Bis-alkylamine Indolo[3,2-<i>b</i>]quinolines as Hemozoin Ligands: Implications for Antimalarial Cytostatic and Cytocidal Activities

Paulo, Alexandra; Figueiras, Marta; Machado, Marta; Charneira, Catarina; Lavrado, João; Santos, Sofia A.; Lopes, Dinora; Gut, Jiří; Rosenthal, Philip J.; Nogueira, Fátima; Moreira, Rui

doi:10.1021/jm500075d

Cited by 21 publications

(10 citation statements)

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“…[23] Malarial parasites ingest and digest >70% of host hemoglobin as an amino acid source inside erythrocytes, and hemoglobin degradation, as well as hemozoin formation, are essential for parasite survival, making these processes important targets for antimalarials development. [24] Indole derivatives could exert antimalarial activity through different mechanisms of action including hemoglobin degradation and hemozoin formation, [25] so indole derivatives possess potential activity against both drug-sensitive and Abbreviations: CC 50 , half-maximal cytotoxicity concentration; CQS, chloroquine-sensitive; CQR, chloroquine-resistant; HCV, hepatitis virus C; HIV, human immunodeficiency virus; IC 50 , halfmaximal inhibitory concentration; MDR, multidrug-resistant; P. falciparum, Plasmodium falciparum; P. knowlesi, Plasmodium knowlesi; P. malariae, Plasmodium malariae; P. ovale, Plasmodium ovale; P. vivax, Plasmodium vivax; SAR, structure-activity relationship; SI, selectivity index; RI, resistance index; WHO, World Health Organization.…”

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confidence: 99%

The antimalarial activity of indole alkaloids and hybrids

Sun

et al. 2020

Archiv der Pharmazie

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Malaria, caused by the genus Plasmodium, remains a global public health concern. It is estimated by the World Health Organization that over 40% of the world's population lives in areas at risk for malarial transmission, and around half a million people succumb to this infectious disease annually, which is related to the rapid spread of drug-resistant parasite strains. Indole derivatives, which possess broadspectrum pharmacological properties, play a crucial role in the discovery of new drugs. Many indole derivatives exhibited potential in vitro and in vivo activity against both drug-sensitive and drug-resistant malaria, suggesting that the indole moiety is a useful template for the development of novel antimalarial agents.

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confidence: 99%

The antimalarial activity of indole alkaloids and hybrids

Sun

et al. 2020

Archiv der Pharmazie

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“…As expected, no cross-resistance of the proposed compounds with quinolone-type anti-malarials is foreseeable, as the calculated RIs for Dd2 and 3D7 were ≅1 (Table 1 ), which is considerably lower than the RI determined for CQ (21.5) [ 20 , 68 ].…”

Section: Discussionmentioning

confidence: 80%

New endoperoxides highly active in vivo and in vitro against artemisinin-resistant Plasmodium falciparum

Lobo

Cabral

Sena

et al. 2018

Malar J

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BackgroundThe emergence and spread of Plasmodium falciparum resistance to artemisinin-based combination therapy in Southeast Asia prompted the need to develop new endoperoxide-type drugs.MethodsA chemically diverse library of endoperoxides was designed and synthesized. The compounds were screened for in vitro and in vivo anti-malarial activity using, respectively, the SYBR Green I assay and a mouse model. Ring survival and mature stage survival assays were performed against artemisinin-resistant and artemisinin-sensitive P. falciparum strains. Cytotoxicity was evaluated against mammalian cell lines V79 and HepG2, using the MTT assay.ResultsThe synthesis and anti-malarial activity of 21 new endoperoxide-derived compounds is reported, where the peroxide pharmacophore is part of a trioxolane (ozonide) or a tetraoxane moiety, flanked by adamantane and a substituted cyclohexyl ring. Eight compounds exhibited sub-micromolar anti-malarial activity (IC50 0.3–71.1 nM), no cross-resistance with artemisinin or quinolone derivatives and negligible cytotoxicity towards mammalian cells. From these, six produced ring stage survival < 1% against the resistant strain IPC5202 and three of them totally suppressed Plasmodium berghei parasitaemia in mice after oral administration.ConclusionThe investigated, trioxolane–tetrazole conjugates LC131 and LC136 emerged as potential anti-malarial candidates; they show negligible toxicity towards mammalian cells, ability to kill intra-erythrocytic asexual stages of artemisinin-resistant P. falciparum and capacity to totally suppress P. berghei parasitaemia in mice.Electronic supplementary materialThe online version of this article (10.1186/s12936-018-2281-x) contains supplementary material, which is available to authorized users.

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“…The antiplasmodial SAR of indolo[3,2‐b]quinolines 88 (Figure ) showed that chloro at R 1 and R 2 positions improved the antiplasmodial activity against CQS 3D7 and CQR W2 strains, and hybrids with alkylamino at R 3 position were more potent than the corresponding cycloalkylamino analogs . The RI of the hybrids was 0.3‐0.7, demonstrating their potency to treat drug‐resistant malaria.…”

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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Bis-alkylamine Indolo[3,2-b]quinolines as Hemozoin Ligands: Implications for Antimalarial Cytostatic and Cytocidal Activities

Cited by 21 publications

References 68 publications

The antimalarial activity of indole alkaloids and hybrids

The antimalarial activity of indole alkaloids and hybrids

New endoperoxides highly active in vivo and in vitro against artemisinin-resistant Plasmodium falciparum

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

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