New hybrid trifluoromethylquinolines as antiplasmodium agents

Silva, Renata M.R.J. da; Gandi, Marilia O.; Mendonça, Jorge S.; Carvalho, Alcione Silva de; Coutinho, Julia Penna; Aguiar, Anna Caroline Campos; Krettli, Antoniana U.; Boechat, Núbia

doi:10.1016/j.bmc.2019.01.044

Cited by 26 publications

(13 citation statements)

References 38 publications

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“…The presence of an aminoguanidine functional group also enhanced the antimalarial activity of the hybrid molecules [42]. In addition, there are several recent reports of synthesized quinoline-based hybrids that exhibited promising therapeutic outcomes, especially potent antimalarial efficacy, such as trifloromethylquinoline hybrids [43], primaquine- and chloroquine-quinoxaline 1,4-di- N -oxide hybrids [44], 1,3-dioxoisoindoline-4-aminoquinolines [45], and atorvastatin–quinoline hybrid compounds [46]. Factors such as presence of the quinoline-amine group between the trifluoromethylquinoline ring and the water insoluble region enhanced the antimalarial activity of the hybrid molecules.…”

Section: Combination Therapy Strategiesmentioning

confidence: 99%

Combination Therapy Strategies for the Treatment of Malaria

Alven

Aderibigbe

2019

Molecules

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Malaria is a vector- and blood-borne infection that is responsible for a large number of deaths around the world. Most of the currently used antimalarial therapeutics suffer from drug resistance. The other limitations associated with the currently used antimalarial drugs are poor drug bioavailability, drug toxicity, and poor water solubility. Combination therapy is one of the best approaches that is currently used to treat malaria, whereby two or more therapeutic agents are combined. Different combination therapy strategies are used to overcome the aforementioned limitations. This review article reports two strategies of combination therapy; the incorporation of two or more antimalarials into polymer-based carriers and hybrid compounds designed by hybridization of two antimalarial pharmacophores.

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Section: Combination Therapy Strategiesmentioning

confidence: 99%

Combination Therapy Strategies for the Treatment of Malaria

Alven

Aderibigbe

2019

Molecules

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“…The antiplasmodial SAR for quinoline‐1,2,4‐triazole hybrids 48 (Figure ) showed that electron‐donating methyl could improve the activity against CQR W2 strain, while electron‐withdrawing trifluoromethyl reduced the activity when compared with the unsubstituted analog . The most active hybrid 48b with IC 50 of 83 nM was around five times more potent than CQ (IC 50 : 250 nM) against CQR W2 strain, and it also showed highest potency on the day 5 after infection by reducing parasitemia by 66% in P berghei‐infected mice malaria model …”

Section: Quinoline Hybridized With Novel Antimalarial Pharmacophores mentioning

confidence: 99%

Hybrid molecules with potential in vitro antiplasmodial and in vivo antimalarial activity against drug‐resistant Plasmodium falciparum

Feng

Chang

et al. 2019

Medicinal Research Reviews

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Malaria is a tropical disease, leading to around half a million deaths annually. Antimalarials such as quinolines are crucial to fight against malaria, but malaria control is extremely challenged by the limited pipeline of effective pharmaceuticals against drug-resistant strains of Plasmodium falciparum which are resistant toward almost all currently accessible antimalarials. To tackle the growing resistance, new antimalarial drugs are needed urgently. Hybrid molecules which contain two or more pharmacophores have the potential to overcome the drug resistance, and hybridization of quinoline privileged antimalarial building block with other antimalarial pharmacophores may provide novel molecules with enhanced in vitro and in vivo activity against drug-resistant (including multidrug-resistant) P falciparum. In recent years, numerous of quinoline hybrids were developed, and their activities against a panel of drug-resistant P falciparum strains were screened. Some of quinoline hybrids were found to possess promising in vitro and in vivo potency. This review emphasized quinoline hybrid molecules with

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“…Furthermore, they suggested that heme may be the probable target of these hybrid molecules. Later in the same year, da Silva et al [19] tested N-(5-methyl-4H-1,2,4-triazol-3-yl)-2,8-bis(trifluoromethyl)quinolin-4-amine (VIII) against P. berghei-infected mice. This compound was active on the 5th day after infection, reducing parasitemia by 66%, consistent with its in vitro activity.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Molecular Docking, and Antimalarial Activity of Hybrid 4-Aminoquinoline-pyrano[2,3-c]pyrazole Derivatives

et al. 2021

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Widespread resistance of Plasmodium falciparum to current artemisinin-based combination therapies necessitate the discovery of new medicines. Pharmacophoric hybridization has become an alternative for drug resistance that lowers the risk of drug–drug adverse interactions. In this study, we synthesized a new series of hybrids by covalently linking the scaffolds of pyrano[2,3-c]pyrazole with 4-aminoquinoline via an ethyl linker. All synthesized hybrid molecules were evaluated through in vitro screenings against chloroquine-resistant (K1) and -sensitive (3D7) P. falciparum strains, respectively. Data from in vitro assessments showed that hybrid 4b displayed significant antiplasmodial activities against the 3D7 strain (EC50 = 0.0130 ± 0.0002 μM) and the K1 strain (EC50 = 0.02 ± 0.01 μM), with low cytotoxic effect against Vero mammalian cells. The high selectivity index value on the 3D7 strain (SI > 1000) and the K1 strain (SI > 800) and the low resistance index value from compound 4b suggested that the pharmacological effects of this compound were due to selective inhibition on the 3D7 and K1 strains. Molecular docking analysis also showed that 4b recorded the highest binding energy on P. falciparum lactate dehydrogenase. Thus, P. falciparum lactate dehydrogenase is considered a potential molecular target for the synthesized compound.

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New hybrid trifluoromethylquinolines as antiplasmodium agents

Cited by 26 publications

References 38 publications

Combination Therapy Strategies for the Treatment of Malaria

Combination Therapy Strategies for the Treatment of Malaria

Hybrid molecules with potential in vitro antiplasmodial and in vivo antimalarial activity against drug‐resistant Plasmodium falciparum

Synthesis, Molecular Docking, and Antimalarial Activity of Hybrid 4-Aminoquinoline-pyrano[2,3-c]pyrazole Derivatives

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