Synthesis and biological activity of furoxan derivatives against Mycobacterium tuberculosis

Fernandes, Guilherme; Souza, Paula Carolina de; Mariño, Leonardo; Chegaev, Konstantin; Guglielmo, Stefano; Lazzarato, Loretta; Fruttero, Roberta; Chin, Chung Man; Pavan, Fernando Rogério; Santos, Jean Leandro dos

doi:10.1016/j.ejmech.2016.07.039

Cited by 72 publications

(37 citation statements)

References 57 publications

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“…Moreover, there is ad irect correlation between NO-donorc apability and antitubercular activity:t he more powerful NO-donor hybrid among the series is the most active antitubercular agent. [37] As eries of furoxan-based chalcone hybridsw as synthesized through Wittig reaction of polymer-supported phosphonium ylides 37 a-c with furoxancarbaldehydes 26 a,b (Scheme 14). The resulting derivatives 39 a,b are not mutagenic and can be considered promisingi nvivop hase II enzyme inducers,w hich is very useful in chemopreventive cancer therapy.…”

Section: Introductionmentioning

confidence: 99%

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Molecular Hybridization Tools in the Development of Furoxan‐Based NO‐Donor Prodrugs

Ферштат

Махова

2017

ChemMedChem

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The molecular hybridization of different compounds with known pharmacological activity is a particularly prominent approach for the design of potential drugs with improved pharmacokinetic profiles. Much attention over the last decade has been focused on the synthesis of hybrid structures with a nitric oxide (NO)-donor framework, as NO is a ubiquitous and crucial regulator of cellular metabolism, affecting various physiological and pathophysiological processes. 1,2,5-Oxadiazole 2-oxides (furoxans), which are capable of exogenous NO release in the presence of thiol cofactors, are an important class of prospective NO donors. As such, a wide range of hybrid compounds that combine a furoxan ring with various pharmacologically active structures have been created. This review focuses on recent results in the synthesis and pharmacological activity of furoxan-based hybrids. Special attention is given to chemo- and regioselective methods used in the preparation of these hybrid structures, and the role of synergistic effects on their pharmacological activity, associated with the furoxan fragment.

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Section: Introductionmentioning

confidence: 99%

“…Synthesis of furoxan-hydrazonehybrids linked via phenol bridge. [37] Reagents and conditions:a )o-, m-, or p-HOC 6 H 4 CHO,D BU, CH 2 Cl 2 ,R T; b) isonicotinic hydrazide,H Cl (cat. ), EtOH, RT,1 2h,8 3-95 %.…”

Section: Introductionmentioning

confidence: 99%

Molecular Hybridization Tools in the Development of Furoxan‐Based NO‐Donor Prodrugs

Ферштат

Махова

2017

ChemMedChem

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“…bicyclic nitroimidazoles) have shown Mtb-killing activity [39,40]. Furthermore, NO donor compounds such as DETA/NO, S-nitrosothiols, and furoxan derivatives have also demonstrated anti-Mtb activity in preclinical models [41][42][43]. Despite the efficacy in preclinical models, there has been limited evidence on the efficacy of NO donor compounds in the clinical setting.…”

Section: Discussionmentioning

confidence: 99%

Antibacterial activity of high-dose nitric oxide against pulmonary Mycobacterium abscessus disease

Bogdanovski

Chau

Robinson

et al. 2020

Access Microbiology

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Introduction. Mycobacterium abscessus is an emerging pulmonary pathogen with limited treatment options. Nitric oxide (NO) demonstrates antibacterial activity against various bacterial species, including mycobacteria. In this study, we evaluated the effect of adjunctive inhaled NO therapy, using a novel NO generator, in a CF patient with pulmonary M. abscessus disease, and examined heterogeneity of response to NO in vitro. Methods. In the compassionate-use treatment, a 24-year-old CF patient with pulmonary M. abscessus was treated with two courses of adjunctive intermittent NO, first at 160 p.p.m. for 21 days and subsequently by escalating the dose up to 240 p.p.m. for 8 days. Methemoglobin, pulmonary function, 6 min walk distance (6MWD), qualify of life and sputum microbiology were assessed. In vitro susceptibility tests were performed against patient’s isolate and comparison clinical isolates and quantified by Hill’s slopes calculated from time–kill curves. Results. M. abscessus lung infection eradication was not achieved, but improvements in selected qualify of life domains, lung function and 6MWD were observed during the study. Inhaled NO was well tolerated at 160 p.p.m. Dosing at 240 p.p.m. was stopped due to adverse symptoms, although methemoglobin levels remained within safety thresholds. In vitro susceptibility tests showed a dose-dependent NO effect on M. abscessus susceptibility and significant heterogeneity in response between M. abscessus clinical isolates. The patient’s isolate was found to be the least susceptible strain in vitro. Conclusion. These results demonstrate heterogeneity in M. abscessus susceptibility to NO and suggest that longer treatment regimens could be required to see the reduction or eradication of more resistant pulmonary strains.

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“…Specifically, compound ( 25 ) (Figure 9) exhibited MIC 90 of 7 μM against MDR-TB clinical isolates. Furthermore, the authors have demonstrated that this compound may act through the release of nitric oxide [48]. Smith and coworkers have discovered a nitrotriazole derivative as a promising antitubercular agent.…”

Section: Antituberculosis Compoundsmentioning

confidence: 99%

Advances in Drug Discovery of New Antitubercular Multidrug-Resistant Compounds

2017

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Tuberculosis (TB), a disease caused mainly by the Mycobacterium tuberculosis (Mtb), is according to the World Health Organization (WHO) the infectious disease responsible for the highest number of deaths worldwide. The increased number of multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) strains, and the ineffectiveness of the current treatment against latent tuberculosis are challenges to be overcome in the coming years. The scenario of drug discovery becomes alarming when it is considered that the number of new drugs does not increase proportionally to the emergence of drug resistance. In this review, we will demonstrate the current advances in antitubercular drug discovery, focusing on the research of compounds with potent antituberculosis activity against MDR-TB strains. Herein, active compounds against MDR-TB with minimum inhibitory concentrations (MICs) less than 11 µM and low toxicity published in the last 4 years in the databases PubMed, Web of Science and Scopus will be presented and discussed.

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Synthesis and biological activity of furoxan derivatives against Mycobacterium tuberculosis

Cited by 72 publications

References 57 publications

Molecular Hybridization Tools in the Development of Furoxan‐Based NO‐Donor Prodrugs

Molecular Hybridization Tools in the Development of Furoxan‐Based NO‐Donor Prodrugs

Antibacterial activity of high-dose nitric oxide against pulmonary Mycobacterium abscessus disease

Advances in Drug Discovery of New Antitubercular Multidrug-Resistant Compounds

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