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Elsevier, European Journal of Medicinal Chemistry, (108), p. 39-52

DOI: 10.1016/j.ejmech.2015.11.022

Elsevier, European Journal of Medicinal Chemistry, (142), p. 523-549

DOI: 10.1016/j.ejmech.2017.09.035

Elsevier, European Journal of Medicinal Chemistry, (124), p. 361-371

DOI: 10.1016/j.ejmech.2016.08.056

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Discovery of BAZ2A Bromodomain Ligands

Journal article published in 2017 by Beata Żołnowska, Simon J. A. van Kuijk, Marike W. van Gisbergen ORCID, Alice Zamagni, Bernhard Wűnsch, Nadia Zaffaroni, Ala Yaromina, Shane M. Wilkinson, Jean-Yves Winum ORCID, R. S.-M. Wong ORCID, W.-Y. Wong, Eike-Christian Wamhoff ORCID, Giulio Vistoli, Q.-W. Wang, Sonja Visentin and other authors.
This paper is available in a repository.
This paper is available in a repository.

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Abstract

Tuberculosis (TB) remains a serious health problem responsible to cause millions of deaths annually. The scenario becomes alarming when it is evaluated that the number of new drugs does not increase proportionally to the emergence of resistance to the current therapy. Furoxan derivatives, known as nitric oxide (NO) donors, have been described to exhibit antitubercular activity. Herein, a novel series of hybrid furoxan derivatives (1,2,5-oxadiazole 2-N-oxide) (compounds 4a-c, 8a-c and 14a-c) were designed, synthesized and evaluated in vitro against Mycobacterium tuberculosis (MTB) H37Rv (ATCC 27294) and a clinical isolate MDR-TB strain. The furoxan derivatives have exhibited MIC90 values ranging from 1.03 to 62 mM (H37Rv) and 7.0e50.0 mM (MDR-TB). For the most active compounds (8c, 14a, 14b and 14c) the selectivity index ranged from 3.78 to 52.74 (MRC-5 cells) and 1.25e34.78 (J774A.1 cells). In addition, it was characterized for those compounds logPo/w values between 2.1 and 2.9. All compounds were able to release NO at levels ranging from 0.16 to 44.23%. Among the series, the phenylsulfonyl furoxan derivatives (compounds 14a-c) were the best NO-donor with the lowest MIC90 values. The most active compound (14c) was also stable at different pHs (5.0 and 7.4). In conclusion, furoxan derivatives were identified as new promising compounds useful to treat tuberculosis.