Synthesis of 2-aminomethyl-4-phenyl-1-azabicyclo[2.2.1]heptanes via LiAlH4-induced reductive cyclization of 2-(4-chloro-2-cyano-2-phenylbutyl)aziridines and evaluation of their antimalarial activity

D’hooghe, Matthias; Vervisch, Karel; Törnroos, Karl W.; Verhaeghe, Tom; Desmet, Tom; Lategan, Carmen; Smith, Peter J.; Chibale, Kelly; Kimpe, Norbert De

doi:10.1016/j.bmcl.2012.12.029

Cited by 9 publications

(8 citation statements)

References 51 publications

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“…2-[ N -(4-methoxybenzyl)aminomethyl]-4-phenyl-1-azabicyclo[2.2.1]heptane 7 was chosen on the basis of its similarity to the side chain present in quinine 1 and based on our in-house knowledge pertaining to the synthesis of this class of compounds. A series of 1-azabicyclo[2.2.1]heptanes had previously been synthesized in our group and evaluated for in vitro antiplasmodium activity [ 32 ]. Based on in silico docking studies of the most active compound, the moderate antiplasmodium activity observed was hypothesized to (partially) be attributed to inhibition of plasmepsin II, an enzyme essential for hemoglobin digestion in the parasite [ 32 ].…”

Section: Resultsmentioning

confidence: 99%

“…A series of 1-azabicyclo[2.2.1]heptanes had previously been synthesized in our group and evaluated for in vitro antiplasmodium activity [ 32 ]. Based on in silico docking studies of the most active compound, the moderate antiplasmodium activity observed was hypothesized to (partially) be attributed to inhibition of plasmepsin II, an enzyme essential for hemoglobin digestion in the parasite [ 32 ]. Therefore, it seemed reasonable to explore whether or not the observed moderate antiplasmodium activity could contribute to a potential dual mode of action in our target analogues.…”

Section: Resultsmentioning

confidence: 99%

“…For the synthesis of the contemplated bridged piperidine-quinoline analogues, 1-azabicyclo[2.2.1]heptane 7 , bearing a p -methoxybenzyl (PMB) protecting group, was used as a starting point because of the inability to transform the other known 1-azabicyclo[2.2.1]heptanes (with N -benzyl, N -(4-chlorobenzyl) and N -(4-methylbenzyl)) [ 32 ] into the corresponding primary amine via common debenzylation methods. As described in the literature, bridged piperidine 7 was prepared by treatment of the corresponding 2-(bromomethyl)aziridine [ [33] , [34] , [35] ] with α-lithiated phenylacetonitrile in THF, followed by deprotonation with LDA and subsequent quenching with 1-bromo-2-chloroethane [ 36 ], and finally a one-step LiAlH 4 -mediated ring closure to afford the constrained piperidine (Synthesis and Experimental Data, see Supporting Information ) [ 32 ]. It should be noted that the separation of both diastereomers of 1-azabicyclo[2.2.1]heptane 7 is possible via selective crystallization in ethanol [ 36 ], but for practical reasons in view of the reaction scale, constrained piperidine 7 was used as mixture of endo - and exo -isomers ( dr 55/45) for further synthetic elaboration.…”

Section: Resultsmentioning

confidence: 99%

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Synthesis and biological evaluation of novel quinoline-piperidine scaffolds as antiplasmodium agents

Walle

Boone

Puyvelde

et al. 2020

European Journal of Medicinal Chemistry

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The parasitic disease malaria places almost half of the world’s population at risk of infection and is responsible for more than 400,000 deaths each year. The first-line treatment, artemisinin combination therapies (ACT) regimen, is under threat due to emerging resistance of Plasmodium falciparum strains in e.g. the Mekong delta. Therefore, the development of new antimalarial agents is crucial in order to circumvent the growing resistance. Chloroquine, the long-established antimalarial drug, still serves as model compound for the design of new quinoline analogues, resulting in numerous new active derivatives against chloroquine-resistant P. falciparum strains over the past twenty years. In this work, a set of functionalized quinoline analogues, decorated with a modified piperidine-containing side chain, was synthesized. Both amino- and (aminomethyl)quinolines were prepared, resulting in a total of 18 novel quinoline-piperidine conjugates representing four different chemical series. Evaluation of their in vitro antiplasmodium activity against a CQ-sensitive (NF54) and a CQ-resistant (K1) strain of P. falciparum unveiled highly potent activities in the nanomolar range against both strains for five 4-aminoquinoline derivatives. Moreover, no cytotoxicity was observed for all active compounds at the maximum concentration tested. These five new aminoquinoline hit structures are therefore of considerable value for antimalarial research and have the potency to be transformed into novel antimalarial agents upon further hit-to-lead optimization studies.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Synthesis and biological evaluation of novel quinoline-piperidine scaffolds as antiplasmodium agents

Walle

Boone

Puyvelde

et al. 2020

European Journal of Medicinal Chemistry

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“…as new azaheterobicyclic scaffolds which displayed strong binding interaction with Plm II in in-silico studies(73). Structure based virtual screening led to discovery of a novel non-peptide Plm II inhibitor (compound 69,Figure 24) with moderate potency (IC 50 =4.6 µM)(74).…”

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New paradigm of an old target: An update on structural biology and current progress in drug design towards plasmepsin II

Dan

Bhakat

2015

European Journal of Medicinal Chemistry

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“…Quinolines interact and form a non-covalent complex with heme and also inhibit the synthesis of hemozoin. On the other hand, quinuclidine(1-azabicyclo [2.2.2]octane), synthesized by Loffler and Stieze in 1909, is a structural component of some biomolecules, including quinine 10,11 . Although development of a new drug candidate against a specific disease is a difficult task, with the help of informatics-driven chemistry, it is now fairly easy.…”

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confidence: 99%

<i>In Vitro</i> Evaluation of the Antimalarial Activity of a Designed Novel Quinuclidine Derivative

Sharma¹,

Goswami²,

Rudrapal³

et al. 2016

Current Science

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A simple Schiff base, N-(pyridine-4-yl-methylene) quinuclidine-3-amine was synthesized from 3-aminoquinuclidine and 4-pyridine carboxaldehyde. The physico-chemical properties of the synthesized compound were studied. Molecular docking study was carried out and the quinuclidine derivative was evaluated for its in vitro antimalarial activity against chloroquine-sensitive Plasmodium falciparum strain. Although higher dose of synthesized compound was required for antimalarial activity (EC 50 = 13.125 g/ml) in comparison to chloroquine (EC 50 5.144 g/ml), the correlation coefficient confirmed good fit of the data. Furthermore, the result of the molecular docking provided insights into the ligand-protein interactions responsible for the inhibitory potency.Keywords: Antimalarial, docking, HPLC, Plasmodium falcipurum, quinuclidine, mass, NMR.MALARIA, a disease affecting large populations, has proved to be an obstacle in the cultural and socioeconomic progress of society in the tropical and subtropical world. It is widespread in all parts of India except in areas, which are not favourable for transmission and multiplication of malaria parasites [1][2][3][4][5][6] . Quinine, the oldest known antimalarial, led to the discovery of chloroquine, the most widely used antimalarial drug for almost more than half a century. However, chloroquine has lost its importance as an antimalarial due to widespread drug resistance 7,8 . Quinolines, however, are still considered as important lead structures and several researchers have been working on synthesis of their analogues 9 . Quinolines interact and form a non-covalent complex with heme and also inhibit the synthesis of hemozoin. On the other hand, quinuclidine(1-azabicyclo [2.2.2]octane), synthesized by Loffler and Stieze in 1909, is a structural component of some biomolecules, including quinine 10,11 . Although development of a new drug candidate against a specific disease is a difficult task, with the help of informatics-driven chemistry, it is now fairly easy. However, in silico prediction of biological activity is not always reflected in the biological system.In view of the resistance developed by malarial parasites and considering the biological activity of quinuclidine moiety-bearing biomolecules, a simple Schiff base carrying the quinuclidine structural component was designed 12 . Accordingly, N-(pyridine-4-yl-methylene) quinuclidine-3-amine (C) was synthesized (Scheme 1) from 3-aminoquinuclidine (A) and 4-pyridine carboxaldehyde (B). On the basis of the results of in silico antimalarial activity study, in vitro study was carried out for antimalarial activity of this Schiff base. The results of this study are promising and would help in the development of novel antimalarial drugs.All the reactions were carried out in borosilicate glassware with proper precautions. The solvents and reagents were synthesis-grade chemicals procured commercially and used as such without further tests and purification. Chemical structures have been drawn in ChemDraw version 7.0.1. Melting point ...

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Synthesis of 2-aminomethyl-4-phenyl-1-azabicyclo[2.2.1]heptanes via LiAlH4-induced reductive cyclization of 2-(4-chloro-2-cyano-2-phenylbutyl)aziridines and evaluation of their antimalarial activity

Cited by 9 publications

References 51 publications

Synthesis and biological evaluation of novel quinoline-piperidine scaffolds as antiplasmodium agents

Synthesis and biological evaluation of novel quinoline-piperidine scaffolds as antiplasmodium agents

New paradigm of an old target: An update on structural biology and current progress in drug design towards plasmepsin II

<i>In Vitro</i> Evaluation of the Antimalarial Activity of a Designed Novel Quinuclidine Derivative

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