEEV-infected mice at 5 mg kg-1 day-1 and viral replication appeared to be inhibited through interference of viral nonstructural proteins.",
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AU - Tower, Nichole A.

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AU - McKellip, Sara

AU - Sosa, Melinda

AU - Rasmussen, Lynn

AU - Smith, Layton H.

AU - White, E. Lucile

AU - Aubé, Jeffrey

AU - Jonsson, Colleen

AU - Chung, Donghoon

AU - Golden, Jennifer E.

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