Discovery of tetrahydropyrazolopyrimidine carboxamide derivatives as potent and orally active antitubercular agents - PubMed (original) (raw)

doi: 10.1021/ml400071a. eCollection 2013 May 9.

Gang Wang 1, Wai Ling Chan 1, Shi Hua Ang 1, Josephine Wong 1, Ida Ma 1, Srinivasa P S Rao 1, Ujjini Manjunatha 1, Suresh B Lakshminarayana 1, Maxime Herve 1, Cyrille Kounde 1, Bee Huat Tan 1, Pamela Thayalan 1, Seow Hwee Ng 1, Mahesh Nanjundappa 1, Sindhu Ravindran 1, Peck Gee 1, Maria Tan 1, Liu Wei 1, Anne Goh 1, Pei-Yu Chen 1, Kok Sin Lee 1, Chen Zhong 2, Trixie Wagner 3, Ina Dix 3, Arnab K Chatterjee 2, Kevin Pethe 2, Kelli Kuhen 2, Richard Glynne 2, Paul Smith 1, Pablo Bifani 1, Jan Jiricek 1

Affiliations

Discovery of tetrahydropyrazolopyrimidine carboxamide derivatives as potent and orally active antitubercular agents

Fumiaki Yokokawa et al. ACS Med Chem Lett. 2013.

Erratum in

Abstract

Tetrahydropyrazolo[1,5-a]pyrimidine scaffold was identified as a hit series from a Mycobacterium tuberculosis (Mtb) whole cell high through-put screening (HTS) campaign. A series of derivatives of this class were synthesized to evaluate their structure-activity relationship (SAR) and structure-property relationship (SPR). Compound 9 had a promising in vivo DMPK profile in mouse and exhibited potent in vivo activity in a mouse efficacy model, achieving a reduction of 3.5 log CFU of Mtb after oral administration to infected mice once a day at 100 mg/kg for 28 days. Thus, compound 9 is a potential candidate for inclusion in combination therapies for both drug-sensitive and drug-resistant TB.

Keywords: Antituberculosis; structure−activity relationship; structure−property relationship; tetrahydropyrazolo[1,5-a]pyrimidine.

PubMed Disclaimer

Figures

Figure 1

Figure 1

Initial SAR for tetrahydropyrazolopyrimidines.

Scheme 1

Scheme 1. General Scheme for Synthesis of Tetrahydropyrazolopyrimidines

Reagents and conditions: (a) AcOH at 110 °C; (b) NaBH4, EtOH at room temperature; (c) KOH, aq. EtOH at 60 °C; (d) preparative chiral HPLC; (e) HATU, _i-_PrNEt2, DMF.

Scheme 2

Scheme 2. Synthesis of Tetrahydropyrazolopyrimidines

Reagents and conditions: (a) (i) NaBH4, EtOH at room temperature, (ii) BBr3, CHCl3 at room temperature; (b) KOH, aq. EtOH at 60 °C; (c) preparative chiral HPLC; (d) HATU, _i-_PrNEt2, DMF; (e) 2-methoxy-bromoethane, Cs2CO3, DMF (for 13 and 19), oxetan-3-yl 4-methylbenzenesulfonate, K2CO3, DMF (for 14); (f) morpholine, Pd(OAc)2, Xantphos, Cs2CO3, toluene (for 12).

Figure 2

Figure 2

In vivo efficacy results in TB mouse model.

Similar articles

Cited by

References

    1. World Health Organization. Multidrug and Extensively Drug-Resistant TB: 2010 Global Report on Surveillance and Response.
    1. Ma Z.; Lienhardt C.; McIlleron H.; Nunn A. J.; Wang X. Global tuberculosis drug development pipeline: the need and the reality. Lancet 2010, 375, 2100–2109. - PubMed
    1. Koul A.; Arnoult E.; Lounis N.; Guillemont J.; Andries K. The challenge of new drug discovery for tuberculosis. Nature 2011, 469, 483–490. - PubMed
    1. Pethe K.; Sequeira P. C.; Agarwalla S.; Rhee K.; Kuhen K.; Phong W. Y.; Patel V.; Beer D.; Walker J. R.; Duraiswamy J.; Jiricek J.; Keller T. H.; Chatterjee A.; Tan M. P.; Ujjini M.; Rao S. P.; Camacho L.; Bifani P.; Mak P. A.; Ma I.; Barnes S. W.; Chen Z.; Plouffe D.; Thayalan P.; Ng S. H.; Au M.; Lee B. H.; Tan B. H.; Ravindran S.; Nanjundappa M.; Lin X.; Goh A.; Lakshminarayana S. B.; Shoen C.; Cynamon M.; Kreiswirth B.; Dartois V.; Peters E. C.; Glynne R.; Brenner S.; Dick T. A chemical genetic screen in Mycobacterium tuberculosis identifies carbon-source-dependent growth inhibitors devoid of in vivo efficacy. Nat. Commun. 2010, 1, 57. - PMC - PubMed
    1. Maddry J. A.; Ananthan S.; Goldman R. C.; Hobrath J. V.; Kwong C. D.; Maddox C.; Rasmussen L.; Reynolds R. C.; Secrist J. A. III; Sosa M. I.; White E. L.; Zhang W. Antituberculosis activity of the molecular libraries screening center network library. Tuberculosis 2009, 89, 354–363. - PMC - PubMed

LinkOut - more resources