Lipoxygenase Inhibition Activity of Coumarin Derivatives—QSAR and Molecular Docking Study

Lončarić, Melita; Strelec, Ivica; Pavić, Valentina; Šubarić, Domagoj; Rastija, Vesna; Molnar, Maja

doi:10.3390/ph13070154

Cited by 26 publications

(26 citation statements)

References 54 publications

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“…In the work of Lončarić et al [ 39 ], it was also observed that substitution at position 6 of the coumarin scaffold with a bromine group led to potent soybean lipoxygenase inhibition. However, according to the molecular docking studies, the compounds of this study have interactions with the binding site of human lipoxygenase (5-LOX, in complex with arachidonic acid (PDB code: 3V99)) and soybean LOX (soybean LOX-3 in complex with (−)-epigallocatechin gallate ((−)-EGCG) (PDB code: 1JNQ)).…”

Section: Resultsmentioning

confidence: 99%

Synthesis, Bioactivity, Pharmacokinetic and Biomimetic Properties of Multi-Substituted Coumarin Derivatives

et al. 2021

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A series of novel multi-substituted coumarin derivatives were synthesized, spectroscopically characterized, and evaluated for their antioxidant activity, soybean lipoxygenase (LOX) inhibitory ability, their influence on cell viability in immortalized human keratinocytes (HaCaT), and cytotoxicity in adenocarcinomic human alveolar basal epithelial cells (A549) and human melanoma (A375) cells, in vitro. Coumarin analogues 4a–4f, bearing a hydroxyl group at position 5 of the coumarin scaffold and halogen substituents at the 3-phenyl ring, were the most promising ABTS•+ scavengers. 6,8-Dibromo-3-(4-hydroxyphenyl)-4-methyl-chromen-2-one (4k) and 6-bromo-3-(4,5-diacetyloxyphenyl)-4-methyl-chromen-2-one (3m) exhibited significant lipid peroxidation inhibitory activity (IC50 36.9 and 37.1 μM). In the DCF-DA assay, the 4′-fluoro-substituted compound 3f (100%), and the 6-bromo substituted compounds 3i (80.9%) and 4i (100%) presented the highest activity. The 3′-fluoro-substituted coumarins 3e and 4e, along with 3-(4-acetyloxyphenyl)-6,8-dibromo-4-methyl-chromen-2-one (3k), were the most potent lipoxygenase (LOX) inhibitors (IC50 11.4, 4.1, and 8.7 μM, respectively) while displaying remarkable hydroxyl radical scavenging ability, 85.2%, 100%, and 92.9%, respectively. in silico docking studies of compounds 4e and 3k, revealed that they present allosteric interactions with the enzyme. The majority of the analogues (100 μΜ) did not affect the cell viability of HaCaT cells, though several compounds presented over 60% cytotoxicity in A549 or A375 cells. Finally, the human oral absorption (%HOA) and plasma protein binding (%PPB) properties of the synthesized coumarins were also estimated using biomimetic chromatography, and all compounds presented high %HOA (>99%) and %PPB (60–97%) values.

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Section: Resultsmentioning

confidence: 99%

Synthesis, Bioactivity, Pharmacokinetic and Biomimetic Properties of Multi-Substituted Coumarin Derivatives

et al. 2021

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“…Genetic algorithm is a general-purpose optimization and search technique which is based on the evolutionary process of natural selection. Genetic algorithm permits the individuals of a population to evolve under certain specific selection rules to a condition that maximizes the fitness function [ 32 ]. The PyMOL Molecular Graphics (Version 1.8.4.0, Schrödinger, LLC) was used for the visualizations and graphics generations [ 33 ].…”

Section: Methodsmentioning

confidence: 99%

Design, Synthesis, Biological Evaluation and Silico Prediction of Novel Sinomenine Derivatives

Gao

Xin

et al. 2021

Molecules

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Sinomenine is a morphinan alkaloid with a variety of biological activities. Its derivatives have shown significant cytotoxic activity against different cancer cell lines in many studies. In this study, two series of sinomenine derivatives were designed and synthesized by modifying the active positions C1 and C4 on the A ring of sinomenine. Twenty-three compounds were synthesized and characterized by spectroscopy (IR, 1H-NMR, 13C-NMR, and HRMS). They were further evaluated for their cytotoxic activity against five cancer cell lines, MCF-7, Hela, HepG2, SW480 and A549, and a normal cell line, Hek293, using MTT and CCK8 methods. The chlorine-containing compounds exhibited significant cytotoxic activity compared to the nucleus structure of sinomenine. Furthermore, we searched for cancer-related core targets and verified their interaction with derivatives through molecular docking. The chlorine-containing compounds 5g, 5i, 5j, 6a, 6d, 6e, and 6g exhibited the best against four core targets AKT1, EGFR, HARS and KARS. The molecular docking results were consistent with the cytotoxic results. Overall, results indicate that chlorine-containing derivatives might be a promising lead for the development of new anticancer agents.

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“…Coumarin has been classified as an oxygenated heterocycle rather than a benzoic acid derivative. Many coumarin hybrids have been reported to be used for medical disorders, namely as anti-allergic [ 103 ], antiviral [ 104 ], vasodilatory [ 105 ], antibacterial [ 106 , 107 ], exhibiting cyclooxygenase inhibition [ 108 ], lipoxygenase [ 109 ], antithrombotic [ 110 ], and anticancer activity [ 111 ]. The molecular hybridization of the coumarin nucleus to a biodynamic system that is a biologically active pharmacophore has enhanced biological activities.…”

Section: Coumarin Hybridsmentioning

confidence: 99%

A Review of the Recent Developments of Molecular Hybrids Targeting Tubulin Polymerization

Ebenezer

Shapi

Tuszyński

2022

IJMS

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Microtubules are cylindrical protein polymers formed from αβ-tubulin heterodimers in the cytoplasm of eukaryotic cells. Microtubule disturbance may cause cell cycle arrest in the G2/M phase, and anomalous mitotic spindles will form. Microtubules are an important target for cancer drug action because of their critical role in mitosis. Several microtubule-targeting agents with vast therapeutic advantages have been developed, but they often lead to multidrug resistance and adverse side effects. Thus, single-target therapy has drawbacks in the effective control of tubulin polymerization. Molecular hybridization, based on the amalgamation of two or more pharmacophores of bioactive conjugates to engender a single molecular structure with enhanced pharmacokinetics and biological activity, compared to their parent molecules, has recently become a promising approach in drug development. The practical application of combined active scaffolds targeting tubulin polymerization inhibitors has been corroborated in the past few years. Meanwhile, different designs and syntheses of novel anti-tubulin hybrids have been broadly studied, illustrated, and detailed in the literature. This review describes various molecular hybrids with their reported structural–activity relationships (SARs) where it is possible in an effort to generate efficacious tubulin polymerization inhibitors. The aim is to create a platform on which new active scaffolds can be modeled for improved tubulin polymerization inhibitory potency and hence, the development of new therapeutic agents against cancer.

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Lipoxygenase Inhibition Activity of Coumarin Derivatives—QSAR and Molecular Docking Study

Cited by 26 publications

References 54 publications

Synthesis, Bioactivity, Pharmacokinetic and Biomimetic Properties of Multi-Substituted Coumarin Derivatives

Synthesis, Bioactivity, Pharmacokinetic and Biomimetic Properties of Multi-Substituted Coumarin Derivatives

Design, Synthesis, Biological Evaluation and Silico Prediction of Novel Sinomenine Derivatives

A Review of the Recent Developments of Molecular Hybrids Targeting Tubulin Polymerization

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