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Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

Research Article

Pyrazole and imidazo[1,2-b]pyrazole Derivatives as New Potential Antituberculosis Agents

Author(s): Elda Meta, Chiara Brullo*, Michele Tonelli, Scott G. Franzblau, Yuehong Wang, Rui Ma, Wan Baojie, Beatrice S. Orena, Maria R. Pasca and Olga Bruno

Volume 15, Issue 1, 2019

Page: [17 - 27] Pages: 11

DOI: 10.2174/1573406414666180524084023

Price: $65

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Abstract

Background: We screened a large library of differently decorated imidazo-pyrazole and pyrazole derivatives as possible new antitubercular agents and this preliminary screening showed that many compounds are able to totally inhibit Mycobacterium growth (>90 %). Among the most active compounds, we selected some new possible hits based on their similarities and, at the same time, on their novelty with respect to the pipeline drugs.

Methods: In order to increase the potency and obtain more information about structure-activity relationship (SAR), we designed and synthesized three new series of compounds (2a–e, 3a–e, and 4a–l).

Conclusion: Performed tests confirmed that both new pyrazoles and imidazo-pyrazoles could represent a new starting point to obtain more potent compounds and further work is now underway to identify the protein targets of this new class of anti-TB agents.

Keywords: Pyrazole, imidazo[1, 2-b]pyrazole, antitubercular agents, MABA, LORA, Tuberculosis (TB).

Graphical Abstract
[1]
WHO Report 2016. Available at: http://www.who.int/tb/areas-of-work/research/ en/ (Accessed, October 2017).
[2]
The Lilly TB Drug Discovery Initiative. Available at:. http://www.tbdrugdiscovery.org (Accessed, October 2017).
[3]
Ballell, L.; Bates, R.; Young, R.J.; Alvarez-Gomez, D. Alva-rez-Ruiz, E.; Barroso, V.; Blanco, D.; Crespo, B.; Escribano, J.; González, R.; Lozano, S.; Huss, S.; Santos-Villarejo, A.; Martín-Plaza, J.J.; Mendoza, A.; Rebollo-Lopez, M.J.; Remui-ñan-Blanco, M.; Lavandera, J.L.; Pérez-Herran, E.; Gamo-Benito, F.J.; García-Bustos, J.F.; Barros, D.; Castro, J.P.; Cammack, N. Fueling open-source drug discovery: 177 small-molecule leads against tuberculosis. ChemMedChem, 2013, 8, 313-321.
[4]
Bruno, O.; Brullo, C.; Bondavalli, F.; Schenone, S.; Ranise, A.; Arduino, N.; Bertolotto, M.B.; Montecucco, F.; Ottonello, L.; Dallegri, F.; Tognolini, M.; Ballabeni, V.; Bertoni, S.; Bar-ocelli, E. Synthesis and biological evaluation of N-pyrazolyl-N'-alkyl/benzyl/ phenylureas: A new class of potent inhibitors of interleukin 8-induced neutrophil chemotaxis. J. Med. Chem., 2007, 50, 3618-3626.
[5]
Brullo, C.; Spisani, S.; Selvatici, R.; Bruno, O. N-Aryl-2-phenyl-2,3-dihydro-imidazo[1,2-b]pyrazole-1-carboxamides 7-substituted strongly inhibiting both fMLP-OMe- and IL-8-induced human neutrophil chemotaxis. Eur. J. Med. Chem., 2012, 47, 573-579.
[6]
Meta, E.; Brullo, C.; Sidibe, A.; Imhof, B.A.; Bruno, O. De-sign, synthesis and biological evaluation of new pyrazolyl-ureas and imidazopyrazolecarboxamides able to interfere with MAPK and PI3K upstream signaling involved in the angio-genesis. Eur. J. Med. Chem., 2017, 133, 24-35.
[7]
Grosse, S.; Mathieu, V.; Pillard, C.; Massip, S.; Marchivie, M.; Jarry, C.; Bernard, P.; Kiss, R.; Guillaumet, G. New imid-azo[1,2-b]pyrazoles as anticancer agents: synthesis, biological evaluation and structure activity relationship analysis. Eur. J. Med. Chem., 2014, 84, 718-730.
[8]
Mevellec, L.A.; Jeanty, M.L.; Jousseaume, T.F.A.J. PCT Int.Appl WO 2015144801, May 26, 2015.
[9]
Suessmeier, F.; Lobell, M.; Gruenewald, S.; Haerter, M.; Buchmann, B.; Telser, J.; Joerissen, H.; Heroult, M.; Kahnert, A.; Lustig, K.; Lindner, N. U.S. 20130190290, January 23, 2013.
[10]
Abdelhamid, A.O.; Abdelall, E.K.A.; Zakic, Y.H.; Eman, K.A.; Zaki, Y.H. Reactions with hydrazonoyl halides: Synthe-sis and antimicrobial evaluation of some new imidazo[1,2-a]pyrimidine, imidazo [1,2-a]pyridine, imidazo[1,2-b]pyrazole, and quinoxaline derivatives. J. Heterocycl. Chem., 2010, 47, 477-482.
[11]
Selvatici, R.; Brullo, C.; Bruno, O.; Spisani, S. Differential inhibition of signalling pathways by two new imidazo-pyrazoles molecules in fMLF-OMe- and IL8-stimulated hu-man neutrophil. Eur. J. Pharmacol., 2013, 718, 428-434.
[12]
Cho, S.; Lee, H.S.; Franzblau, S. Microplate Alamar Blue Assay (MABA) and Low Oxygen Recovery Assay (LORA) for mycobacterium tuberculosis. Methods Mol. Biol., 2015, 1285, 281-292.
[13]
Schenone, S.; Bruno, O.; Fossa, P.; Ranise, A.; Menozzi, G.; Mosti, L.; Bondavalli, F.; Martini, C.; Trincavelli, L. Synthesis and biological data of 4-amino-1-(2-chloro-2-phenylethyl)-1H-pyrazolo[3, 4-b]pyridine-5-carboxylic acid ethyl esters, a new series of A1-adenosine receptor (A1AR) ligands. Bioorg. Med. Chem. Lett., 2001, 11, 2529-2531.
[14]
Bondavalli, F.; Botta, M.; Bruno, O.; Ciacci, A.; Corelli, F.; Fossa, P.; Lucacchini, A.; Manetti, F.; Martini, C.; Menozzi, G.; Mosti, L.; Ranise, A.; Schenone, S.; Tafi, A.; Trincavelli, M.L. Synthesis, molecular modeling studies, and pharmaco-logical activity of selective A(1) receptor antagonists. J. Med. Chem., 2002, 45, 4875-4887.
[15]
Piscitelli, F.; Ligresti, A.; La Regina, G.; Gatti, V.; Brizzi, A.; Pasquini, S.; Allarà, M.; Carai, M.A.; Novellino, E.; Colombo, G.; Di Marzo, V.; Corelli, F.; Silvestri, R. 1-Aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamide: an effective scaf-fold for the design of either CB1 or CB2 receptor ligands. Eur. J. Med. Chem., 2011, 46, 5641-5653.
[16]
Ninomiya, K.; Shioiri, T.; Yamada, S. Amino acids and pep-tides. XII. Phosphorus in organic synthesis. VIII. Reaction of malonic acid half esters with diphenyl phosphorazidate. Chem. Pharm. Bull. , 1974, 22(6), 1795-1799.

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