Design, synthesis, and characterization of novel aminoalcohol quinolines with strong in vitro antimalarial activity

被引：12

作者：

Dassonville-Klimpt, A. ^{[1
]}

Schneider, J. ^{[1
]}

Damiani, C. ^{[1
]}

Tisnerat, C. ^{[1
]}

Cohen, A. ^{[2
]}

Azas, N. ^{[2
]}

Marchivie, M. ^{[3
]}

Guillon, J. ^{[4
,5
]}

Mullie, C. ^{[1
]}

Agnamey, P. ^{[1
]}

Totet, Anne ^{[1
]}

Dormoi, J. ^{[6
,7
,8
]}

Taudon, N. ^{[9
]}

Pradines, B. ^{[6
,7
,8
,10
]}

Sonnet, P. ^{[1
]}

机构：

[1] Univ Picardie Jules Verne, AGIR, UFR Pharm, UR, F-4294 Amiens, France

[2] Univ Aix Marseille, IRD, AP HM, VITROME,IHU Mediterranee Infect,SSA, Marseille, France

[3] Univ Bordeaux, CNRS, Bordeaux INP, ICMCB,UMR 5026, F-33600 Pessac, France

[4] Univ Bordeaux, Lab ARNA, UFR Sci Pharmaceut, Bordeaux, France

[5] INSERM, UMR 5320, Lab ARNA, CNRS, Bordeaux, France

[6] Inst Rech Biomed Armees, Unit Parasitol & Entomol, Dept Microbiol & Malad Infect, Marseille, France

[7] Aix Marseille Univ, IRD, SSA, VITROME,AP HM, Marseille, France

[8] IHU Mediterranee Infect, Marseille, France

[9] IRBA, Unit Dev Analyt & Bioanal, Bretigny Sur Orge, France

[10] Ctr Natl Reference Paludisme, Marseille, France

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2022年 / 228卷

关键词：

Malaria; P; falciparum; Antimalarial drug resistance; Mefloquine analogs; Aminoalcohol quinolines; in vitro; In vivo; PLASMODIUM-FALCIPARUM; MEFLOQUINE RESISTANCE; GENETIC DIVERSITY; PFMDR1; GENE; CHLOROQUINE; MALARIA; MODEL; ASSAY; AMPLIFICATION; HALOFANTRINE;

D O I：

10.1016/j.ejmech.2021.113981

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Malaria is the fifth most lethal parasitic infections in the world. Herein, five new series of aminoalcohol quinolines including fifty-two compounds were designed, synthesized and evaluated in vitro against Pf3D7 and PfW2 strains. Among them, fourteen displayed IC50 values below or near of 50.0 nM whatever the strain with selectivity index often superior to 100.17b was found as a promising antimalarial candidate with IC50 values of 14.9 nM and 11.0 nM against respectively Pf3D7 and PfW2 and a selectivity index higher than 770 whatever the cell line is. Further experiments were achieved to confirm the safety and to establish the preliminary ADMET profile of compound 17b before the in vivo study performed on a mouse model of P. berghei ANKA infection. The overall data of this study allowed to establish new structure-activity relationships and the development of novel agents with improved pharmacokinetic properties. (C) 2021 Elsevier Masson SAS. All rights reserved.

引用

页数：26

共 70 条

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