Design, synthesis, and evaluation of new 2-(quinoline-4-yloxy) acetamide-based antituberculosis agents

被引：40

作者：

Borsoi, Ana Flavia ^{[1
,2
]}

Paz, Josiane Delgado ^{[1
,3
]}

Abbadi, Bruno Lopes ^{[1
]}

Macchi, Fernanda Souza ^{[1
,3
]}

Sperotto, Nathalia ^{[1
,2
]}

Pissinate, Kenia ^{[1
]}

Rambo, Raoni S. ^{[1
]}

Ramos, Alessandro Silva ^{[1
]}

Machado, Diana ^{[4
]}

Viveiros, Miguel ^{[4
]}

Bizarro, Cristiano Valim ^{[1
,3
]}

Basso, Luiz Augusto ^{[1
,2
,3
]}

Machado, Pablo ^{[1
,3
]}

机构：

[1] Pontificia Univ Catolica Rio Grande do Sul, Ctr Pesquisas Biol Mol & Func, Inst Nacl Ciencia & Tecnol Tuberculose, BR-90616900 Porto Alegre, RS, Brazil

[2] Pontificia Univ Catolica Rio Grande do Sul, Programa Posgrad Med & Ciencias Saude, BR-90616900 Porto Alegre, RS, Brazil

[3] Pontificia Univ Catolica Rio Grande do Sul, Programa Posgrad Biol Celular & Mol, BR-90616900 Porto Alegre, RS, Brazil

[4] Univ NOVA Lisboa, Inst Higiene & Med Trop, UNL, IHMT,GHTM, Lisbon, Portugal

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2020年 / 192卷

关键词：

Mycobacterium tuberculosis; Molecular simplification; Multidrug-resistant strains; SAR; Intracellular activity; Cytochrome bc(1) complex; DRUG DISCOVERY; 2-(QUINOLIN-4-YLOXY)ACETAMIDES; RESISTANCE; CHALLENGE; DELAMANID; LEADS; ASSAY;

D O I：

10.1016/j.ejmech.2020.112179

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 mu M 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 bc(1) 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. (c) 2020 Published by Elsevier Masson SAS.

引用

页数：10

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