Properties and Reactions of Isoquinolines and Their Hydrogenated Derivatives

Dyke, S.F.; Kinsman, Richard G.

doi:10.1002/9780470187111.ch1

Cited by 10 publications

(5 citation statements)

References 531 publications

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“…Besides, a quinolinyl group probably increases antimalarial activity due to its capacity to protonate under weakly acidic conditions, thus enhancing their interactions with the protease at His67. Furthermore, these nitrogencontaining heterocycles may be somewhat concentrated in the food vacuoles of malarial parasites at pH 5 since pK a values of quinoline and isoquinoline are 4.94 and 5.40 in water at 20 ºC, respectively [83]. Additionally, this chemical entity, common in established antimalarials, may interfere with heme detoxification in addition to protease inhibition potentially leading to a dual inhibitor.…”

Section: -Chalconesmentioning

confidence: 98%

Falcipain Inhibition as a Promising Antimalarial Target

Marco¹,

Coteron

2012

CTMC

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Falcipains are Plasmodium falciparum cysteine proteases involved in different processes of the erythrocytic cycle of the malaria parasite like hydrolysis of host hemoglobin, erythrocyte invasion, and erythrocyte rupture. These proteases constitute promising targets in the search for novel therapies that would ease the burden caused by the increasing resistance to current antimalarial drugs. Despite biochemical characterization of four falcipains so far, the search for new falcipain inhibitors has been limited to falcipain-2 and/ or falcipain-3, due to their interesting hemoglobinase capacity and the ample availability of tools to study them. We describe progress towards the discovery of promising falcipain inhibitors, in the light of their drug-like properties and the effect of the inhibition of several of these cysteine proteases. Some important aspects to focus on future development of falcipain inhibition are also discussed.

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Section: -Chalconesmentioning

confidence: 98%

Falcipain Inhibition as a Promising Antimalarial Target

Marco¹,

Coteron

2012

CTMC

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“…First, this may be due to the protonation of nitrogen-containing heterocycles under weakly acidic condition, which may enhance their interaction with histidine 67 on active site of cysteine protease, or inhibitors may form a hydrogen bond with protonated histidine 67 (free histidine has a pK a * 6) (Budavari et al, 1989). Further, it was shown that nitrogen-containing heterocycles exhibit significant accumulation in food vacuole of parasites at pH 5 since the pKa values of quinoline and isoquinoline are 4.5 and 5.4 in water at 20°C, respectively (Dyke and Kinsman, 1981). Moreover, vacuolar drug accumulation ratio (VAR) of various 4-aminoquinolibe series drugs were analyzed (Hawley et al, 1996).…”

Section: Resultsmentioning

confidence: 99%

Potent antimalarial activity of newly synthesized substituted chalcone analogs in vitro

et al. 2008

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Several new chalcone analogues were synthesized and evaluated as inhibitors of malaria parasite. Inhibitory activity was determined in vitro against a chloroquine-sensitive Plasmodium falciparum strain of parasites. The compound 3-(4-methoxyphenyl)-1-(4-pyrrol-1-yl-phenyl)prop-2-en-1-one was found to be the most active with 50% inhibition concentration (IC 50 ) of 1.61 lg/ml. This inhibitory concentration is comparable to a prototype phytochemical chalcone, licochalcone A, with an IC 50 of 1.43 lg/ml. The present study suggests that small, lipophilic nitrogen heterocyclic ring A together with small hydrophobic functionality at ring B can enhance antimalarial activity. These results suggest that chalcones are a class of compounds that provides an option of developing inexpensive, synthetic therapeutic antimalarial agents in the future.

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“…However, the molecular electrostatic potential (MEP) profile of uncomplexed Compound 1 indicates the strongest nucleophilic center at the nitrogen atom of the heterocycle. Thus, protonation at this center could be involved in the mechanism of antimalarial activity of these compounds, either by enhancing interaction with the biological target or by concentrating the compound in the acidic food vacuoles of the parasites [56].…”

Section: D Pharmacophore and Its Correlation With Experimental Activitymentioning

confidence: 99%

An In Silico 3D Pharmacophore Model of Chalcones Useful in the Design of Novel Antimalarial Agents

Bhattacharjee¹,

Nichols²,

Gerena³

et al. 2007

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Malaria, the most important of the human parasitic diseases, causes about 500 million infections worldwide and over 1 million deaths every year. The search for novel drug candidates against specific parasitic targets is an important goal for antimalarial drug discovery. Recently the antimalarial activity of chalcones has generated great interest. These compounds are small non-chiral molecules with relative high lipophilicity (clogP approximately 5-7), have molecular weights in the range of 300 to 600 g/mol, and possess in vivo efficacy against both P. berghei and P. yeolii. Preliminary data on our on-going chalcone synthesis project indicate that these compounds are active in vitro against P. falciparum, but are rapidly metabolized in liver microsome assays. Structurally-related compounds not including the enone linker are found to be much more metabolically stable and yet have comparable in vitro efficacy. In this study, we have utilized the efficacy data from an in-house on-going chalcone project to develop a 3D pharmacophore for antimalarial activity and used it to conduct virtual screening (in silico search) of a chemical library which resulted in identification of several potent chalcone-like antimalarials. The pharmacophore is found to contain an aromatic and an aliphatic hydrophobic site, one hydrogen bond donor site, and a ring aromatic feature distributed over a 3D space. The identified compounds were not only found to be potent in vitro against several drug resistant and susceptible strains of P. falciparum and have better metabolic stability, but included one with good in vivo efficacy in a mouse model of malaria.

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Properties and Reactions of Isoquinolines and Their Hydrogenated Derivatives

Cited by 10 publications

References 531 publications

Falcipain Inhibition as a Promising Antimalarial Target

Falcipain Inhibition as a Promising Antimalarial Target

Potent antimalarial activity of newly synthesized substituted chalcone analogs in vitro

An In Silico 3D Pharmacophore Model of Chalcones Useful in the Design of Novel Antimalarial Agents

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