Quinoqxaline Drug Candidate 2016

Design and synthesis of novel quinoxaline derivatives as potential candidates for treatment of multidrug-resistant and latent tuberculosis

• Mery Santivañez-Veliz^{a, b},
• Silvia Pérez-Silanes^{a, b},
• Enrique Torres^a,
• Elsa Moreno-Viguri^{a, b, ,}

• ^a Department of Organic and Pharmaceutical Chemistry, University of Navarra, Irunlarrea s/n, 31008 Pamplona, Spain
• ^b Institute of Tropical Health, University of Navarra, Irunlarrea s/n, E-31008 Pamplona, Spain

Received 15 January 2016, Revised 15 March 2016, Accepted 16 March 2016, Available online 18 March 2016

 

http://dx.doi.org/10.1016/j.bmcl.2016.03.066

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Abstract

Twenty-four quinoxaline derivatives were evaluated for their antimycobacterial activity using BacTiter-Glo microbial cell viability assay. Five compounds showed MIC values <3.1 μM and IC50 values <1.5 μM in primary screening and therefore, they were moved on for further evaluation. Compounds 21 and 18 stand out, showing MIC values of 1.6 μM and IC50 values of 0.5 and 1.0 μM, respectively. Both compounds were the most potent against three evaluated drug-resistant strains. Moreover, they exhibited intracellular activity in infected macrophages, considering log-reduction and cellular viability. In addition, compounds 16 and 21 were potent against non-replicating Mycobacterium tuberculosis and compound 21 was bactericidal. Therefore, quinoxaline derivatives could be considered for making further advances in the future development of antimycobacterial agents.

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Graphical abstract

Abbreviations

• TB, tuberculosis;
• M. Tb., Mycobacterium tuberculosis;
• BTG, BacTiter-Glo microbial cell viability assay;
• MDG, Millennium Development Goals;
• BFX, benzofuroxan;
• NRP, non-replicating persistence;
• MBC, Minimal bactericidal concentration;
• LORA, Low Oxygen Recovery Assay;
• SDR, single drug-resistant;
• FBS, bovine serum;
• NA, not available;
• RIF, rifampin;
• INH, isoniazid;
• OFX, ofloxacin

Keywords

• Tuberculosis;
• Antimycobacterial;
• Quinoxaline;
• Intracellular activity