TY - JOUR
T1 - Design, synthesis, and evaluation of new 2-(quinoline-4-yloxy)acetamide-based antituberculosis agents
AU - Borsoi, Ana Flávia
AU - Paz, Josiane Delgado
AU - Abbadi, Bruno Lopes
AU - Macchi, Fernanda Souza
AU - Sperotto, Nathalia
AU - Pissinate, Kenia
AU - Rambo, Raoní S
AU - Ramos, Alessandro Silva
AU - Machado, Diana
AU - Viveiros, Miguel
AU - Bizarro, Cristiano Valim
AU - Basso, Luiz Augusto
AU - Machado, Pablo
N1 - Funding Information:
This work was supported by Banco Nacional de Desenvolvimento Econômico e Social (BNDES) [grant number 14.2.0914.1 ] and the National Institute of Science and Technology on Tuberculosis (CNPq-FAPERGS-CAPES) [grant numbers: 421703-2017-2 and 17-1265-8 ]. C. V. Bizarro, L. A. Basso, and P. Machado are Research Career Awardees of the National Research Council of Brazil (CNPq). This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nivel Superior, Brasil (CAPES) , Finance Code 001 .
Publisher Copyright:
© 2020
PY - 2020/4/15
Y1 - 2020/4/15
N2 - Using a classical molecular simplification approach, a series of 36 quinolines were synthesized and evaluated as in vitro inhibitors of Mycobacterium tuberculosis (M. tuberculosis) growth. Structure-activity relationship (SAR) studies leaded to potent antitubercular agents, with minimum inhibitory concentration (MIC) values as low as 0.3 μM against M. tuberculosis H37Rv reference strain. Furthermore, the lead compounds were active against multidrug-resistant strains, without cross-resistance with some first- and second-line drugs. Testing the molecules against a spontaneous mutant strain containing a single mutation in the qcrB gene (T313A) indicated that the synthesized quinolines targeted the cytochrome bc1 complex. In addition, leading compounds were devoid of apparent toxicity to HepG2 and Vero cells and showed moderate elimination rates in human liver S9 fractions. Finally, the selected structures inhibited M. tuberculosis growth in a macrophage model of tuberculosis infection. Taken together, these data indicate that this class of compounds may furnish candidates for the future development of antituberculosis drugs.
AB - Using a classical molecular simplification approach, a series of 36 quinolines were synthesized and evaluated as in vitro inhibitors of Mycobacterium tuberculosis (M. tuberculosis) growth. Structure-activity relationship (SAR) studies leaded to potent antitubercular agents, with minimum inhibitory concentration (MIC) values as low as 0.3 μM against M. tuberculosis H37Rv reference strain. Furthermore, the lead compounds were active against multidrug-resistant strains, without cross-resistance with some first- and second-line drugs. Testing the molecules against a spontaneous mutant strain containing a single mutation in the qcrB gene (T313A) indicated that the synthesized quinolines targeted the cytochrome bc1 complex. In addition, leading compounds were devoid of apparent toxicity to HepG2 and Vero cells and showed moderate elimination rates in human liver S9 fractions. Finally, the selected structures inhibited M. tuberculosis growth in a macrophage model of tuberculosis infection. Taken together, these data indicate that this class of compounds may furnish candidates for the future development of antituberculosis drugs.
KW - Cytochrome bc(1) complex
KW - Intracellular activity
KW - Molecular simplification
KW - Multidrug-resistant strains
KW - Mycobacterium tuberculosis
KW - SAR
UR - https://pubmed.ncbi.nlm.nih.gov/32113048/
U2 - 10.1016/j.ejmech.2020.112179
DO - 10.1016/j.ejmech.2020.112179
M3 - Article
C2 - 32113048
SN - 0223-5234
VL - 192
SP - 112179
EP - 112189
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
M1 - 112179
ER -
