Applied Chemical Engineering

Coumarin derivatives in pharmaceutical and biomedical engineering: Advances in design, synthesis, and therapeutic applications

Yasser Fakri Mustafa

Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, 41001, Iraq

DOI: https://doi.org/10.59429/ace.v8i3.5728

Keywords: Coumarin derivatives; green synthesis; pharmaceutical applications; anticancer activity; antioxidant properties; biomedical engineering

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Abstract

Background: Coumarin derivatives have emerged as pivotal compounds in pharmaceutical and biomedical research due to their multifaceted therapeutic potential. Naturally occurring in a wide range of plants, coumarins exhibit diverse biological activities including antimicrobial, anticancer, antioxidant, anti-inflammatory, and anticoagulant effects. Their structural versatility, comprising fused benzene and α-pyrone rings, offers a valuable scaffold for the design of novel pharmacophores targeting complex diseases such as cancer, neurodegenerative disorders, and infectious diseases. Methods: This review synthesizes recent advancements in the design, synthesis, and therapeutic applications of coumarin derivatives. It explores traditional synthetic routes such as the Pechmann and Perkin condensations alongside modern environmentally friendly techniques including microwave-assisted synthesis and solvent-free reactions. Furthermore, the article examines mechanistic insights into coumarins' bioactivity, involving pathways like apoptosis induction, oxidative stress modulation, and inhibition of molecular targets including carbonic anhydrases, kinases, and efflux pumps. Results: Numerous coumarin derivatives have demonstrated significant in vitro and in vivo bioactivity. Antimicrobial derivatives showed broad-spectrum efficacy, including multidrug-resistant pathogens. Anticancer coumarins exhibited cytotoxicity in several human cancer cell lines, with some outperforming standard chemotherapeutics. Derivatives also showed potent antioxidant effects, primarily through radical scavenging and modulation of redox signaling pathways. On the other hand, the synthesis of hybrid coumarin molecules further enhanced biological efficacy and solubility, addressing key pharmacokinetic challenges. Conclusion: Coumarins represent a versatile and promising class of compounds for future drug development. Ongoing innovation in green chemistry and molecular design is essential to overcome existing limitations such as low aqueous solubility and regulatory restrictions. This review reinforces coumarins' potential as lead structures in pharmaceutical engineering, advocating for continued exploration of their applications across therapeutic domains.

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[125]. Abdulaziz NT, Mustafa YF. The Effect of Heat Variable on the Chemical Composition and Bioactivities of a Citrullus lanatus Seed Aqueous Extracts. Journal of Medicinal and Chemical Sciences 2022;5(7):1166–76.

[126]. Vigueras G, Izquierdo-García E, de la Torre-Rubio E, Abad-Montero D, Santana MD, Marchán V, Ruiz J. Metal–coumarin derivatives as promising photosensitizers: unlocking their cancer phototherapy potential. Inorganic Chemistry Frontiers 2025;

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[128]. Zeki MN, Mustafa YF. Synthesis and evaluation of novel ring-conjugated coumarins as biosafe broad-spectrum antimicrobial candidates. Journal of Molecular Structure 2024;1309:138192.

[129]. Heghes SC, Vostinaru O, Mogosan C, Miere D, Iuga CA, Filip L. Safety Profile of Nutraceuticals Rich in Coumarins: An Update. Frontiers in Pharmacology 2022;13:803338.

[130]. Mazin Zeki N, M.Z. Othman K, Fakri Mustafa Y. Computational Chemistry: A game-changer in the drug discovery field. Applied Chemical Engineering 2025;8(1):ACE-5601.

[131]. Stiefel C, Schubert T, Morlock GE. Bioprofiling of Cosmetics with Focus on Streamlined Coumarin Analysis. ACS Omega 2017;2(8):5242–50.

[132]. Zeki NM, Mustafa YF. Digital alchemy: Exploring the pharmacokinetic and toxicity profiles of selected coumarin-heterocycle hybrids. Results in Chemistry 2024;10:101754.

[133]. Jebir MR, Mustafa YF. Kidney stones: natural remedies and lifestyle modifications to alleviate their burden. International Urology and Nephrology 2024;56(3):1025–33.

[134]. Banikazemi Z, Mirazimi SM, Dashti F, Mazandaranian MR, Akbari M. Coumarins and gastrointestinal cancer: A new therapeutic option ? Frontiers in oncology 2021;11:752784.

[135]. Szwaczko K, Paduch R, Dziuba K, Szafrański K, Wiater A. Modulation of Human Colon Cell Activity by Synthetic Coumarin Derivatives Bearing a Phosphonate Group. Molecules 2025;30(13):2846.

[136]. Raya I, Chupradit S, Kadhim MM, Mahmoud MZ, Jalil AT, Surendar A, Ghafel ST, Mustafa YF, Bochvar AN. Role of Compositional Changes on Thermal, Magnetic and Mechanical Properties of Fe-P-C-Based Amorphous Alloys. Chinese Physics B 2022;31(1):016401.

[137]. Al-Shakarchi W, Abdulaziz NT, Mustafa YF. A review of the chemical, pharmacokinetic, and pharmacological aspects of quercetin. Eurasian Chemical Communications 2022;4(7):645–56.

[138]. Kasim SM, Al-Dabbagh BM, Mustafa YF. A review on the biological potentials of carbazole and its derived products. Eurasian Chemical Communications 2022;4(6):495–512.

[139]. Szwaczko K. Coumarins Synthesis and Transformation via C–H Bond Activation—A Review. Inorganics 2022;10(2):23.

[140]. Betz UAK, Arora L, Assal RA, Azevedo H, Baldwin J, Becker MS, Bostock S, Cheng V, Egle T, Ferrari N, Schneider-Futschik EK, Gerhardy S, Hammes A, Harzheim A, Herget T, Jauset C, Kretschmer S, Lammie C, et al. Game changers in science and technology - now and beyond. Technological Forecasting and Social Change 2023;193:122588.

[141]. Mustafa YF. Coumarins from toxic phenol: An algorithm of their synthesis and assessment as biosafe, wide-spectrum, potent antimicrobial prospects. Applied Chemical Engineering 2024;7(3):5527.

[142]. Alshaher MM, Mustafa YF. Synthesis of triclosan-derived coumarins as potent, biocompatible, broad-spectrum antimicrobial agents. Applied Chemical Engineering 2024;7(4):5579.

[143]. Waheed SA, Mustafa YF. Synthesis of coumarin-based derivatives from different starting materials: A review of ongoing developments. Iraqi Journal of Pharmacy 2022;18(2):126–38.

[144]. Raya I, Widjaja G, HACHEM K, M.N. R, Ahmed AA, M. Kadhim M, Mustafa YF, Mahmood ZH, Aravindhan S. MnCo2O4/Co3O4 Nanocomposites: Microwave-Assisted Synthesis, Characterization and Photocatalytic Performance. Journal of Nanostructures 2021;11(4):728–35.

[145]. Al Anazi AA, Satar R, Jabbar HS, Sapaev IB, Altalbawy FMA, Alameri AA, Obaid RF, Ramírez-Coronel AA, Alfilh RHC, Mustafa YF, Heidarpour M. Effectual and Rapid Synthesis of Hantzsch Derivatives in Solvent-Free Conditions Catalyzed by a Mesoporous Basic Silica-Based Nanomaterial. Silicon 2023;15(8):3453–61.

[146]. Shukhratovich Abdullaev S, H Althomali R, Raza Khan A, Sanaan Jabbar H, Abosoda M, Ihsan A, Aggarwal S, Mustafa YF, Hammoud Khlewee I, Jabbar A mhussan. Integrating of analytical techniques with enzyme-mimicking nanomaterials for the fabrication of microfluidic systems for biomedical analysis. Talanta 2024;273:125896.

[147]. Graziano G, Stefanachi A, Contino M, Prieto-Díaz R, Ligresti A, Kumar P, Scilimati A, Sotelo E, Leonetti F. Multicomponent Reaction-Assisted Drug Discovery: A Time- and Cost-Effective Green Approach Speeding Up Identification and Optimization of Anticancer Drugs. International Journal of Molecular Sciences 2023;24(7):6581.

[148]. Chupradit S, Kavitha M, Suksatan W, Ansari MJ, Mashhadani ZI Al, Kadhim MM, Mustafa YF, Shafik SS, Kianfar E. Morphological Control : Properties and Applications of Metal Nanostructures. Advances in Materials Science and Engineering 2022;2022:ID 1971891.

[149]. Alinezhad H, Amiri PHT, Tavakkoli SM, Muhiebes RM, Mustafa YF. Progressive Types of Fe3O4 Nanoparticles and Their Hybrids as Catalysts. Journal of Chemical Reviews 2022;4(4):288–312.

[150]. Trojanowicz M. Flow Chemistry in Contemporary Chemical Sciences: A Real Variety of Its Applications. Molecules 2020;25(6):1434.

[151]. Ghasemi Darestani N, Gilmanova AI, Al-Gazally ME, Zekiy AO, Ansari MJ, Zabibah RS, Jawad MA, Al-Shalah SAJ, Rizaev JA, Alnassar YS, Mohammed NM, Mustafa YF, Darvishi M, Akhavan-Sigari R. Mesenchymal stem cell-released oncolytic virus: an innovative strategy for cancer treatment. Cell Communication and Signaling 2023;21(1):43.

[152]. Ismael SS, Waheed NAM, Kasim SM, Mustafa YF. Novel Coumarin-Indole Hybrids as Cytotoxic Candidates: Synthesis and Antiproliferative Activity. Pharmacognosy Journal 2023;15(6):1105–11.

[153]. Jasim MHM, Mustafa YF. Synthesis of Acetaminophen‐Based Coumarins as Selective COX‐2 Inhibitors: An in vitro‐in silico Study. Chemistry & Biodiversity 2024;21(10):e202401309.

[154]. Holbert CE, Cullen MT, Casero RA, Stewart TM. Polyamines in cancer: integrating organismal metabolism and antitumour immunity. Nature Reviews Cancer 2022;22(8):467–80.

[155]. Mustafa YF, Hassan DA. Dioxolocoumarins: Bridging chemistry and pharmacology with multifunctional therapeutics. Applied Chemical Engineering 2024;7(4):ACE-5592.

[156]. Mustafa YF. Synthesis, characterization, and biomedical assessment of novel bisimidazole–coumarin conjugates. Applied Nanoscience (Switzerland) 2023;13(3):1907–18.

[157]. Mustafa YF, Bashir MK, Oglah MK. Synthesis, antioxidant and antitumor activities of new coumarins grafted to 5-fluorouracil. Caspian Journal of Environmental Sciences 2022;20(2):359–65.

[158]. Supuran CT. Coumarin carbonic anhydrase inhibitors from natural sources. Journal of Enzyme Inhibition and Medicinal Chemistry 2020;35(1):1462–70.

[159]. Mustafa YF. When the gut Speaks: The hidden toll of irritable bowel syndrome on body and mind. Gastroenterology & Endoscopy 2025;3(3):135–51.

[160]. Gumus A, Bozdag M, Akdemir A, Angeli A, Selleri S, Carta F, Supuran CT. Thiosemicarbazide-Substituted Coumarins as Selective Inhibitors of the Tumor Associated Human Carbonic Anhydrases IX and XII. Molecules 2022;27(14):4610.

[161]. Mustafa YF. Synthesis, characterization and antibacterial activity of novel heterocycle, coumacine, and two of its derivatives. Saudi pharmaceutical journal 2018;26(6):870–5.

[162]. Ban AA, Ibrahim BY, Mustafa YF. The Protective Role of Natural Coumarins Derivatives and Anpro Supplement Against Aflatoxin B1 Pollution in the Quails Coturnix Japonica Diet. Mesopotamia Journal of Agriculture 2023;51(1):1–13.

[163]. Zhang S, Liao X, Ding T, Ahn J. Role of β-Lactamase Inhibitors as Potentiators in Antimicrobial Chemotherapy Targeting Gram-Negative Bacteria. Antibiotics 2024;13(3):260.

[164]. Mustafa YF, Khalil RR, Mohammed ET. Synthesis and antitumor potential of new 7-halocoumarin-4-acetic acid derivatives. Egyptian Journal of Chemistry 2021;64(7):3711–6.

[165]. Šeregelj V, Šovljanski O, Tumbas Šaponjac V, Vulić J, Ćetković G, Markov S, Čanadanović-Brunet J. Horned Melon (Cucumis metuliferus E. Meyer Ex. Naudin)—Current Knowledge on Its Phytochemicals, Biological Benefits, and Potential Applications. Processes 2022;10(1):94.

[166]. Luo X, He W, Yin H, Li Q, Liu Q, Huang Y, Zhang S. Two New Coumarins from Micromelum falcatum with Cytotoxicity and Brine Shrimp Larvae Toxicity. Molecules 2012;17(6):6944–52.

[167]. Oglah MK, Mustafa YF. Synthesis, antioxidant, and preliminary antitumor activities of new curcumin analogues. Journal of Global Pharma Technology 2020;12(2):854–62.

[168]. Priya AK, Alagumalai A, Balaji D, Song H. Bio-based agricultural products: a sustainable alternative to agrochemicals for promoting a circular economy. RSC Sustainability 2023;1(4):746–62.

[169]. Mustafa YF. Synthesis, in silico analysis, and biomedical effects of coumarins derived from resveratrol. Phytomedicine Plus 2024;3(4):100501.

[170]. Mustafa YF. Synthesis, characterization and preliminary cytotoxic study of sinapic acid and its analogues. Journal of Global Pharma Technology 2019;11(9):1–10.

[171]. Yahya MQ, Mustafa YF. Transforming Poisonous Phenol into Biosafe Antimicrobial Coumarins: Synthesis and Evaluation. Russian Journal of Bioorganic Chemistry 2024;50(4):1595–608.

[172]. Kasperkiewicz K, Ponczek MB, Owczarek J, Guga P. Antagonists of vitamin K—popular coumarin drugs and new synthetic and natural coumarin derivatives. Molecules 2020;25(1465):1–24.

[173]. Konkoľová E, Hudáčová M, Hamuľaková S, Jendželovský R, Vargová J, Ševc J, Fedoročko P, Kožurková M. Tacrine-Coumarin Derivatives as Topoisomerase Inhibitors with Antitumor Effects on A549 Human Lung Carcinoma Cancer Cell Lines. Molecules 2021;26(4):1133.

[174]. Sharmeen J, Mahomoodally F, Zengin G, Maggi F. Essential Oils as Natural Sources of Fragrance Compounds for Cosmetics and Cosmeceuticals. Molecules 2021;26(3):666.

[175]. Al-Shakarchi W, Saber Y, Merkhan MM, Mustafa YF. Sub Chronic Toxicity Study of Coumacines. Pharmacognosy Journal 2023;15(1):160–4.

[176]. Li C, Wang D, Xue W, Peng J, Wang T, Zhang Z. Synthesis and photophysical properties of vertically π-expanded coumarins. Dyes and Pigments 2021;186:108956.

[177]. Zhou H, Jian Y, Shao Q, Guo F, Zhang M, Wan F, Yang L, Liu Y, Yang L, Li Y, Yang P, Li Z, Li S, Ding W. Development of Sustainable Insecticide Candidates for Protecting Pollinators: Insight into the Bioactivities, Selective Mechanism of Action and QSAR of Natural Coumarin Derivatives against Aphids. Journal of Agricultural and Food Chemistry 2023;71(47):18359–74.

[178]. Al-Shakarchi W, Saber Y, Merkhan MM, Mustafa YF. Acute toxicity of coumacines: An in vivo study. Georgian medical news 2023;(338):126–31.

[179]. Younis MA, Hamid OA, Dhaher R, Saber Y, Al-shakarchi W, Merkhan MM, Mustafa YF. Characterization of the renal safety profiles of coumacines. Pharmakeftiki 2023;35(4):57–63.

[180]. Pitaro M, Croce N, Gallo V, Arienzo A, Salvatore G, Antonini G. Coumarin-Induced Hepatotoxicity: A Narrative Review. Molecules 2022;27(24):9063.

[181]. Eggel M, Würbel H. Internal consistency and compatibility of the 3Rs and 3Vs principles for project evaluation of animal research. Laboratory Animals 2021;55(3):233–43.

[182]. Delgado A, Gonçalves S, Romano A. Mediterranean Diet: The Role of Phenolic Compounds from Aromatic Plant Foods. Foods 2023;12(4):840.

[183]. Wilson E. What is Benefit Sharing? Respecting Indigenous Rights and Addressing Inequities in Arctic Resource Projects. Resources 2019;8(2):74.

[184]. McNair L. Ethical and regulatory oversight of clinical research: The role of the Institutional Review Board. Experimental Biology and Medicine 2022;247(7):561–6.

[185]. Gordon BG. Vulnerability in Research: Basic Ethical Concepts and General Approach to Review. Ochsner Journal 2020;20(1):34–8.