Applied Chemical Engineering

From laboratory to computer models: Enhancing coumarin discovery through interdisciplinary research

Marwa Mohammed Alshaher

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

Yasser Fakri Mustafa

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

DOI: https://doi.org/10.59429/ace.v8i1.5613

---

Abstract

Coumarin-derived compounds have garnered extensive interest due to their diverse applications in medicinal chemistry, pharmacology, food, and cosmetics. There are pros and cons to both in vitro and in silico methods used in coumarin-based research. The focus is on their roles, pros, and cons in finding out the biomedical properties of these compounds. In vitro studies, conducted in controlled environments, enable detailed investigations into cellular mechanisms, enzyme interactions, and cytotoxic effects. These studies are valuable for elucidating coumarin’s biological activity and therapeutic potential. Although these studies are accurate, morally acceptable, and repeatable, their inability to fully replicate complex biological systems necessitates extrapolation to real-life situations. In contrast, in silico studies leverage computational tools to model molecular interactions, predict pharmacokinetic behaviors, and simulate biological pathways. These techniques are time- and cost-efficient, capable of high-throughput screening, and useful for hypothesis generation. However, their reliability depends on the accuracy of input data and assumptions, which can limit their predictive power in real-world scenarios. Integrating these two study types provides a synergistic framework that enhances coumarin-based research. In silico models can guide the design of experiments, while in vitro assays validate computational predictions. Emerging technologies, such as machine learning, organ-on-a-chip systems, and 3D cell cultures, promise to further refine this integration, enabling faster, more accurate, and ethical research. We conducted an investigation and a literature review, utilizing PubMed data and limiting the publication period from 2000 to mid-2024. This study demonstrates the effective combination of in vitro and in silico methods to advance coumarin-based research and unlock its full therapeutic potential.

---

References

[1]. Ahmed F. A current summary of coumarin-based compounds and their therapeutic applications. Egyptian Journal of Chemistry. 2024;67(13):1417–37.

[2]. Mustafa YF, Abdulaziz NT. Biological potentials of hymecromone-based derivatives: A systematic review. Systematic Reviews in Pharmacy. 2020;11(11):438–52.

[3]. Jasim SF, Mustafa YF. Synthesis and Antidiabetic Assessment of New Coumarin-Disubstituted Benzene Conjugates: An In Silico-In Virto Study. Journal of Medicinal and Chemical Sciences. 2022;5(6):887–99.

[4]. Lončar M, Jakovljević M, Šubarić D, Pavlić M, Buzjak Služek V, Cindrić I, Molnar M. Coumarins in Food and Methods of Their Determination. Foods. 2020;9(5):645.

[5]. Mustafa YF, Abdulaziz NT. Hymecromone and its products as cytotoxic candidates for brain cancer : A brief review. NeuroQuantology. 2021;19(7):175–86.

[6]. Hafsan H, Saleh MM, Zabibah RS, Obaid RF, Jabbar HS, Mustafa YF, Sultan MQ, Gabr GA, Ramírez-Coronel AA, Khodadadi M, Dadras M. Dietary Thymol Improved Growth, Body Composition, Digestive Enzyme Activities, Hematology, Immunity, Antioxidant Defense, and Resistance to Streptococcus iniae in the Rainbow Trout (Oncorhynchus mykiss). El Basuini M, editor. Aquaculture Nutrition. 2022;2022:3288139.

[7]. Mahmood AAJ, Mustafa YF, Abdulstaar M. New coumarinic azo-derivatives of metoclopramide and diphenhydramine: Synthesis and in vitro testing for cholinesterase inhibitory effect and protection ability against chlorpyrifos. International Medical Journal Malaysia. 2014;13(1):3–12.

[8]. Gupta V, Ambatwar R, Bhanwala N, Khatik GL. Coumarin as a Privileged and Medicinally Important Scaffold in the Treatment of Tuberculosis. Current Topics in Medicinal Chemistry. 2023;23(16):1489–502.

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

[10]. Annunziata F, Pinna C, Dallavalle S, Tamborini L, Pinto A. An overview of coumarin as a versatile and readily accessible scaffold with broad-ranging biological activities. International Journal of Molecular Sciences. 2020;21(13):1–83.

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

[12]. Mustafa YF. Classical approaches and their creative advances in the synthesis of coumarins: A brief review. Journal of Medicinal and Chemical Sciences. 2021;4(6):612–25.

[13]. Mustafa YF, Najem MA, Tawffiq ZS. Coumarins from Creston apple seeds: Isolation, chemical modification, and cytotoxicity study. Journal of Applied Pharmaceutical Science. 2018;8(8):49–56.

[14]. Zeki NM, Mustafa YF. Natural linear coumarin-heterocyclic conjugates: A review of their roles in phytotherapy. Fitoterapia. 2024;175:105929.

[15]. 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.

[16]. Mustafa YF, Bashir MK, Oglah MK, Khalil RR, Mohammed ET. Bioactivity of some natural and semisynthetic coumarin derived compounds. NeuroQuantology. 2021;19(6):129–38.

[17]. Bashir MK, Mustafa YF, Oglah MK. Synthesis and antitumor activity of new multifunctional coumarins. Periodico Tche Quimica. 2020;17(36):871–83.

[18]. Kim S, Thiessen PA, Cheng T, Yu B, Shoemaker BA, Wang J, Bolton EE, Wang Y, Bryant SH. Literature information in PubChem: associations between PubChem records and scientific articles. Journal of Cheminformatics. 2016;8(1):32.

[19]. Mustafa YF, Khalil RR, Mohammed ET. Antimicrobial activity of aqueous extracts acquired from the seeds of two apples’ cultivars. Systematic Reviews in Pharmacy. 2020;11(2):382–7.

[20]. Mustafa YF, Abdulaziza NT, Jasima MH. 4-Methylumbelliferone and its derived compounds: A brief review of their cytotoxicity. Egyptian Journal of Chemistry. 2021;64(4):1807–16.

[21]. Waheed SA, Mustafa YF. Benzocoumarin backbone is a multifunctional and affordable scaffold with a vast scope of biological activities. Journal of Medicinal and Chemical Sciences. 2022;5(5):703–21.

[22]. Jasim SF, Mustafa YF. A Review of Classical and Advanced Methodologies for Benzocoumarin Synthesis. Journal of Medicinal and Chemical Sciences. 2022;5(5):676–94.

[23]. Flores-Morales V, Villasana-Ruíz AP, Garza-Veloz I, González-Delgado S, Martinez-Fierro ML. Therapeutic Effects of Coumarins with Different Substitution Patterns. Molecules. 2023;28(5):2413.

[24]. Hachem K, Jasim SA, Al-Gazally ME, Riadi Y, Yasin G, Turki Jalil A, Abdulkadhm MM, Saleh MM, Fenjan MN, Mustafa YF, Dehno Khalaji A. Adsorption of Pb(II) and Cd(II) by magnetic chitosan-salicylaldehyde Schiff base: Synthesis, characterization, thermal study and antibacterial activity. Journal of the Chinese Chemical Society. 2022;69(3):512–21.

[25]. Pisani L, Catto M, Muncipinto G, Nicolotti O, Carrieri A, Rullo M, Stefanachi A, Leonetti F, Altomare C. A twenty-year journey exploring coumarin-based derivatives as bioactive molecules. Frontiers in Chemistry. 2022;10:1002547.

[26]. Roomi AB, Widjaja G, Savitri D, Jalil AT, Mustafa YF, Thangavelu L, Kazhibayeva G, Suksatan W, Chupradit S, Aravindhan S. SnO2:Au/Carbon Quantum Dots Nanocomposites: Synthesis, Characterization, and Antibacterial Activity. Journal of Nanostructures. 2021;11(3):514–23.

[27]. 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.

[28]. Fregonezi NF, Aparecida de Souza F, Aleixo NA, Stefany da Silva Gomes P, Silvestre RB, De Grandis RA, Bento da Silva P, Pavan FR, Chorilli M, Resende FA. Cyto-genotoxic evaluation of novel anti-tubercular copper (II) complexes containing isoniazid-based ligands. Regulatory Toxicology and Pharmacology. 2020;113:104653.

[29]. Lesage R, Van Oudheusden M, Schievano S, Van Hoyweghen I, Geris L, Capelli C. Mapping the use of computational modelling and simulation in clinics: A survey. Frontiers in Medical Technology. 2023;5:1125524.

[30]. Cardoso BD, Castanheira EMS, Lanceros‐Méndez S, Cardoso VF. Recent Advances on Cell Culture Platforms for In Vitro Drug Screening and Cell Therapies: From Conventional to Microfluidic Strategies. Advanced Healthcare Materials. 2023;12(18):e2202936.

[31]. Chen J, Gu Z, Lai L, Pei J. In silico protein function prediction: the rise of machine learning-based approaches. Medical Review. 2023;3(6):487–510.

[32]. Madorran E, Stožer A, Bevc S, Maver U. In vitro toxicity model: Upgrades to bridge the gap between preclinical and clinical research. Bosnian Journal of Basic Medical Sciences. 2020;20(2):157–168.

[33]. Gheidari D, Mehrdad M, Karimelahi Z. Virtual screening, ADMET prediction, molecular docking, and dynamic simulation studies of natural products as BACE1 inhibitors for the management of Alzheimer’s disease. Scientific Reports. 2024;14(1):26431.

[34]. Wang L, Hu D, Xu J, Hu J, Wang Y. Complex in vitro model: A transformative model in drug development and precision medicine. Clinical and Translational Science. 2024;17(2):e13695.

[35]. Chang Y, Hawkins BA, Du JJ, Groundwater PW, Hibbs DE, Lai F. A Guide to In Silico Drug Design. Pharmaceutics. 2022;15(1):49.

[36]. Wright Muelas M, Ortega F, Breitling R, Bendtsen C, Westerhoff H V. Rational cell culture optimization enhances experimental reproducibility in cancer cells. Scientific Reports. 2018;8(1):3029.

[37]. Matzko R, Konur S. Technologies for design-build-test-learn automation and computational modelling across the synthetic biology workflow: a review. Network Modeling Analysis in Health Informatics and Bioinformatics. 2024;13(1):22.

[38]. Zhang C, Sui Y, Liu S, Yang M. In vitro and in vivo experimental models for cancer immunotherapy study. Current Research in Biotechnology. 2024;7:100210.

[39]. Verma SK, Nandi A, Simnani FZ, Singh D, Sinha A, Naser SS, Sahoo J, Lenka SS, Panda PK, Dutt A, Kaushik NK, Singh D, Suar M. In silico nanotoxicology: The computational biology state of art for nanomaterial safety assessments. Materials & Design. 2023;235:112452.

[40]. Kang M, Long T, Chang C, Meng T, Ma H, Li Z, Li P, Chen Y. A Review of the Ethical Use of Animals in Functional Experimental Research in China Based on the “Four R” Principles of Reduction, Replacement, Refinement, and Responsibility. Medical Science Monitor. 2022;29:e938807.

[41]. Gao S, Fang A, Huang Y, Giunchiglia V, Noori A, Schwarz JR, Ektefaie Y, Kondic J, Zitnik M. Empowering biomedical discovery with AI agents. Cell. 2024;187(22):6125–51.

[42]. Petrucciani A, Hoerter A, Kotze L, Du Plessis N, Pienaar E. In silico agent-based modeling approach to characterize multiple in vitro tuberculosis infection models. Puniya BL, editor. PLOS ONE. 2024;19(3):e0299107.

[43]. Shi D, Mi G, Wang M, Webster TJ. In vitro and ex vivo systems at the forefront of infection modeling and drug discovery. Biomaterials. 2019;198:228–49.

[44]. Xu H, Qin J, Qin L, Guo C, Yang B. Bioinformatics and In Silico Findings Uncover Bio-Targets of Calycosin Against Heart Failure and Diabetes Mellitus. Frontiers in Endocrinology. 2022;13:790619.

[45]. Danchin A. In vivo , in vitro and in silico : an open space for the development of microbe‐based applications of synthetic biology. Microbial Biotechnology. 2022;15(1):42–64.

[46]. Agamah FE, Mazandu GK, Hassan R, Bope CD, Thomford NE, Ghansah A, Chimusa ER. Computational/in silico methods in drug target and lead prediction. Briefings in Bioinformatics. 2020;21(5):1663–75.

[47]. Grossmann I, Rotella A, Hutcherson CA, Sharpinskyi K, Varnum MEW, Achter S, Dhami MK, Guo XE, Kara-Yakoubian M, Mandel DR, Raes L, Tay L, Vie A, Wagner L, Adamkovic M, Arami A, Arriaga P, Bandara K, et al. Insights into the accuracy of social scientists’ forecasts of societal change. Nature Human Behaviour. 2023;7:484–501.

[48]. Mustafa YF. Harmful Free Radicals in Aging: A Narrative Review of Their Detrimental Effects on Health. Indian Journal of Clinical Biochemistry. 2024;39(2):154–67.

[49]. Upchurch WJ, Iaizzo PA. In vitro contractile studies within isolated tissue baths: Translational research from Visible Heart ® Laboratories. Experimental Biology and Medicine. 2022;247(7):584–97.

[50]. Jebir RM, Mustafa YF. Watermelon Allsweet: A promising natural source of bioactive products. Journal of Medicinal and Chemical Sciences. 2022;5(5):652–66.

[51]. Mustafa YF, Mohammed NA alwahab. A promising oral 5-fluorouracil prodrug for lung tumor: Synthesis, characterization and release. Biochemical and Cellular Archives. 2021;21(Supp 1):1991–9.

[52]. Huldani H, Rashid AI, Turaev KN, Opulencia MJC, Abdelbasset WK, Bokov DO, Mustafa YF, Al-Gazally ME, Hammid AT, Kadhim MM, Ahmadi SH. Concanavalin A as a promising lectin-based anti-cancer agent: the molecular mechanisms and therapeutic potential. Cell Communication and Signaling. 2022;20(1):1–14.

[53]. Khalil RR, Mohammed ET, Mustafa YF. Evaluation of in vitro antioxidant and antidiabetic properties of Cydonia Oblonga seeds’ extracts. Journal of Medicinal and Chemical Sciences. 2022;5(6):1048–58.

[54]. Rohmah MK, Salahdin OD, Gupta R, Muzammil K, Qasim MT, Al-qaim ZH, Abbas NF, Jawad MA, Yasin G, Mustafa YF, Heidary A, Abarghouei S. Modulatory role of dietary curcumin and resveratrol on growth performance, serum immunity responses, mucus enzymes activity, antioxidant capacity and serum and mucus biochemicals in the common carp, Cyprinus carpio exposed to abamectin. Fish and Shellfish Immunology. 2022;129:221–30.

[55]. Hirsch C, Schildknecht S. In Vitro Research Reproducibility: Keeping Up High Standards. Frontiers in Pharmacology. 2019;10:1484.

[56]. Setia Budi H, Javed Ansari M, Abdalkareem Jasim S, Abdelbasset WK, Bokov D, Fakri Mustafa Y, Najm MAA, Kazemnejadi M. Preparation of antibacterial Gel/PCL nanofibers reinforced by dicalcium phosphate-modified graphene oxide with control release of clindamycin for possible application in bone tissue engineering. Inorganic Chemistry Communications. 2022;139:109336.

[57]. Mustafa YF, Ismael RN, Jebir RM. Natural coumarins from two cultivars of watermelon seeds as biosafe anticancer agents, an algorithm for their isolation and evaluation. Journal of Molecular Structure. 2024;1295(P1):136644.

[58]. Budi HS, Younus LA, Lafta MH, Parveen S, Mohammad HJ, Al-qaim ZH, Jawad MA, Parra RMR, Mustafa YF, Alhachami FR, Karampoor S, Mirzaei R. The role of miR-128 in cancer development, prevention, drug resistance, and immunotherapy. Frontiers in Oncology. 2023;12:1067974.

[59]. Dantas RF, Evangelista TCS, Neves BJ, Senger MR, Andrade CH, Ferreira SB, Silva-Junior FP. Dealing with frequent hitters in drug discovery: a multidisciplinary view on the issue of filtering compounds on biological screenings. Expert Opinion on Drug Discovery. 2019;14(12):1269–82.

[60]. Abdulaziz NT, Mustafa YF. Antibacterial and Antitumor Potentials of Some Novel Coumarins. International Journal of Drug Delivery Technology. 2022;12(1):239–47.

[61]. Mustafa YF, Zain Al-Abdeen SH, Khalil RR, Mohammed ET. Novel functionalized phenyl acetate derivatives of benzo [e]-bispyrone fused hybrids: Synthesis and biological activities. Results in Chemistry. 2023;5:100942.

[62]. Budi HS, Jameel MF, Widjaja G, Alasady MS, Mahmudiono T, Mustafa YF, Fardeeva I, Kuznetsova M. Study on the role of nano antibacterial materials in orthodontics (a review). Brazilian Journal of Biology. 2024;84(e257070):1–7.

[63]. Zhao M, Ma J, Li M, Zhang Y, Jiang B, Zhao X, Huai C, Shen L, Zhang N, He L, Qin S. Cytochrome P450 Enzymes and Drug Metabolism in Humans. International Journal of Molecular Sciences. 2021;22(23):12808.

[64]. Khalil RR, Mohammed ET, Mustafa YF. Various promising biological effects of Cranberry extract: A review. Clinical Schizophrenia and Related Psychoses. 2021;15(S6):1–9.

[65]. Mustafa YF, Oglah MK, Bashir MK. Conjugation of sinapic acid analogues with 5- Fluorouracil: Synthesis, preliminary cytotoxicity, and release study. Systematic Reviews in Pharmacy. 2020;11(3):482–9.

[66]. Waheed SA, Mustafa YF. Novel naphthalene-derived coumarin composites: synthesis, antibacterial, and antifungal activity assessments. Eurasian Chemical Communications. 2022;4(8):709–24.

[67]. Foroozesh M, Sridhar J, Goyal N, Liu J. Coumarins and P450s, Studies Reported to-Date. Molecules. 2019;24(8):1620.

[68]. Ismael RN, Mustafa YF, Al-qazaz HK. Citrullus lanatus, a Potential Source of Medicinal Products : A Review. Journal of Medicinal and Chemical Sciences. 2022;5(4):607–18.

[69]. Jasim SF, Mustafa YF. Synthesis, ADME Study, and antimicrobial evaluation of novel naphthalene-based derivatives. Journal of Medicinal and Chemical Sciences. 2022;5(5):793–807.

[70]. Jasim SF, Mustafa YF. New fused-coumarin composites: Synthesis, anticancer and antioxidant potentials evaluation. Eurasian Chemical Communications. 2022;4(7):607–19.

[71]. Lee J, Beers JL, Geffert RM, Jackson KD. A Review of CYP-Mediated Drug Interactions: Mechanisms and In Vitro Drug-Drug Interaction Assessment. Biomolecules. 2024;14(1):99.

[72]. Ismael RN, Mustafa YF, Al-Qazaz HK. Cancer-curative potential of novel coumarins from watermelon princess: A scenario of their isolation and activity. Eurasian Chemical Communications. 2022;4(7):657–72.

[73]. Kim Y, Bae S, Chung WK, Kwon J, Song I, Lee S. Exploration of pharmacokinetic differences between East Asians and Caucasians: insights from pharmacokinetic studies in healthy subjects. Translational and Clinical Pharmacology. 2024;32(3):127.

[74]. Kasim SM, Abdulaziz NT, Jasim MH, Mustafa YF. Resveratrol in cancer chemotherapy: Is it a preventer, protector, or fighter? Eurasian Chemical Communications. 2023;5(7):576–87.

[75]. Bashir MK, Mustafa YF, Oglah MK. Antitumor, antioxidant, and antibacterial activities of glycosyl-conjugated compounds: A review. Systematic Reviews in Pharmacy. 2020;11(4):175–87.

[76]. Maashi MS, Al-Mualm M, Al-Awsi GRL, Opulencia MJC, Al-Gazally ME, Abdullaev B, Abdelbasset WK, Ansari MJ, Jalil AT, Alsaikhan F, Shalaby MN, Mustafa YF. Apigenin alleviates resistance to doxorubicin in breast cancer cells by acting on the JAK/STAT signaling pathway. Molecular Biology Reports. 2022;49:8777–84.

[77]. Ahmed ME salato AE naby. In vitro propagation and improving accumulation of coumarin in Lycium barbarum, a rare plant in the flora of Egypt. Bulletin of the National Research Centre. 2022;46(1):220.

[78]. 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.

[79]. Aldewachi H, Mustafa YF, Najm R, Ammar F. Adulteration of Slimming Products and its Detection Methods. Systematic Reviews in Pharmacy. 2020;11(3):289–96.

[80]. 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.

[81]. Almeida CMM. Overview of Sample Preparation and Chromatographic Methods to Analysis Pharmaceutical Active Compounds in Waters Matrices. Separations. 2021;8(2):16.

[82]. Waheed SA, Mustafa YF. The in vitro effects of new albocarbon-based coumarins on blood glucose-controlling enzymes. Journal of Medicinal and Chemical Sciences. 2022;5(6):954–67.

[83]. Habibi W, Talbi S, Hamri S, Hafid A, Khouili M. Coumarin Derivatives: Microwave Synthesis and Biological Properties—A Review. Journal of Heterocyclic Chemistry. 2024;61(12):2070–96.

[84]. Ahmed BA, Mustafa YF, Ibrahim BY. Isolation and characterization of furanocoumarins from Golden Delicious apple seeds. J Med Chem Sci. 2022;5:537–45.

[85]. Mustafa YF. Triple coumarin-based 5-fluorouracil prodrugs, their synthesis, characterization, and release kinetics. Journal of Molecular Structure. 2024;1301:137415.

[86]. 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.

[87]. Mustafa YF, Mohammed ET, Khalil RR. Antioxidant and antitumor activities of methanolic extracts obtained from Red Delicious and Granny Smith apples’ seeds. Systematic Reviews in Pharmacy. 2020;11(4):570–6.

[88]. Hjazi A, Nasir F, Noor R, Alsalamy A, Zabibah RS, Romero-Parra RM, Ullah MI, Mustafa YF, Qasim MT, Akram SV. The pathological role of C-X-C chemokine receptor type 4 (CXCR4) in colorectal cancer (CRC) progression; special focus on molecular mechanisms and possible therapeutics. Pathology - Research and Practice. 2023;248:154616.

[89]. Mattarozzi M, Laski E, Bertucci A, Giannetto M, Bianchi F, Zoani C, Careri M. Metrological traceability in process analytical technologies and point-of-need technologies for food safety and quality control: not a straightforward issue. Analytical and Bioanalytical Chemistry. 2023;415(1):119–35.

[90]. Al Abdeen SHZ, Mustafa YF, Mutlag SH. Synthesis and biomedical activities of novel multifunctional benzodipyrone-based derivatives. Eurasian Chemical Communications. 2022;4(10):938–49.

[91]. Sadybekov A V., Katritch V. Computational approaches streamlining drug discovery. Nature. 2023;616(7958):673–85.

[92]. Mustafa YF, Bashir MK, Oglah MK. Influence of albocarbon-cyclic hybridization on biomedical activities: A review. Journal of Medicinal and Chemical Sciences. 2022;5(4):518–35.

[93]. Firoozeh AZ, Bokov DO, Salahdin OD, Abdelbasset WK, Jawad MA, Kadhi MM, Qasim MT, Kzar HH, Al-Gazally ME, Mustafa YF, Khatami M. Cytotoxicity evaluation of environmentally friendly synthesis Copper/Zinc bimetallic nanoparticles on MCF‑7 cancer cells. Rendiconti Lincei Scienze Fisiche e Naturali. 2022;33:441–7.

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

[95]. Mushebenge AGA, Ugbaja SC, Mbatha NA, B. Khan R, Kumalo HM. Assessing the Potential Contribution of In Silico Studies in Discovering Drug Candidates That Interact with Various SARS-CoV-2 Receptors. International Journal of Molecular Sciences. 2023;24(21):15518.

[96]. Hammoodi SH, Ismael SS, Mustafa YF. Mutual prodrugs for colon targeting: A review. Eurasian Chemical Communications. 2022;4(12):1251–65.

[97]. Chen Z, Lu D, Cao J, Zhao F, Feng G, Xu C, Deng Y, Xiang X ‐D. Development of high‐throughput wet‐chemical synthesis techniques for material research. Materials Genome Engineering Advances. 2023;1(1):e5.

[98]. Mustafa YF. Effects of heat variables on the starch content of cooked white rice: Searching for diabetes-friendly food. Bioactive Carbohydrates and Dietary Fibre. 2024;31:100395.

[99]. Mustafa YF. Coumarins from carcinogenic phenol: synthesis, characterization, in silico, biosafety, anticancer, antioxidant, and anti-inflammatory assessments. Chemical Papers. 2024;78:493–504.

[100]. 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.

[101]. Bruno A, Costantino G, Sartori L, Radi M. The In Silico Drug Discovery Toolbox: Applications in Lead Discovery and Optimization. Current Medicinal Chemistry. 2019;26(21):3838–73.

[102]. Younes HA, Mustafa YF. Sweet Bell Pepper: A Focus on Its Nutritional Qualities and Illness‑Alleviated Properties. Indian Journal of Clinical Biochemistry. 2024;39:459–69.

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

[104]. Al Abdeen SHZ, Mustafa YF, Mutlag SH. Synthesis of disubstituted anisolodipyronederived ester compounds: The search for new bioactive candidates. Eurasian Chemical Communications. 2022;4(11):1171–83.

[105]. Kohlbacher SM, Langer T, Seidel T. QPHAR: quantitative pharmacophore activity relationship: method and validation. Journal of Cheminformatics. 2021;13(1):57.

[106]. Younes AH, Mustafa YF. Plant‐Derived Coumarins: A Narrative Review Of Their Structural And Biomedical Diversity. Chemistry & Biodiversity. 2024;21(6):e202400344.

[107]. Al-Mohaya M, Mesut B, Kurt A, Çelik YS. In silico approaches which are used in pharmacy. Journal of Applied Pharmaceutical Science. 2024;14(4):239–253.

[108]. 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.

[109]. Silva CAG da, Ramos FN, de Moraes RV, Santos EL dos. ChatGPT: Challenges and Benefits in Software Programming for Higher Education. Sustainability. 2024;16(3):1245.

[110]. Mustafa YF, Abdulaziz NT. Anticancer potential of hymecromone-based compounds: A review. Biochemical and Cellular Archives. 2021;21(2):4151–61.

[111]. Cattaneo I, Astuto MC, Binaglia M, Devos Y, Dorne JLCM, Fernandez Agudo A, Fernandez Dumont A, Garcia-Vello P, Kass GEN, Lanzoni A, Liem AKD, Panzarea M, Paraskevopulos K, Parra Morte JM, Tarazona J V., Terron A. Implementing New Approach Methodologies (NAMs) in food safety assessments: Strategic objectives and actions taken by the European Food Safety Authority. Trends in Food Science & Technology. 2023;133:277–90.

[112]. Abdulaziz NT, Mohammed ET, Khalil RR, Mustafa YF. Unrevealing the total phenols, total flavonoids, antioxidant, anti-inflammatory, and cytotoxic effects of Garden Cress seed ethanolic extracts. Review of Clinical Pharmacology and Pharmacokinetics - International Edition. 2024;38(2):187–96.

[113]. Mustafa YF. Emerging trends and future opportunities for coumarin-heterocycle conjugates as antibacterial agents. Results in Chemistry. 2023;6:101151.

[114]. 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.

[115]. Fatoki TH, Balogun TC, Ojewuyi AE, Omole AC, Olukayode OV, Adewumi AP, Umesi AJ, Ijeoma NP, Apooyin AE, Chinedu CP, Idowu IE, Isah MJ. In silico molecular targets, docking, dynamics simulation and physiologically based pharmacokinetics modeling of oritavancin. BMC Pharmacology and Toxicology. 2024;25(1):79.

[116]. Jibroo RN, Mustafa YF, Al-Shakarchi W. Heterocycles fused on a 6,7-coumarin framework: an in-depth review of their structural and pharmacological diversity. Chemical Papers. 2024;78:7239–7311.

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

[118]. Mustafa YF. Biocompatible chlorocoumarins from harmful chlorophenols, their synthesis and biomedicinal evaluation. Journal of Molecular Structure. 2024;1309:138193.

[119]. Mustafaa YF. New Coumarin-Metronidazole Composites: Synthesis, Biocompatibility, and Anti-anaerobic Bacterial Activity. Russian Journal of Bioorganic Chemistry. 2024;50(1):201–10.

[120]. Mustafa YF, Faisal AF, Alshaher MM, Hassan DA. Food-Derived Micronutrients as Alleviators of Age-Related Dysfunction: A Dive into Their Effects and Cellular Mechanisms. Indian Journal of Clinical Biochemistry. 2025; https://doi.org/10.1007/s12291-024-01297-7

[121]. Correia C, Ferreira A, Santos J, Lapa R, Yliperttula M, Urtti A, Vale N. New In Vitro-In Silico Approach for the Prediction of In Vivo Performance of Drug Combinations. Molecules. 2021;26(14):4257.

[122]. 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.

[123]. Fasano C, Lepore Signorile M, De Marco K, Forte G, Disciglio V, Sanese P, Grossi V, Simone C. In Silico Deciphering of the Potential Impact of Variants of Uncertain Significance in Hereditary Colorectal Cancer Syndromes. Cells. 2024;13(16):1314.

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

[125]. Lin X, Li X, Lin X. A Review on Applications of Computational Methods in Drug Screening and Design. Molecules. 2020;25(6):1375.

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

[127]. 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.

[128]. Faisal AF, Mustafa YF. The role of coumarin scaffold in the chemical engineering of bioactive molecules: A narrative review. Applied Chemical Engineering. 2025;8(1):5595.

[129]. Mustafa YF. Synthesis of 7,8-dihydroxy-4-phenylbenzo[g]coumarins as potential multitarget anti-skin-aging candidates. Journal of Molecular Structure. 2025;1321:139806.

[130]. Mustafa YF. Synthesis of novel 6-aminocoumarin derivatives as potential –biocompatible antimicrobial and anticancer agents. Journal of Molecular Structure. 2025;1320:139658.

[131]. Mustafa YF. 3-mercaptocoumarins as potential bioactive candidates: From novel synthesis to comparative analysis. Journal of Molecular Structure. 2025;1320:139657.

[132]. Mustafa YF, Hassan DA, Faisal AF, Alshaher MM. Synthesis of novel skipped diene-3-halocoumarin conjugates as potent anticancer and antibacterial biocompatible agents. Results in Chemistry. 2024;11:101846.

[133]. Laycock BG, Chan CM, Halley PJ. A review of computational approaches used in the modelling, design, and manufacturing of biodegradable and biobased polymers. Progress in Polymer Science. 2024;157:101874.

[134]. Çubukçu HC, Topcu Dİ, Yenice S. Machine learning-based clinical decision support using laboratory data. Clinical Chemistry and Laboratory Medicine (CCLM). 2024;62(5):793–823.

[135]. Hussein HK, Aubead NM, Kzar HH, Karim YS, Amin AH, Al-Gazally ME, Ahmed TI, Jawad MA, Hammid AT, Jalil AT, Mustafa YF, Saleh MM, Heydari H. Association of cord blood asprosin concentration with atherogenic lipid profile and anthropometric indices. Diabetology & Metabolic Syndrome. 2022;14(1):74.

[136]. Mohammed ET, Khalil RR, Mustafa YF. Phytochemical Analysis and Antimicrobial Evaluation of Quince Seeds’ Extracts. Journal of Medicinal and Chemical Sciences. 2022;5(6):968–79.

[137]. Nejres AM, Ali HK, Behnam SP, Mustafa YF. Potential effect of ammonium chloride on the optical physical properties of polyvinyl alcohol. Systematic Reviews in Pharmacy. 2020;11(6):726–32.

[138]. Jebir RM, Mustafa YF. Novel coumarins isolated from the seeds of Citrullus lanatus as potential antimicrobial agents. Eurasian Chemical Communications. 2022;4(8):692–708.

[139]. Doyle SE, Cazzola CN, Coleman CM. Design considerations when creating a high throughput screen-compatible in vitro model of osteogenesis. SLAS Discovery. 2024;29(7):100184.

[140]. Cometta S, Hutmacher DW, Chai L. In vitro models for studying implant-associated biofilms - A review from the perspective of bioengineering 3D microenvironments. Biomaterials. 2024;309:122578.

[141]. Jebir RM, Mustafa YF. Natural products catalog of allsweet watermelon seeds and evaluation of their novel coumarins as antimicrobial candidates. Journal of Medicinal and Chemical Sciences. 2022;5(5):831–47.

[142]. Son A, Park J, Kim W, Lee W, Yoon Y, Ji J, Kim H. Integrating Computational Design and Experimental Approaches for Next-Generation Biologics. Biomolecules. 2024;14(9):1073.

[143]. Adiyaman R, McGuffin LJ. Methods for the Refinement of Protein Structure 3D Models. International Journal of Molecular Sciences. 2019;20(9):2301.

[144]. Zeki NM, Mustafa YF. Coumarin hybrids: a sighting of their roles in drug targeting. Chemical Papers. 2024;78:5753–5772.

[145]. Pastorino P, Prearo M, Barceló D. Ethical principles and scientific advancements: In vitro, in silico, and non-vertebrate animal approaches for a green ecotoxicology. Green Analytical Chemistry. 2024;8:100096.

[146]. Zhu Q, Hattori S. Organic crystal structure prediction and its application to materials design. Journal of Materials Research. 2023;38(1):19–36.

[147]. Younes AH, Mustafa YF. Unveiling the Biomedical Applications of Novel Coumarins Isolated From Capsicum Annuum L. Seeds by a Multivariate Extraction Technique. Chemistry and Biodiversity. 2024;21(6):e202400581.

[148]. Younes AH, Mustafa YF. Novel coumarins from green sweet bell pepper seeds: Their isolation, characterization, oxidative stress-mitigating, anticancer, anti-inflammatory, and antidiabetic properties. Journal of Molecular Structure. 2024;1312:138629.

[149]. Yubero P, Lavin AA, Poyatos JF. The limitations of phenotype prediction in metabolism. Cannon W, editor. PLOS Computational Biology. 2023;19(11):e1011631.

[150]. Mustafa YF. Nutraceutical-based telomerase inhibitors: Renewed hope for cancer therapy. Phytomedicine Plus. 2024;4(2):100537.

[151]. Mustafa YF. 4-Chloroskimmetine-based derivatives as potential anticancer and antibacterial prospects: Their synthesis and in vitro inspections. Results in Chemistry. 2024;7:101511.

[152]. Pappalardo M, Sipala FM, Nicolosi MC, Guccione S, Ronsisvalle S. Recent Applications of In Silico Approaches for Studying Receptor Mutations Associated with Human Pathologies. Molecules. 2024;29(22):5349.

[153]. Zeki NM, Mustafa YF. Novel heterocyclic coumarin annulates: synthesis and figuring their roles in biomedicine, bench-to-bedside investigation. Chemical Papers. 2024;78:4935–51.

[154]. Some Experimental Studies on the Anticoagulant Activity of the Synthetic Coumarin Derivatives. Jordan Journal of Biological Sciences. 2022;15(04):643–7.

[155]. 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.

[156]. Mustafa YF. Chemotherapeutic applications of folate prodrugs: A review. NeuroQuantology. 2021;19(8):99–112.

[157]. Zamanian MY, Parra RMR, Soltani A, Kujawska M, Mustafa YF, Raheem G, Al-Awsi L, Lafta HA, Taheri N, Heidari M, Golmohammadi M, Bazmandegan G. Targeting Nrf2 signaling pathway and oxidative stress by resveratrol for Parkinson’s disease: an overview and update on new developments. Molecular Biology Reports. 2023;50:5455–5464.

[158]. Waheed SA, Mustafa YF. Synthesis and evaluation of new coumarins as antitumor and antioxidant applicants. Journal of Medicinal and Chemical Sciences. 2022;5(5):808–19.

[159]. Abdulaziz NT, Al-bazzaz FY, Mustafa YF. Natural products for attenuating Alzheimer’s disease: A narrative review. Eurasian Chemical Communications. 2023;5(4):358–70.

[160]. Bala MM, Celinska-Lowenhoff M, Szot W, Padjas A, Kaczmarczyk M, Swierz MJ, Undas A. Antiplatelet and anticoagulant agents for secondary prevention of stroke and other thromboembolic events in people with antiphospholipid syndrome. Cochrane Database of Systematic Reviews. 2020;2020(10):CD012169.

[161]. Murata Y, Neuhoff S, Rostami-Hodjegan A, Takita H, Al-Majdoub ZM, Ogungbenro K. In Vitro to In Vivo Extrapolation Linked to Physiologically Based Pharmacokinetic Models for Assessing the Brain Drug Disposition. The AAPS Journal. 2022;24(1):28.

[162]. Singh AV, Chandrasekar V, Paudel N, Laux P, Luch A, Gemmati D, Tisato V, Prabhu KS, Uddin S, Dakua SP. Integrative toxicogenomics: Advancing precision medicine and toxicology through artificial intelligence and OMICs technology. Biomedicine & Pharmacotherapy. 2023;163:114784.

[163]. Mustafa YF. Combretastatin A4-based coumarins: synthesis, anticancer, oxidative stress-relieving, anti-inflammatory, biosafety, and in silico analysis. Chemical Papers. 2024;78:3705–3720.

[164]. Zeki NM, Mustafa YF. 6,7-Coumarin-heterocyclic hybrids: A comprehensive review of their natural sources, synthetic approaches, and bioactivity. Journal of Molecular Structure. 2024;1303:137601.

[165]. Gomes AFT, de Medeiros WF, Medeiros I, Piuvezam G, da Silva-Maia JK, Bezerra IWL, Morais AH de A. In Silico Screening of Therapeutic Targets as a Tool to Optimize the Development of Drugs and Nutraceuticals in the Treatment of Diabetes mellitus: A Systematic Review. International Journal of Molecular Sciences. 2024;25(17):9213.

[166]. Hossam Abdelmonem B, Abdelaal NM, Anwer EKE, Rashwan AA, Hussein MA, Ahmed YF, Khashana R, Hanna MM, Abdelnaser A. Decoding the Role of CYP450 Enzymes in Metabolism and Disease: A Comprehensive Review. Biomedicines. 2024;12(7):1467.

[167]. McNamara PJ, Meiman D. Predicting Drug Binding to Human Serum Albumin and Alpha One Acid Glycoprotein in Diseased and Age Patient Populations. Journal of Pharmaceutical Sciences. 2019;108(8):2737–47.

[168]. Shahpouri P, Mehralitabar H, Kheirabadi M, Kazemi Noureini S. Potential suppression of multidrug-resistance-associated protein 1 by coumarin derivatives: an insight from molecular docking and MD simulation studies. Journal of Biomolecular Structure and Dynamics. 2024;42(17):9184–200.

[169]. Tincu (Iurciuc) CE, Andrițoiu CV, Popa M, Ochiuz L. Recent Advancements and Strategies for Overcoming the Blood–Brain Barrier Using Albumin-Based Drug Delivery Systems to Treat Brain Cancer, with a Focus on Glioblastoma. Polymers. 2023;15(19):3969.

[170]. Zeki NM, Mustafa YF. Annulated Heterocyclic[g]Coumarin Composites: Synthetic Approaches and Bioactive Profiling. Chemistry and Biodiversity. 2024;21(3):e202301855.

[171]. Zeki NM, Mustafa YF. Coumarin hybrids for targeted therapies: A promising approach for potential drug candidates. Phytochemistry Letters. 2024;60:117–33.

[172]. Mustafa YF. Coumarins derived from natural methoxystilbene as oxidative stress-related disease alleviators: Synthesis and in vitro-in silico study. Journal of Molecular Structure. 2024;1302:137471.

[173]. Jibroo RN, Mustafa YF, Al-Shakarchi W. Synthesis and evaluation of linearly fused thiadiazolocoumarins as prospects with broad-spectrum bioactivity. Results in Chemistry. 2024;7:101494.

[174]. Faisal AF, Mustafa YF. Chili pepper: A delve into its nutritional values and roles in food-based therapy. Food Chemistry Advances. 2025;6:100928.

[175]. Faisal AF, Mustafa YF. The Multifaceted Chemistry of Chili Peppers: A Biodiversity Treasure for Nutrition and Biomedicine. Chemistry & Biodiversity. 2025; https://doi.org/10.1002/cbdv.202402690

[176]. Zeki NM, Mustafa YF. Synthesis of Novel Dioxathiole-6,7-coumarin Hybrids As Cytosafe-Multifunctional Applicants: An In Vitro—In Silico Study. Russian Journal of Bioorganic Chemistry. 2024;50(5):2076–91.

[177]. Oprea TI, Weininger D. Rethinking Medicinal Chemistry in the Cheminformatics Age. Journal of Medicinal Chemistry. 2024;67(20):17935–9.

[178]. Jibroo RN, Mustafa YF. Linearly ring-fused coumarins: A review of their cancer-fighting attributes. Results in Chemistry. 2024;8:101611.

[179]. 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.