N10,N11-di-alkylamine indolo[3,2-b]quinolines as hemozoin inhibitors: Design, synthesis and antiplasmodial activity

Figueiras, Marta; Coelho, Lis; Wicht, Kathryn J.; Santos, Sofia A.; Lavrado, João; Gut, Jiří; Rosenthal, Philip J.; Nogueira, Fátima; Egan, Timothy J.; Moreira, Rui; Paulo, Alexandra

doi:10.1016/j.bmc.2015.02.007

Cited by 17 publications

(7 citation statements)

References 26 publications

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“…Following this work, the same authors developed a series of N 10, N 11-di-alkylamine bioisosteres ( Scheme 2 ), with the rationale that replacement of the oxygen atom by a NH group would increase the basicity of the quinoline nitrogen, leading to improved accumulation in the digestive vacuole by a pH-trap mechanism. Results showed that the compounds exhibited selectivity for malaria parasite compared to human cells, with IC 50 values against P. falciparum W2 strain in the nanomolar range, and showed improved vacuolar accumulation ratios [ 66 ].…”

Section: Recent Development Of Indole-based Small Molecules Targeting Malaria Trypanosomiasis and Leishmaniasismentioning

confidence: 99%

Recent Progress in the Development of Indole-Based Compounds Active against Malaria, Trypanosomiasis and Leishmaniasis

Pacheco

Santos

2022

Molecules

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Human protozoan diseases represent a serious health problem worldwide, affecting mainly people in social and economic vulnerability. These diseases have attracted little investment in drug discovery, which is reflected in the limited available therapeutic arsenal. Authorized drugs present problems such as low efficacy in some stages of the disease or toxicity, which result in undesirable side effects and treatment abandonment. Moreover, the emergence of drug-resistant parasite strains makes necessary an even greater effort to develop safe and effective antiparasitic agents. Among the chemotypes investigated for parasitic diseases, the indole nucleus has emerged as a privileged molecular scaffold for the generation of new drug candidates. In this review, the authors provide an overview of the indole-based compounds developed against important parasitic diseases, namely malaria, trypanosomiasis and leishmaniasis, by focusing on the design, optimization and synthesis of the most relevant synthetic indole scaffolds recently reported.

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Section: Recent Development Of Indole-based Small Molecules Targeting Malaria Trypanosomiasis and Leishmaniasismentioning

confidence: 99%

Recent Progress in the Development of Indole-Based Compounds Active against Malaria, Trypanosomiasis and Leishmaniasis

Pacheco

Santos

2022

Molecules

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“…The most active hybrid 88a (IC 50 : 25 nM) was comparable to ART (IC 50 : 14 nM), and 2.6‐fold more potent than CQ (IC 50 : 14 nM) against CQR W2 strain. Further study revealed that the ether can be replaced by amino, and for hybrids 89 , the introduction of chloro at R 1 position reduced the activity when compared with unsubstituted analogs . Hybrid 89a (IC 50 : 20 nM) was found to be the most potent compound, and was 11.4‐folds more active than CQ (IC 50 : 229 nM) against CQR W2 strain.…”

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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“…The extraction and separation test revealed that it contains cryptolepine, neocryptolepine, quindoline, hydroxycryptolepine, and other ingredients. Further research revealed that the main component cryptolepine, whose total synthesis was prior to separation and determination, had exhibited unprecedented pharmacological effects, including antimalarial activity, − antibacterial activity, − anticancer activity, − antifungal activity, − anti-inflammatory activity, , antidiabetic activity, antituberculosis activity, and so on. − Although fruitful achievements had been widely reported, the exploration of cryptolepine and its derivatives in fungicide chemistry was barely conducted. This implied us that more emphasis should be laid on the study of cryptolepine and its derivatives in the control of crop fungi.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Antifungal Evaluation of Cryptolepine Derivatives against Phytopathogenic Fungi

Chen

Liu

Zhang

et al. 2021

J. Agric. Food Chem.

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Inspired by the widely antiphytopathogenic application of diversified derivatives from natural sources, cryptolepine and its derivatives were subsequently designed, synthesized, and evaluated for their antifungal activities against four agriculturally important fungi Rhizoctonia solani, Botrytis cinerea, Fusarium graminearum, and Sclerotinia sclerotiorum. The results obtained from in vitro assay indicated that compounds a1–a24 showed great fungicidal property against B. cinerea (EC50 < 4 μg/mL); especially, a3 presented significantly prominent inhibitory activity with an EC50 of 0.027 μg/mL. In the pursuit of further expanding the antifungal spectrum of cryptolepine, ring-opened compound f1 produced better activity with an EC50 of 3.632 μg/mL against R. solani and an EC50 of 5.599 μg/mL against F. graminearum. Furthermore, a3 was selected to be a candidate to investigate its preliminary antifungal mechanism to B. cinerea, revealing that not only spore germination was effectively inhibited and the normal physiological structure of mycelium was severely undermined but also detrimental reactive oxygen was obviously accumulated and the normal function of the nucleus was fairly disordered. Besides, in vivo curative experiment against B. cinerea found that the therapeutic action of a3 was comparable to that of the positive control azoxystrobin. These results suggested that compound a3 could be regarded as a novel and promising agent against B. cinerea for its valuable potency.

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N10,N11-di-alkylamine indolo[3,2-b]quinolines as hemozoin inhibitors: Design, synthesis and antiplasmodial activity

Cited by 17 publications

References 26 publications

Recent Progress in the Development of Indole-Based Compounds Active against Malaria, Trypanosomiasis and Leishmaniasis

Recent Progress in the Development of Indole-Based Compounds Active against Malaria, Trypanosomiasis and Leishmaniasis

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

Design, Synthesis, and Antifungal Evaluation of Cryptolepine Derivatives against Phytopathogenic Fungi

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