Structure activity relationship in β-carboline derived anti-malarial agents

Kamboj, Aarzoo; Sihag, Binita; Brar, Deshkanwar; Kaur, Arvinder; Salunke, Deepak B.

doi:10.1016/j.ejmech.2021.113536

Cited by 26 publications

(5 citation statements)

References 43 publications

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“…Alternatively, the strains reported here may be optimized toward THH production and find use for studying the harmala-class alkaloids and their derivatives. THH is a bioactive scaffold with reported antimalarial activity 79 and 5HT5A affinity, indicating potential for selective serotonin reuptake inhibition. 80 Methoxylation of THH at C6 produces tetrahydroharmine, a monoamine oxidase inhibitor found in the psychoactive ayahuasca, 81 suggesting that many interesting bioactivities are to be found within this alkaloid class.…”

Section: ■ Discussionmentioning

confidence: 99%

Yeast Platforms for Production and Screening of Bioactive Derivatives of Rauwolscine

Bradley,

Hansson,

Lehka

et al. 2024

ACS Synth. Biol.

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Monoterpene indole alkaloids (MIAs) make up a highly bioactive class of metabolites produced by a range of tropical and subtropical plants. The corynanthe-type MIAs are a stereochemically complex subclass with therapeutic potential against a large number of indications including cancer, psychotic disorders, and erectile dysfunction. Here, we report yeast-based cell factories capable of de novo production of corynanthe-type MIAs rauwolscine, yohimbine, tetrahydroalstonine, and corynanthine. From this, we demonstrate regioselective biosynthesis of 4 fluorinated derivatives of these compounds and de novo biosynthesis of 7-chlororauwolscine by coexpression of a halogenase with the biosynthetic pathway. Finally, we capitalize on the ability of these cell factories to produce derivatives of these bioactive scaffolds to establish a proof-of-principle drug discovery pipeline in which the corynanthe-type MIAs are screened for bioactivity on human drug targets, expressed in yeast. In doing so, we identify antagonistic and agonistic behavior against the human adrenergic G protein-coupled receptors ADRA2A and ADRA2B, and the serotonergic receptor 5HT4b, respectively. This study thus demonstrates a proto-drug discovery pipeline for bioactive plant-inspired small molecules based on one-pot biocatalysis of natural and new-to-nature corynanthe-type MIAs in yeast.

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Section: ■ Discussionmentioning

confidence: 99%

Yeast Platforms for Production and Screening of Bioactive Derivatives of Rauwolscine

Bradley,

Hansson,

Lehka

et al. 2024

ACS Synth. Biol.

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“…[22] Quinoline and side-chain analogues contribute a centric role in providing huge quinoline-based medications with a significant contribution in the new anti-malarial drug development. [23] Apart from quinolines, [24] other nitrogen, nitrogen/ sulphur/ oxygen containing heterocycles [11] such as indole, [25] phenothiazine, [26] triazoles, [14] β-carboline, [27,28] have also been well explored.…”

Section: Heterocycles As Privileged Scaffold Towards Anti-malarial Ag...mentioning

confidence: 99%

Biannual Account of Anti‐malarial Agents reported in 2021 and 2022: A Comprehensive Coverage

Dhameliya,

Patel,

Kathuria

et al. 2024

ChemistrySelect

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Malaria remains a severe infectious disease caused by Plasmodium parasites among the primarily afflicting impoverished populations. According to World Health Organization (WHO) report, there were an estimated 247 million malarial cases globally, resulting in approximately 6,19,000 fatalities. Particularly prevalent in tropical and subtropical regions, the development of drug resistance has exacerbated this public health challenge. Consequently, there has been a concrete effort to explore novel compounds with anti‐malarial properties. In continuation of our previous works, this review focuses on heterocyclic compounds documented in 2021 and 2022, including artemisinin, benzimidazole, benzofuran, β‐lactam, coumarin, furan, indole, morpholine, piperazine, pyrimidine, quinoline, triazole, etc. highlighting their efficacy, structural characteristics, in vitro and in vivo activities, among other relevant aspects for the broad interest of medicinal chemists working on the design and development of novel anti‐malarial agents.

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“…Several reviews addressed the anticancer activity of β-carboline derivatives and proposed different modes of action [ 9 , 15 , 17 ]. Similarly, the antimalarial activity of harmine and other β-carboline derivatives is also well-documented [ 18 , 19 , 20 ]. On the other hand, ferrocene is an important compound in bioinorganometallic chemistry due to its high stability, favorable redox properties, and low toxicity [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

Harmicens, Novel Harmine and Ferrocene Hybrids: Design, Synthesis and Biological Activity

Poje

Marinović

Pavić

et al. 2022

IJMS

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Cancer and malaria are both global health threats. Due to the increase in the resistance to the known drugs, research on new active substances is a priority. Here, we present the design, synthesis, and evaluation of the biological activity of harmicens, hybrids composed of covalently bound harmine/β-carboline and ferrocene scaffolds. Structural diversity was achieved by varying the type and length of the linker between the β-carboline ring and ferrocene, as well as its position on the β-carboline ring. Triazole-type harmicens were prepared using Cu(I)-catalyzed azide-alkyne cycloaddition, while the synthesis of amide-type harmicens was carried out by applying a standard coupling reaction. The results of in vitro biological assays showed that the harmicens exerted moderate antiplasmodial activity against the erythrocytic stage of P. falciparum (IC50 in submicromolar and low micromolar range) and significant and selective antiproliferative activity against the MCF-7 and HCT116 cell lines (IC50 in the single-digit micromolar range, SI > 5.9). Cell localization experiments showed different localizations of nonselective harmicene 36 and HCT116-selective compound 28, which clearly entered the nucleus. A cell cycle analysis revealed that selective harmicene 28 had already induced G1 cell cycle arrest after 24 h, followed by G2/M arrest with a concomitant drastic reduction in the percentage of cells in the S phase, whereas the effect of nonselective compound 36 on the cell cycle was much less pronounced, which agreed with their different localizations within the cell.

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Structure activity relationship in β-carboline derived anti-malarial agents

Cited by 26 publications

References 43 publications

Yeast Platforms for Production and Screening of Bioactive Derivatives of Rauwolscine

Yeast Platforms for Production and Screening of Bioactive Derivatives of Rauwolscine

Biannual Account of Anti‐malarial Agents reported in 2021 and 2022: A Comprehensive Coverage

Harmicens, Novel Harmine and Ferrocene Hybrids: Design, Synthesis and Biological Activity

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