New hybrid trifluoromethylquinolines as antiplasmodium agents

[Display omitted] Malaria remains a major public health problem worldwide, and it is responsible for high rates of morbidity and mortality. Resistance to current antimalarial drugs has been identified, and new drugs are urgently needed. In this study, we designed and synthesized seventeen novel quin...

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Published in:	Bioorganic & medicinal chemistry Vol. 27; no. 6; pp. 1002 - 1008
Main Authors:	da Silva, Renata M.R.J., Gandi, Marilia O., Mendonça, Jorge S., Carvalho, Alcione S., Coutinho, Julia Penna, Aguiar, Anna C.C., Krettli, Antoniana U., Boechat, Nubia
Format:	Journal Article
Language:	English
Published:	England Elsevier Ltd 15-03-2019
Subjects:	Amodiaquine Animals Antimalarials - chemistry Antimalarials - pharmacology Antimalarials - therapeutic use Cell Line Drug Discovery Erythrocytes - drug effects Erythrocytes - parasitology Halogenation Haplorhini Humans Hybrids Malaria Malaria - drug therapy Mefloquine Methylation Mice P. falciparum Plasmodium berghei - drug effects Plasmodium falciparum - drug effects Quinoline Quinolines - chemistry Quinolines - pharmacology Quinolines - therapeutic use Quinoline Amodiaquine Hybrids Mefloquine Malaria P. falciparum
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Summary:	[Display omitted] Malaria remains a major public health problem worldwide, and it is responsible for high rates of morbidity and mortality. Resistance to current antimalarial drugs has been identified, and new drugs are urgently needed. In this study, we designed and synthesized seventeen novel quinolines based on the structures of mefloquine ((2,8-bis(trifluoromethyl)quinolin-4-yl)(piperidin-2-yl)methanol) and amodiaquine (4-((7-chloroquinolin-4-yl)amino)-2-((diethylamino)methyl)phenol) using ring bioisosteric replacement and molecular hybridization of the functional groups. The compounds were evaluated in vitro against Plasmodium falciparum and in vivo in mice infected with P. berghei. All derivatives presented anti-P. falciparum activity with IC50 values ranging from 0.083 to 33.0 µM. The compound with the best anti-P. falciparum activity was N-(5-methyl-4H-1,2,4-triazol-3-yl)-2,8-bis(trifluoromethyl)quinolin-4-amine (12) which showed an IC50 of 0.083 µM. The three most active compounds were selected for antimalarial activity tests against P. berghei-infected mice. Compound 12 was the most active on the 5th day after infection, reducing parasitemia by 66%, which is consistent with its in vitro activity. This is an important result as 12, a simpler molecule than mefloquine, does not contain the stereogenic center, and consequently, its synthesis in the laboratory is easier and less expensive. This system proved promising for the design of potential antimalarial compounds.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0968-0896 1464-3391
DOI:	10.1016/j.bmc.2019.01.044