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

Mery Santivañez-Veliz; Silvia Pérez-Silanes; Enrique Torres; Elsa Moreno-Viguri

doi:10.1016/j.bmcl.2016.03.066

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

Bioorg Med Chem Lett. 2016 May 1;26(9):2188-93. doi: 10.1016/j.bmcl.2016.03.066. Epub 2016 Mar 18.

Authors

Mery Santivañez-Veliz¹, Silvia Pérez-Silanes¹, Enrique Torres², Elsa Moreno-Viguri³

Affiliations

¹ Department of Organic and Pharmaceutical Chemistry, University of Navarra, Irunlarrea s/n, 31008 Pamplona, Spain; Institute of Tropical Health, University of Navarra, Irunlarrea s/n, E-31008 Pamplona, Spain.
² Department of Organic and Pharmaceutical Chemistry, University of Navarra, Irunlarrea s/n, 31008 Pamplona, Spain.
³ Department of Organic and Pharmaceutical Chemistry, University of Navarra, Irunlarrea s/n, 31008 Pamplona, Spain; Institute of Tropical Health, University of Navarra, Irunlarrea s/n, E-31008 Pamplona, Spain. Electronic address: emviguri@unav.es.

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.

Keywords: Antimycobacterial; Intracellular activity; Quinoxaline; Tuberculosis.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Antitubercular Agents / chemical synthesis
Antitubercular Agents / pharmacology*
Cell Line
Cyclic N-Oxides / chemistry
Cyclic N-Oxides / pharmacology*
Drug Resistance, Multiple, Bacterial / drug effects
Latent Tuberculosis / drug therapy
Mice
Mycobacterium tuberculosis / drug effects
Quinoxalines / chemical synthesis
Quinoxalines / chemistry
Quinoxalines / pharmacology*
Tuberculosis, Multidrug-Resistant / drug therapy

Substances

Antitubercular Agents
Cyclic N-Oxides
Quinoxalines
quindoxin

Abstract

Publication types

MeSH terms

Substances

Grants and funding