Therapeutic Journey and Recent Advances in the Synthesis of Coumarin Derivatives

Background: Coumarin is an oxygen-containing compound in medicinal chemistry. Coumarin plays an important role in both natural systems like plants and also in synthetic medicinal applications as drug molecules. Many structurally different coumarin compounds were found to show a big range of similarity with the vital molecular targets for their pharmacological action and small modifications in their structures resulted insignificant changes in their biological activities. Objective: This review gives detailed information about the studies of the recent advances in various pharmacological aspects of coumarins. Method: Various oxygen-containing heterocyclic compounds represented remarkable biological significances. The fused aromatic oxygen-heterocyclic nucleus is able to change its electron density; thus changing the chemical, physical and biological properties respectively due to its multiple binding modes with the receptors, which play crucial role in pharmacological screening of drugs. A number of heterocyclic compounds have been synthesized which have their nucleus derived from various plants and animals. In coumarins, benzene ring is fused with pyrone nucleus which provides stability to the nucleus. Coumarins have shown a wide range of pharmacological activities such as anti-tumour, anti-coagulant, anti-inflammatory, anti-oxidant, antiviral, anti-malarial, anti-HIV and antimicrobial activity etc. Results: Reactive oxygen species like superoxide anion, hydroxyl radical and hydrogen peroxide are a type of unstable molecule that contains oxygen, which reacts with other molecules in the cell during the metabolism process but it may produce cytotoxicity when reactive oxygen species increase in number, by the damage of biological macromolecules. Hydroxyl radical (˙OH), is a strong oxidizing agent and it is responsible for the cytotoxicity by oxygen in different plants, animals and other microbes. coumarin is the oldest and effective compound having antimicrobial activity, anti-inflammatory, antioxidant, antidepressant activity, analgesic, anticonvulsant activity, etc. Naturally existing coumarin compounds act against SARS-CoV-2 by preventing viral replication through the targeting on active site against the Mpro target protein. Conclusion: This review highlights the different biological activities of coumarin derivatives. In this review we provide an updated summary of the researches which are related to recent advances in biological activities of coumarins analogue and their most recent activities against COVID -19. Natural compounds act as a rich resource for novel drug development against various SARS-CoV-2 viral strains including viruses like herpes simplex virus, influenza virus, human immunodeficiency virus, hepatitis B and C viruses, middle east respiratory syndrome and severe acute respiratory syndrome.

Glycyrol Alone or in Combination with Gefitinib Is Effective against Gefitinib-Resistant HCC827GR Lung Cancer Cells

Gefitinib has been clinically demonstrated to be effective in the first-line setting for patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC). However, acquired therapeutic resistance to gefitinib almost unavoidably develops, posing a major hurdle for its clinical utilization. Our previous study showed that glycyrol (GC), a representative of coumarin compounds isolated from the medicinal plant licorice, was effective against A549 lung cancer cells in both cell culture and a murine xenograft model. In this follow-up study, we evaluated the effect of glycyrol against gefitinib-resistant NSCLC and its ability to overcome the resistance using gefitinib-resistant HCC827GR cells. Results showed that glycyrol was effective against HCC827GR cells in both in vitro and in vivo. Moreover, glycyrol was able to significantly increase the sensitivity of HCC827GR cells to gefitinib, mechanistically associated with inactivating MET, which is a known important contributor to the resistance of HCC827GR cells to gefitinib. The findings of the present study suggest that glycyrol holds potential to be developed as a novel agent against gefitinib-resistant NSCLC.

Screening of tarragon accessions based on physiological and phytochemical responses under water deficit

In this study, screening of Artemisia dracunculus accessions was investigated under water deficit based on physiological and phytochemical traits. The results clearly indicated that water deficit significantly reduced the relative water content, chlorophyll, and carotenoid contents and increased malondialdehyde, electrolyte leakage, and antioxidant activities. The responses of tarragon accessions to water deficit, however, were inconsistent. The HPLC analysis revealed the presence of chlorogenic, syringic, ferulic, vanillic, chicoric, and p-coumaric acids as major phenolic acids, while quercetin and herniarin were detected as the predominant flavonoid and coumarin compounds in the extracts. Our findings revealed that the water deficit not only increased the amounts of herniarin, luteolin, apigenin, caffeic acid, and syringic acid, but also introduced quercetin that was not present under normal conditions in Estahbanat. Nevertheless, these results were highly impacted by the accession type. The results indicated that Hamadan, Varamin and Estahbanat accessions could be introduced as tolerant accessions. Given the very different responses of tarragon accessions to water deficit and the diversity between these accessions, the findings of the present study could be an effective step in identifying and achieving homogeneous, drought-tolerant and high-yield potential accessions, and may help tarragon breeding programs as well as development of cultivation.

Isolasi Senyawa Kumarin pada Tanaman

Indonesia is a country rich in biodiversity. Of several plants that can be used as alternative medicine to treat disease. The efficacy of plants as medicine in health is related to plants having chemical compounds which are the result of secondary metabolites contained in these plants. One of the secondary metabolites in plants is coumarin. Coumarins can be found in almost all plants from roots, stems, leaves, flowers and fruit. The purpose of this study was to isolate and identify coumarin compounds contained in these plants. In the process of isolating coumarin compounds that can be done by several methods including extraction, phytochemical screening, fractionation, isolation of coumarins and identification of isolates. Plants containing coumarin compounds that were used in the isolation of coumarins that we reviewed were sundai lime peel (Citrus nobilis Lour), rambutan fruit seeds (Nephelium lappaceum L), water henna leaves (Impatiens Balsemina Linn), harp bark (Sandoricum koetjape) and Artemisia annua L.

Screening of Iranian Tarragon Accessions Based on Physiological and Phytochemical Responses Under Water Deficit: Applications for Development and Breeding

In this study, screening of tarragon accessions based on physiological and phytochemical traits was investigated under water deficit. The compounding impacts of water deficit * accessions significantly altered the chlorophyll and carotenoid contetnt, malondialdehyde, electrolyte leakage, superoxide dismutase, catalase and ascorbate peroxidase. The HPLC analyse revealed the presence of chlorogenic, syringic, ferulic, vanilic, chicoric and p-coumaric acids as major phenolic acids, while quercetin and herniarin were detected as the predominant flavonoid and coumarin compounds in the extracts. The quality and quantity of tarragon secondary metabolites were impacted by water deficit, suggesting that drought stress either increased the amounts of some common compounds or introduced some new compounds that were not present under normal conditions. In some genotypes, the content of some secondary metabolites in tarragon had the highest values under severe water deficit stress. The results indicated that Hamadan, Varamin and Estahbanat accessions could be introduced as tolerant accessions. Due to the very different response of tarragon accessions to water deficit and the existence of diversity between these accessions, the findings of the present study could be an effective step in identifying and achieving homogeneous, drought-tolerant and high-yield potential accessions, and may help tarragon breeding programs and development of cultivation.

Novel coumarin compounds potentiate the effect of cisplatin on lung cancer cells by enhancing pro-apoptotic gene expressions, G2/M cell arrest, oxidative and antiangiogenic effects

Coumarin is a functional compound with a pronounced wide range of biological activities and has recently been shown to have anticancer effects on various human cancer cells. Cisplatin is widely used in the treatment of many cancers but its effectiveness is limited due to acquired resistance and dose-related side effects. This study aimed to reveal the chemosensitizing ability of novel synthesized coumarin-triazole hybrid compounds (3a-f) alone or their combination with cisplatin in A549 cells.MTT assay was used for cytotoxic effects. Lactate dehydrogenase (LDH), antioxidant/oxidant status, DNA fragmentation were determined spectrophotometrically by using commercial kits. Muse™ Cell Analyzer was used to assess cell cycle progression. Pro/anti-apoptotic gene expressions were determined by Real-Time qPCR. The antiangiogenic activity was determined by VEGF expression and Hen's chorioallantoic membrane model. Compounds 3c, d, e, and f potentiated the cisplatin-induced cytotoxicity through the increase of LDH release and DNA fragmentation, induced G2/M cell cycle arrest, overproduction of oxidative stress, and decrease of cellular antioxidant levels. These compounds combined with cisplatin caused upregulation in the pro-apoptotic Bax, Bıd, caspase-3, caspase-8, caspase-9, Fas, and p53 gene expressions while downregulating anti-apoptotic DFFA, NFkB1, and Bcl2 gene expressions. These combinations caused vascular loss and a reduction in VEGF expression. These results suggest that a combinational regimen of coumarin compounds with cisplatin overcome the acquired resistance of cancer cells to cisplatin and, considering compounds have relatively low toxicity in normal cells, decrease the dose requirement of cisplatin in cancer treatments.

Anticancer potential of coumarin and its derivatives

: Coumarins are found in higher plants like Rutaceae and Umbelliferae and essential oils of cinnamon bark, cassia leaf, and lavender oil. Coumarin compounds show different biological properties viz antimicrobial, antibacterial, antifungal, antioxidant, antitumor, anti-HIV, antihypertension, anticoagulant, anticancer, antiviral, anti-inflammatory, analgesics, antidiabetic, anti-depressive, and other bioactive properties. Coumarin and its derivatives possess anticancer activity against different types of cancers such as prostate, renal, breast, laryngeal, lung, colon, CNS, leukemia, malignant melanoma. In this review, current developments of coumarin based anticancer agents viz simple coumarin, furanocoumarin, pyranocoumarin, pyrone-substituted coumarin and their important derivatives have been discussed. The coumarin-triazole, coumarin-chalcone, coumarin-thiosemicarbazone derivatives and coumarin-metal complexes have been found to more potent than coumarin. Hence, further study and structural improvement on coumarin and its derivatives may lead to the design and development of more potent anticancer agents.

Biological Evidences of Dicoumarol: A Review

Dicoumarol, a natural anticoagulant drug chemically designated as is metabolized from coumarin in the sweet clover (Melilotus alba and Melilotus officinalis) by molds, such as Penicillium nigricans and Penicillium jensi. Coumarin (1,2-benzopyrone), the parent molecule of dicoumarol, is the simplest compound of a large class of naturally occurring phenolic substances made of fused benzene and pyrone rings . In addition, the coumarin anticoagulants, dicoumarol (Dicumarol) and its synthetic derivative warfarin sodium (Coumadin), have been shown to decrease metastases in experimental animals. Warfarin sodium, largely replacing dicoumarol therapeutically as an anticoagulant, has been used for the treatment of a variety of cancers and shown to improve tumor response rates and survival in patients with several types of cancer. However, despite numerous studies, little information has been acquired on the cellular mechanism of action of coumarin compounds in the treatment of malignancies. Possibly for this reason, the coumarin compounds have not received much attention for the treatment of cancer.