Optimization of N-benzyl-5-nitrofuran-2-carboxamide As an Antitubercular Agent

Overview

Journal Bioorg Med Chem Lett

Specialty Biochemistry

Date 2019 Jan 3

PMID 30600207

Citations 2

Authors

Ricardo Gallardo-Macias

Pradeep Kumar

Mark Jaskowski

Todd Richmann

Riju Shrestha

Riccardo Russo

Eric Singleton

Matthew D Zimmerman

Hsin Pin Ho

Veronique Dartois

Nancy Connell

David Alland

Joel S Freundlich

Affiliations

Soon will be listed here.

Abstract

The optimization campaign for a nitrofuran antitubercular hit (N-benzyl-5-nitrofuran-2-carboxamide; JSF-3449) led to the design, synthesis, and biological profiling of a family of analogs. These compounds exhibited potent in vitro antitubercular activity (MIC = 0.019-0.20 μM) against the Mycobacterium tuberculosis H37Rv strain and low in vitro cytotoxicity (CC = 40->120 μM) towards Vero cells. Significant improvements in mouse liver microsomal stability and mouse pharmacokinetic profile were realized by introduction of an α, α-dimethylbenzyl moiety. Among these compounds, JSF-4088 is highlighted due to its in vitro antitubercular potency (MIC = 0.019 μM) and Vero cell cytotoxicity (CC > 120 μM). The findings suggest a rationale for the continued evolution of this promising series of antitubercular small molecules.

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References

Ma D, Cai Q . N,N-dimethyl glycine-promoted Ullmann coupling reaction of phenols and aryl halides. Org Lett. 2003; 5(21):3799-802. DOI: 10.1021/ol0350947. View

Fan Y, Wu J, Ke X, Huang Z . Design, synthesis and evaluation of oxime-functionalized nitrofuranylamides as novel antitubercular agents. Bioorg Med Chem Lett. 2018; 28(18):3064-3066. DOI: 10.1016/j.bmcl.2018.07.046. View

Shah N, Auld S, Brust J, Mathema B, Ismail N, Moodley P . Transmission of Extensively Drug-Resistant Tuberculosis in South Africa. N Engl J Med. 2017; 376(3):243-253. PMC: 5330208. DOI: 10.1056/NEJMoa1604544. View

Singh R, Manjunatha U, Boshoff H, Ha Y, Niyomrattanakit P, Ledwidge R . PA-824 kills nonreplicating Mycobacterium tuberculosis by intracellular NO release. Science. 2008; 322(5906):1392-5. PMC: 2723733. DOI: 10.1126/science.1164571. View

Manjunatha U, Boshoff H, Dowd C, Zhang L, Albert T, Norton J . Identification of a nitroimidazo-oxazine-specific protein involved in PA-824 resistance in Mycobacterium tuberculosis. Proc Natl Acad Sci U S A. 2006; 103(2):431-6. PMC: 1326169. DOI: 10.1073/pnas.0508392103. View

Tangallapally R, Yendapally R, Lee R, Lenaerts A, Lee R . Synthesis and evaluation of cyclic secondary amine substituted phenyl and benzyl nitrofuranyl amides as novel antituberculosis agents. J Med Chem. 2005; 48(26):8261-9. PMC: 2527484. DOI: 10.1021/jm050765n. View

Tangallapally R, Yendapally R, Lee R, Hevener K, Jones V, Lenaerts A . Synthesis and evaluation of nitrofuranylamides as novel antituberculosis agents. J Med Chem. 2004; 47(21):5276-83. DOI: 10.1021/jm049972y. View

Rakesh , Bruhn D, Scherman M, Woolhiser L, Madhura D, Maddox M . Pentacyclic nitrofurans with in vivo efficacy and activity against nonreplicating Mycobacterium tuberculosis. PLoS One. 2014; 9(2):e87909. PMC: 3914891. DOI: 10.1371/journal.pone.0087909. View

Bloemberg G, Keller P, Stucki D, Stuckia D, Trauner A, Borrell S . Acquired Resistance to Bedaquiline and Delamanid in Therapy for Tuberculosis. N Engl J Med. 2015; 373(20):1986-8. PMC: 4681277. DOI: 10.1056/NEJMc1505196. View

10.

Talele T . Natural-Products-Inspired Use of the gem-Dimethyl Group in Medicinal Chemistry. J Med Chem. 2017; 61(6):2166-2210. DOI: 10.1021/acs.jmedchem.7b00315. View

11.

Haver H, Chua A, Ghode P, Lakshminarayana S, Singhal A, Mathema B . Mutations in genes for the F420 biosynthetic pathway and a nitroreductase enzyme are the primary resistance determinants in spontaneous in vitro-selected PA-824-resistant mutants of Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2015; 59(9):5316-23. PMC: 4538556. DOI: 10.1128/AAC.00308-15. View

12.

Carroll M, Jeon D, Mountz J, Lee J, Jeong Y, Zia N . Efficacy and safety of metronidazole for pulmonary multidrug-resistant tuberculosis. Antimicrob Agents Chemother. 2013; 57(8):3903-9. PMC: 3719751. DOI: 10.1128/AAC.00753-13. View

13.

Ekins S, Reynolds R, Kim H, Koo M, Ekonomidis M, Talaue M . Bayesian models leveraging bioactivity and cytotoxicity information for drug discovery. Chem Biol. 2013; 20(3):370-8. PMC: 3607962. DOI: 10.1016/j.chembiol.2013.01.011. View

14.

Stover C, Warrener P, VanDevanter D, Sherman D, Arain T, Langhorne M . A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis. Nature. 2000; 405(6789):962-6. DOI: 10.1038/35016103. View

15.

Matsumoto M, Hashizume H, Tomishige T, Kawasaki M, Tsubouchi H, Sasaki H . OPC-67683, a nitro-dihydro-imidazooxazole derivative with promising action against tuberculosis in vitro and in mice. PLoS Med. 2006; 3(11):e466. PMC: 1664607. DOI: 10.1371/journal.pmed.0030466. View

16.

Wilson R, Kumar P, Parashar V, Vilcheze C, Veyron-Churlet R, Freundlich J . Antituberculosis thiophenes define a requirement for Pks13 in mycolic acid biosynthesis. Nat Chem Biol. 2013; 9(8):499-506. PMC: 3720791. DOI: 10.1038/nchembio.1277. View

17.

Wayne L, Sramek H . Metronidazole is bactericidal to dormant cells of Mycobacterium tuberculosis. Antimicrob Agents Chemother. 1994; 38(9):2054-8. PMC: 284683. DOI: 10.1128/AAC.38.9.2054. View

18.

Hurdle J, Lee R, Budha N, Carson E, Qi J, Scherman M . A microbiological assessment of novel nitrofuranylamides as anti-tuberculosis agents. J Antimicrob Chemother. 2008; 62(5):1037-45. PMC: 2566515. DOI: 10.1093/jac/dkn307. View

19.

Inoyama D, Paget S, Russo R, Kandasamy S, Kumar P, Singleton E . Novel Pyrimidines as Antitubercular Agents. Antimicrob Agents Chemother. 2018; 62(3). PMC: 5826157. DOI: 10.1128/AAC.02063-17. View

20.

Yempalla K, Munagala G, Singh S, Magotra A, Kumar S, Rajput V . Nitrofuranyl Methyl Piperazines as New Anti-TB Agents: Identification, Validation, Medicinal Chemistry, and PK Studies. ACS Med Chem Lett. 2015; 6(10):1041-6. PMC: 4601053. DOI: 10.1021/acsmedchemlett.5b00141. View