Substituted 1,3-dioxoisoindoline-4-aminoquinolines coupled via amide linkers: Synthesis, antiplasmodial and cytotoxic evaluation

Rani, Anu; Legac, Jenny; Rosenthal, Philip J.; Kumar, Vipan

doi:10.1016/j.bioorg.2019.04.006

Cited by 15 publications

(9 citation statements)

References 23 publications

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“…Such molecules are active against erythrocytic and live stages of malaria infection; therefore, they can help in fighting resistance and meeting the agenda of eradicating malaria [18]. Nowadays, the search for antimalarials focuses on hybrid compounds containing quinoline which is one of the important pharmacophore acting against malaria [19][20][21].…”

Section: Introductionmentioning

confidence: 99%

In silico modeling of tetraoxane-8-aminoquinoline hybrids active against Plasmodium falciparum

Mahmud

Shallangwa

Uzairu

2020

Beni-Suef Univ J Basic Appl Sci

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Background: Quantitative structure-activity relationships (QSAR) is a technique that is used to produce a model that connects biological activities of compounds to their chemical structures, and molecular docking is a technique that reveals the binding mode and interactions between a drug and its target enzyme. These techniques have been successfully applied in the design and development of many drug candidates and herein were employed to build a model that could help in the development of more potent antimalaria drugs. Results: Descriptors of the compounds were calculated using the PaDEL-Descriptor software, and Genetic Function Algorithm (GFA) was used to select descriptors and build the model. A robust and reliable model was generated and validated to have internal and external squared correlation coefficient (R 2) of 0.9622 and 0.8191, respectively, adjusted squared correlation coefficient (R adj) of 0.9471, and leave-one-out (LOO) cross-validation coefficient (Q 2 cv) of 0.9223. The model revealed that the antiplasmodial activities of 1,2,4,5-tetraoxane-8-aminoquinoline hybrids depend on MATS3m, GATS8p, GATS8i, and RDF50s descriptors. MATS3m, GATS8i, and RDF50s influenced the antiplasmodial activities of the compounds positively while GATS8p negatively with the greatest influence. The docking result shows strong interactions between 1,2,4,5-tetraoxane-8-aminoquinoline hybrids and Plasmodium falciparum lactate dehydrogenase (pfLDH) with binding affinities ranging from − 6.3 to − 10.9 kcal/mol which were better than that of chloroquine (− 6.1 kcal/mol), suggesting that these compounds could be better inhibitors of pfLDH than chloroquine. Conclusion: The results of this study could serve as a model for designing new potent 1,2,4,5-tetraoxane-8aminoquinolines with better antiplasmodial activities for the development of highly active antimalaria drugs.

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Section: Introductionmentioning

confidence: 99%

In silico modeling of tetraoxane-8-aminoquinoline hybrids active against Plasmodium falciparum

Mahmud

Shallangwa

Uzairu

2020

Beni-Suef Univ J Basic Appl Sci

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“…Besides the hybrids described above, many other quinoline‐resistance reverser hybrids such as quinoline‐3‐dioxoisoindoline hybrids 24 (Figure ) also showed considerable activity against CQR strains of P falciparum , but the majority of them were less potent than the reference . In spite of that, the enriched SAR may pave the way for the further rationale design of new quinoline‐resistance reverser hybrids.…”

Section: Quinoline‐resistance Reverser Hybrids (Type Iii)mentioning

confidence: 97%

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 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%

“…Hybrid molecules with tertiary amines were rigid, which inhibited their capability to interrelate with the biomacromolecule receptor. The hybrid molecule containing a 3-methyl-1,2,4-triazole substituent exhibited good antimalarial activity of (IC 50 = 0.083 µM) and it was three-fold more potent than chloroquine [45]. Primaquine hybrids exhibited low antimalarial activity in the erythrocytic stage resulting from the modest blood schizonticidal activity of primaquine and the absence of a basic amino group.…”

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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Substituted 1,3-dioxoisoindoline-4-aminoquinolines coupled via amide linkers: Synthesis, antiplasmodial and cytotoxic evaluation

Cited by 15 publications

References 23 publications

In silico modeling of tetraoxane-8-aminoquinoline hybrids active against Plasmodium falciparum

In silico modeling of tetraoxane-8-aminoquinoline hybrids active against Plasmodium falciparum

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

Combination Therapy Strategies for the Treatment of Malaria

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