7-Substituted 2-Nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazines: Novel Antitubercular Agents Lead to a New Preclinical Candidate for Visceral Leishmaniasis

Andrew M. Thompson, Patrick D. O’Connor, Andrew J. Marshall, Vanessa Yardley, Louis Maes, Suman Gupta, Delphine Launay, Stephanie Braillard, Eric Chatelain, Scott G. Franzblau, Baojie Wan, Yuehong Wang, Zhenkun Ma, Christopher B. Cooper, William A. Denny

Research output: Contribution to journalArticle

Abstract

Within a backup program for the clinical investigational agent pretomanid (PA-824), scaffold hopping from delamanid inspired the discovery of a novel class of potent antitubercular agents that unexpectedly possessed notable utility against the kinetoplastid disease visceral leishmaniasis (VL). Following the identification of delamanid analogue DNDI-VL-2098 as a VL preclinical candidate, this structurally related 7-substituted 2-nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazine class was further explored, seeking efficacious backup compounds with improved solubility and safety. Commencing with a biphenyl lead, bioisosteres formed by replacing one phenyl by pyridine or pyrimidine showed improved solubility and potency, whereas more hydrophilic side chains reduced VL activity. In a Leishmania donovani mouse model, two racemic phenylpyridines (71 and 93) were superior, with the former providing >99% inhibition at 12.5 mg/kg (b.i.d., orally) in the Leishmania infantum hamster model. Overall, the 7R enantiomer of 71 (79) displayed more optimal efficacy, pharmacokinetics, and safety, leading to its selection as the preferred development candidate.

Original languageEnglish (US)
Pages (from-to)4212-4233
Number of pages22
JournalJournal of Medicinal Chemistry
Volume60
Issue number10
DOIs
StatePublished - May 25 2017

Fingerprint

Oxazines
Antitubercular Agents
Visceral Leishmaniasis
Solubility
Safety
Leishmania infantum
Leishmania donovani
Cricetinae
Pharmacokinetics
Lead

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Thompson, A. M., O’Connor, P. D., Marshall, A. J., Yardley, V., Maes, L., Gupta, S., ... Denny, W. A. (2017). 7-Substituted 2-Nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazines: Novel Antitubercular Agents Lead to a New Preclinical Candidate for Visceral Leishmaniasis. Journal of Medicinal Chemistry, 60(10), 4212-4233. DOI: 10.1021/acs.jmedchem.7b00034

7-Substituted 2-Nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazines : Novel Antitubercular Agents Lead to a New Preclinical Candidate for Visceral Leishmaniasis. / Thompson, Andrew M.; O’Connor, Patrick D.; Marshall, Andrew J.; Yardley, Vanessa; Maes, Louis; Gupta, Suman; Launay, Delphine; Braillard, Stephanie; Chatelain, Eric; Franzblau, Scott G.; Wan, Baojie; Wang, Yuehong; Ma, Zhenkun; Cooper, Christopher B.; Denny, William A.

In: Journal of Medicinal Chemistry, Vol. 60, No. 10, 25.05.2017, p. 4212-4233.

Research output: Contribution to journalArticle

Thompson, AM, O’Connor, PD, Marshall, AJ, Yardley, V, Maes, L, Gupta, S, Launay, D, Braillard, S, Chatelain, E, Franzblau, SG, Wan, B, Wang, Y, Ma, Z, Cooper, CB & Denny, WA 2017, '7-Substituted 2-Nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazines: Novel Antitubercular Agents Lead to a New Preclinical Candidate for Visceral Leishmaniasis' Journal of Medicinal Chemistry, vol 60, no. 10, pp. 4212-4233. DOI: 10.1021/acs.jmedchem.7b00034

Thompson, Andrew M.; O’Connor, Patrick D.; Marshall, Andrew J.; Yardley, Vanessa; Maes, Louis; Gupta, Suman; Launay, Delphine; Braillard, Stephanie; Chatelain, Eric; Franzblau, Scott G.; Wan, Baojie; Wang, Yuehong; Ma, Zhenkun; Cooper, Christopher B.; Denny, William A. / 7-Substituted 2-Nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazines : Novel Antitubercular Agents Lead to a New Preclinical Candidate for Visceral Leishmaniasis.

In: Journal of Medicinal Chemistry, Vol. 60, No. 10, 25.05.2017, p. 4212-4233.

Research output: Contribution to journalArticle

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