Synthesis of iboga-like isoquinuclidines: Dual opioid receptors agonists having antinociceptive properties

Banerjee, Tuhin; Paul, Subhojit; Sinha, Surajit; Das, Sumantra

doi:10.1016/j.bmc.2014.09.001

Cited by 15 publications

(3 citation statements)

References 35 publications

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“…Developing such new and straightforward syntheses for these classes of compounds is of great interest due to their enormous potential as pharmaceuticals, demonstrated by a number of studies on their biological activities . Inspired by naturally occurring alkaloids, compounds such as ibogaine analogue A have recently been synthesized and biologically evaluated (Figure ) . Isoquinuclidine analogue A has been characterized as an opioid receptor agonist with potential analgesic properties.…”

Section: Introductionmentioning

confidence: 75%

Deeper Insight into the Six‐Step Domino Reaction of Aldehydes with Malononitrile and Evaluation of Antiviral and Antimalarial Activities of the Obtained Bicyclic Products

et al. 2017

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The straightforward and efficient synthesis of complex aza‐ and carbobicyclic compounds, which are of importance for medicinal chemistry, is a challenge for modern chemical methodology. An unprecedented metal‐free six‐step domino reaction of aldehydes with malononitrile was presented in our previous study to provide, in a single operation, these bicyclic nitrogen‐containing molecules. Presented here is a deeper investigation of this atom‐economical domino process by extending the scope of aldehydes, performing post‐modifications of domino products, applying bifunctional organocatalysts and comprehensive NMR studies of selected domino products. The thermodynamic aspects of the overall reaction are also demonstrated using DFT methods in conjunction with a semi‐empirical treatment of van der Waals interactions. Furthermore, biological studies of seven highly functionalized and artemisinin‐containing domino products against human cytomegalovirus (HCMV) and Plasmodium falciparum 3D7 are presented. Remarkably, in vitro tests against HCMV revealed five domino products to be highly active compounds (EC50 0.071–1.8 μm), outperforming the clinical reference drug ganciclovir (EC50 2.6 μm). Against P. falciparum 3D7, three of the investigated artemisinin‐derived domino products (EC50 0.72–1.8 nm) were more potent than the clinical drug chloroquine (EC50 9.1 nm).

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Section: Introductionmentioning

confidence: 75%

Deeper Insight into the Six‐Step Domino Reaction of Aldehydes with Malononitrile and Evaluation of Antiviral and Antimalarial Activities of the Obtained Bicyclic Products

et al. 2017

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“…In order to access safer compounds as potential drugs for SUDs, different medicinal chemistry approaches have been employed to explore the iboga chemical space, including the preparation of structurally related analogs − and structure simplification studies. − Our group is working on a program aimed at mapping the structure–activity relationship of iboga-inspired analogs using ibogaine ( 1 ), voacangine ( 2 ), and other iboga alkaloids as parent compounds . Voacangine ( 2 ) is obtained in good yield by our recently published protocol from the root bark of Voacanga africana , while ibogaine is produced by a well-established methodology through decarboxylation of voacangine (direct isolation form T. iboga is avoided because of low purification yields and limited availability of the shrub) (see Figure ).…”

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confidence: 99%

Reactivity of the Iboga Skeleton: Oxidation Study of Ibogaine and Voacangine

et al. 2023

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The iboga alkaloids scaffold shows great potential as a pharmacophore in drug candidates for the treatment of neuropsychiatric disorders. Thus, the study of the reactivity of this type of motif is particularly useful for the generation of new analogs suitable for medicinal chemistry goals. In this article, we analyzed the oxidation pattern of ibogaine and voacangine using dioxygen, peroxo compounds, and iodine as oxidizing agents. Special focus was placed on the study of the regio-and stereochemistry of the oxidation processes according to the oxidative agent and starting material. We found that the C 16 -carboxymethyl ester present in voacangine stabilizes the whole molecule toward oxidation in comparison to ibogaine, especially in the indole ring, where 7hydroxy-or 7-peroxy-indolenines can be obtained as oxidation products. Nevertheless, the ester moiety enhances the reactivity of the isoquinuclidinic nitrogen to afford C 3 -oxidized products through a regioselective iminium formation. This differential reactivity between ibogaine and voacangine was rationalized using computational DFT calculations. In addition, using qualitative and quantitative NMR experiments combined with theoretical calculations, the absolute stereochemistry at C 7 in the 7hydroxyindolenine of voacangine was revised to be S, which corrects previous reports proposing an R configuration.

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“…From the viewpoint of such structural variations, the C5Hs have attracted significant attention from organic chemists for use as multistep synthetic precursors. 2 Furan itself is also a constituent of various natural products, 3 and so the construction of chiral species for natural product synthesis is also of particular interest. For the preparation of such important synthons, the Friedel-Crafts-type (FC) alkylation of the C5Hs could achieve derivatization while maintaining the aromatic framework.…”

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confidence: 99%

Ruthenium-Catalyzed Asymmetric Dehydrative Allylic Cyclization of Five-Membered Chalcogen Heteroaromatics

et al. 2021

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The asymmetric dehydrative intramolecular allylation reactions of furan and thiophene were performed using a cationic cyclopentadienyl-ruthenium (CpRu) complex of a chiral pyridine carboxylic acid, namely Cl-Naph-PyCOOH. Both furan and thiophene tethered with an allylic alcohol gave the corresponding bicyclic compounds in high yields and enantioselectivities using 0.1–5 mol% of catalyst. The reaction was found to proceed via a similar enantioface selection method mechanism to that previously reported by our group, which involved halogen and hydrogen bond formation, in addition to the generation of an intermediate σ-allyl complex.

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Synthesis of iboga-like isoquinuclidines: Dual opioid receptors agonists having antinociceptive properties

Cited by 15 publications

References 35 publications

Deeper Insight into the Six‐Step Domino Reaction of Aldehydes with Malononitrile and Evaluation of Antiviral and Antimalarial Activities of the Obtained Bicyclic Products

Deeper Insight into the Six‐Step Domino Reaction of Aldehydes with Malononitrile and Evaluation of Antiviral and Antimalarial Activities of the Obtained Bicyclic Products

Reactivity of the Iboga Skeleton: Oxidation Study of Ibogaine and Voacangine

Ruthenium-Catalyzed Asymmetric Dehydrative Allylic Cyclization of Five-Membered Chalcogen Heteroaromatics

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