Exploring the 3-piperidin-4-yl-1H-indole scaffold as a novel antimalarial chemotype

Santos, Sofia A.; Lukens, Amanda K.; Coelho, Lis; Nogueira, Fátima; Wirth, Dyann F.; Mazitschek, Ralph; Moreira, Rui; Paulo, Alexandra

doi:10.1016/j.ejmech.2015.07.047

Cited by 34 publications

(18 citation statements)

References 37 publications

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“…Compound D2AAK1_3 is a new compound and it is an analogue of known 3-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)-1 H -indole and 3-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)-5-methoxy-1 H -indole. 3-(1-Benzyl-1,2,3,6-tetrahydropyridin-4-yl)-1 H -indole was reported as 5-HT 1A and 5-HT 2A receptor ligand (with pKi of 5.00 and 7.81, respectively) [ 17 ], intermediate in synthesis of N 1 -arylsulfonyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1 H -indole derivatives as 5-HT 6 receptor antagonists [ 18 ], intermediate in synthesis of muscarinic receptor allosteric agents [ 19 ] and antimalarial compound [ 20 ]. 3-(1-Benzyl-1,2,3,6-tetrahydropyridin-4-yl)-5-methoxy-1 H -indole was reported as 5-HT 7 receptor ligand [ 21 ] and intermediate in synthesis of muscarinic receptor allosteric agents [ 19 ].…”

Section: Resultsmentioning

confidence: 99%

Synthesis, Structural and Thermal Studies of 3-(1-Benzyl-1,2,3,6-tetrahydropyridin-4-yl)-5-ethoxy-1H-indole (D2AAK1_3) as Dopamine D2 Receptor Ligand

et al. 2018

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Compound D2AAK1_3 was designed as a modification of the lead structure D2AAK1 (an in vivo active multi-target compound with nanomolar affinity to a number of aminergic GPCRs) and synthesized in the reaction of 5-ethoxyindole and 1-benzyl-4-piperidone. This compound has an affinity to the human dopamine D2 receptor with Ki of 151 nM. The aim of these studies was the structural and thermal characterization of the compound D2AAK1_3. In particular; X-ray studies; molecular docking and molecular dynamics as well as thermal analysis were performed. The studied compound crystallizes in orthorhombic system; in chiral space group P212121. The compound has a non-planar conformation. The studied compound was docked to the novel X-ray structure of the human dopamine D2 receptor in the inactive state (PDB ID: 6CM4) and established the main contact between its protonatable nitrogen atom and Asp (3.32) of the receptor. The obtained binding pose was stable in molecular dynamics simulations. Thermal stability of the compound was investigated using the TG-DSC technique in the air atmosphere, while TG-FTIR analyses in air and nitrogen atmospheres were also performed. The studied compound is characterized by good thermal stability. The main volatile products of combustion are the following gases: CO2; H2O toluene and CO while in the case of pyrolysis process in the FTIR spectra; the characteristic bands of NH3; piperidine and indole are additionally observed.

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Section: Resultsmentioning

confidence: 99%

Synthesis, Structural and Thermal Studies of 3-(1-Benzyl-1,2,3,6-tetrahydropyridin-4-yl)-5-ethoxy-1H-indole (D2AAK1_3) as Dopamine D2 Receptor Ligand

et al. 2018

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“…Studies have shown that compounds with piperidine rings [4,8,[21][22][23][24][25][26] have good selectivity and activity for the P. falciparum strain. This prompted us to assess their antiplasmodial activity against the chloroquine-sensitive 3D7 and chloroquine-resistant W2 strains of P. falciparum as well as their cytotoxic activity against HUVEC cells (Tables 3 and 4).…”

Section: The Antimalarial Activity Of Derivatives 6 and Target Compoumentioning

confidence: 99%

“…The 4-arylaminopiperidine is a structural moiety found in many alkaloids [4][5][6][7][8][9][10][11] and pharmaceutical products such as fentanyl and structurally-related analgesic opioids or H1-antihistamines agents such as bamipine [12][13][14][15][16][17] and neurokinin 1 (NK1) receptor antagonists [18][19][20]. Studies have shown that compounds with piperidine rings [4,8,[21][22][23][24][25][26] have good selectivity and activity for the P. falciparum strain.…”

Section: Introductionmentioning

confidence: 99%

“…Research is being pursued for the discovery of new antimalarials with less side effects, a faster onset of action and a better rate of response [4,8,[21][22][23][24][25][26]. In the process of searching for new small molecules interacting with the P. falciparum strain, we have identified the target compounds A with various R1, R2 and R3 substituents ( Figure 1).…”

Section: Introductionmentioning

confidence: 99%

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Synthesis and Antimalarial Activity of 1,4-Disubstituted Piperidine Derivatives

et al. 2020

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In order to prepare, at low cost, new compounds active against Plasmodium falciparum, and with a less side-effects, we have designed and synthesized a library of 1,4-disubstituted piperidine derivatives from 4-aminopiperidine derivatives 6. The resulting compound library has been evaluated against chloroquine-sensitive (3D7) and chloroquine-resistant (W2) strains of P. falciparum. The most active molecules—compounds 12d (13.64 nM (3D7)), 13b (4.19 nM (3D7) and 13.30 nM (W2)), and 12a (11.6 nM (W2))—were comparable to chloroquine (22.38 nM (3D7) and 134.12 nM (W2)).

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“…Both of them were less potent than CQ (IC 50 : 5.46 nM) against CQS 3D7 strain, but hybrid 84a showed higher activity than CQ (IC 50 : 255 nM) against CQR K1 strain. Introduction of hydroxyl at the C‐8 position of quinoline led to significant loss of activity as evidenced by that hybrid 85 showed less than 10% growth inhibitory at the concentration of 5 μM against CQR Dd2 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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Exploring the 3-piperidin-4-yl-1H-indole scaffold as a novel antimalarial chemotype

Cited by 34 publications

References 37 publications

Synthesis, Structural and Thermal Studies of 3-(1-Benzyl-1,2,3,6-tetrahydropyridin-4-yl)-5-ethoxy-1H-indole (D2AAK1_3) as Dopamine D2 Receptor Ligand

Synthesis, Structural and Thermal Studies of 3-(1-Benzyl-1,2,3,6-tetrahydropyridin-4-yl)-5-ethoxy-1H-indole (D2AAK1_3) as Dopamine D2 Receptor Ligand

Synthesis and Antimalarial Activity of 1,4-Disubstituted Piperidine Derivatives

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

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