Abstract
This study revealed the first synthesis of seven novel coumarins annulated with heterocycle composed of four heteroatoms, one sulfur, and three oxygen atoms in a linear pattern. This is an effort to find readily available coumarin frameworks with a broad variety of biological properties that are both adjustable and easy to get. The synthetic annulates' structural framework was confirmed by means of spectroscopic techniques, which included 1H-NMR, 13C-NMR, and FTIR. The synthesized annulates were investigated in vitro for their biomedical potential as antioxidative stress, anti-inflammatory, antidiabetic, anticancer, and antimicrobial agents. In addition, their biosafety toward nontumor cells and commensal bacterial strains was also assessed in vitro. Computer-aided programs were employed to explore the toxicity and pharmacokinetic profiles of the synthesized annulates. Based on the findings that were obtained, the authors stated the following main outcomes. There have been promising and far-reaching biological effects of the synthesized heterocyclic coumarin annulates. HC1 demonstrated strong anti-inflammatory potential through the lipoxygenase-dependent route. Moreover, HC1 exhibited significant antifungal efficacy, surpassing that of nystatin. HC2 held great promise as an antioxidative stress, anticancer, and biosafe candidate. HC3 exhibited a strong antibacterial potential against all tested aerobic bacterial strains, demonstrating a potency equivalent to that of ciprofloxacin. In addition, all of the synthesized annulates, especially HC3, exhibited a noteworthy biosafety profile against the commensal bacterial strains. The strong inhibitory capabilities of HC6 and HC7 toward glucosidase and amylase indicate that they possess great promise as antidiabetic agents. Finally, the synthesized annulates showed favorable toxicity and oral bioavailability properties. It can be inferred that these annulates have the potential to be useful frameworks for developing new drugs with a broad spectrum of bioactivity in the coming years.
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References
Abdelbasset WK, Jasim SA, Sharma SK, Margiana R, Bokov DO, Obaid MA et al (2022) Alginate-based hydrogels and tubes, as biological macromolecule-based platforms for peripheral nerve tissue engineering: a review. Ann Biomed Eng 50(6):628–653
Abdulaziz NT, Mustafa YF (2022) Antibacterial and antitumor potentials of some novel coumarins. Int J Drug Deliv Technol 12(1):239–247
Ahmed K, Choudhary MI, Saleem RSZ (2023) Heterocyclic pyrimidine derivatives as promising antibacterial agents. Eur J Med Chem 259:115701
Al Abdeen SHZ, Mustafa YF, Mutlag SH (2022) Synthesis and biomedical activities of novel multifunctional benzodipyrone-based derivatives. Eurasian Chem Commun 4(10):938–949
Alheety KA, Jamel NM, Ahmed BJ (2019) Synthesis of coumarin by pechman reaction—a review. J Pharm Sci Res 11(9):3344–3347
Al-Jumaili MHA, Hamad AA, Hashem HE, Hussein AD, Muhaidi MJ, Ahmed MA et al (2023) Comprehensive review on the Bis–heterocyclic compounds and their anticancer efficacy. J Mol Struct 1271:133970
Amin KM, Eissa AAM, Abou-Seri SM, Awadallah FM, Hassan GS (2013) Synthesis and biological evaluation of novel coumarin-pyrazoline hybrids endowed with phenylsulfonyl moiety as antitumor agents. Eur J Med Chem 60:187–198
Artursson P, Palm K, Luthman K (2012) Caco-2 monolayers in experimental and theoretical predictions of drug transport. Adv Drug Deliv Rev 64:280–289
Atia YA, Bokov DO, Zinnatullovich KR, Kadhim MM, Suksatan W, Abdelbasset WK et al (2022) The role of amino acid functionalization for improvement of adsorption Thioguanine anticancer drugs on the boron nitride nanotubes for drug delivery. Mater Chem Phys 278:125664
Benet LZ, Hosey CM, Ursu O, Oprea TI (2016) BDDCS, the rule of 5 and drugability. Adv Drug Deliv Rev 101:89–98
Bhimani B, Patel A, Shah D (2024) An update on recent green synthetic approaches to coumarins. Mini-Rev Org Chem 21(1):22–39
Choi J, Yoo MJ, Park SY, Seol JW (2023) Antitumor effects of esculetin, a natural coumarin derivative, against canine mammary gland tumor cells by inducing cell cycle arrest and apoptosis. Vet Sci 10(2):84
Clark DE (2011) What has polar surface area ever done for drug discovery? Future Med Chem 3(4):469–484
Erhirhie EO, Ihekwereme CP, Ilodigwe EE (2018) Advances in acute toxicity testing: strengths, weaknesses and regulatory acceptance. Interdiscip Toxicol 11(1):5–12
Flores-Morales V, Villasana-Ruíz AP, Garza-Veloz I, González-Delgado S, Martinez-Fierro ML (2023) Therapeutic effects of coumarins with different substitution patterns. Molecules 28(5):2413
Gangopadhyay A (2023) Plant-derived natural coumarins with anticancer potentials: future and challenges. J Herb Med 42:100797
Ghany LMAA, Beshay BY, Youssef Moustafa AM, Maghrabi AHA, Ali EHK, Saleem RM et al (2023) Design, synthesis, anti-inflammatory evaluation, and molecular modelling of new coumarin-based analogs combined curcumin and other heterocycles as potential TNF-α production inhibitors via upregulating Nrf2/HO-1, downregulating AKT/mTOR signalling pathway. J Enzyme Inhib Med Chem 38(1):2243551
Hussein HK, Aubead M, Kzar HH, Karim YS, Amin AH, Al-Gazally ME et al (2022) Association of cord blood asprosin concentration with atherogenic lipid profile and anthropometric indices. Diabetol Metab Syndr 14:74
Ismael RN, Mustafa YF, Al-Qazaz HK (2022) Cancer-curative potential of novel coumarins from watermelon princess : a scenario of their isolation and activity. Eurasian Chem Commun 4(7):657–672
Ismael SS, Waheed NAM, Kasim SM, Mustafa YF (2023) Novel coumarin-indole hybrids as cytotoxic candidates : synthesis and antiproliferative activity. Pharmacognosy J 15(6):1105–1111
Jamalis J, Yusof FSM, Chander S, Wahab RA, P Bhagwat D, Sankaranarayanan M et al (2020) Psoralen derivatives: recent advances of synthetic strategy and pharmacological properties. Anti-Inflamm Anti-Allergy Agents Med Chem 19(3):222–239
Jasim SF, Mustafa YF (2022a) Synthesis and antidiabetic assessment of new coumarin-disubstituted benzene conjugates: an in silico-in virto study. J Med Chem Sci 5(6):887–899
Jasim SF, Mustafa YF (2022b) Synthesis, ADME study, and antimicrobial evaluation of novel naphthalene-based derivatives. J Med Chem Sci 5(5):793–807
Jiang C, Guo J, Wang Z, Xiao B, Lee HJ, Lee EO et al (2007) Decursin and decursinol angelate inhibit estrogen-stimulated and estrogen-independent growth and survival of breast cancer cells. Breast Cancer Res 9(6):1–12
Jumintono J, Alkubaisy S, Yánez Silva D, Singh K, Turki Jalil A, Mutia Syarifah S et al (2021) Effect of cystamine on sperm and antioxidant parameters of ram semen stored at 4 °C for 50 hours. Arch Razi Inst 76(4):981–989
Kamel NN, Aly HF, Fouad GI, Abd El-Karim SS, Anwar MM, Syam YM et al (2023) Anti-Alzheimer activity of new coumarin-based derivatives targeting acetylcholinesterase inhibition. RSC Adv 13(27):18496–18510
Karthikeyan S, Grishina M, Kandasamy S, Mangaiyarkarasi R, Ramamoorthi A, Chinnathambi S, Pandian GN, John Kennedy L (2023) A review on medicinally important heterocyclic compounds and importance of biophysical approach of underlying the insight mechanism in biological environment. J Biomol Struct Dyn 41(23):14599–14619
Kasim SM, Abdulaziz NT, Mustafa YF (2022) Synthesis and biomedical activities of coumarins derived from natural phenolic acids. J Med Chem Sci 5(4):546–560
Kecel-Gunduz S, Budama-Kilinc Y, Bicak B, Gok B, Belmen B, Aydogan F, et al (2023) New coumarin derivative with potential antioxidant activity: synthesis, DNA binding and in silico studies (Docking, MD, ADMET). Arabian J Chem 16(2):104440
Khalil RR, Mohammed ET, Mustafa YF (2022) Evaluation of in vitro antioxidant and antidiabetic properties of Cydonia Oblonga seeds’ extracts. J Med Chem Sci 5(6):1048–1058
Kosikowska U, Wujec M, Trotsko N, Płonka W, Paneth P, Paneth A (2020) Antibacterial activity of fluorobenzoylthiosemicarbazides and their cyclic analogues with 1,2,4-triazole scaffold. Molecules (basel, Switzerland) 26(1):1–18
Kumar R, Singh H, Mazumder A, Salahuddin, Yadav RK (2023) Synthetic approaches, biological activities, and structure-activity relationship of pyrazolines and related derivatives. Top Curr Chem (cham) 381(3):12
Lam TP, Tran NVN, Pham LHD, Lai NVT, Dang BTN, Truong NLN et al (2024) Flavonoids as dual-target inhibitors against α-glucosidase and α-amylase: a systematic review of in vitro studies. Nat Prod Bioprospecting 14(1):4
Li X, Chen A, Zhou Y, Huang L, Fang Z, Gan H et al (2015) Two-stage flow synthesis of coumarin via O-acetylation of salicylaldehyde. Journal of Flow Chemistry 5(2):82–86
Maideen NMP (2019) Drug interactions of dipeptidyl peptidase 4 inhibitors involving CYP enzymes and P-gp efflux pump. World J Meta-Anal 7(4):156–161
Medina FG, Marrero JG, Macías-Alonso M, González MC, Córdova-Guerrero I, Teissier García AG et al (2015) Coumarin heterocyclic derivatives: chemical synthesis and biological activity. Nat Prod Rep 32(10):1472–1507
Mirghani R, Saba T, Khaliq H, Mitchell J, Do L, Chambi L et al (2022) Biofilms: formation, drug resistance and alternatives to conventional approaches. AIMS Microbiol 8(3):240–278
Molchanova N, Nielsen JE, Sørensen KB, Prabhala BK, Hansen PR, Lund R et al (2020) Halogenation as a tool to tune antimicrobial activity of peptoids. Sci Rep 10(1):1–10
Mustafa YF (2023a) Emerging trends and future opportunities for coumarin-heterocycle conjugates as antibacterial agents. Res Chem 6:101151
Mustafa YF (2023c) Synthesis, characterization, and biomedical assessment of novel bisimidazole–coumarin conjugates. Appl Nanosci (switzerland) 13:1907–1918
Mustafa YF (2023e) Modern developments in the application and function of metal/metal oxide nanocomposite-based antibacterial agents. BioNanoScience 13:840–852
Mustafa YF (2024a) Triple coumarin-based 5-fluorouracil prodrugs, their synthesis, characterization, and release kinetics. J Mol Struct 1301:137415
Mustafa YF (2024b) Coumarins derived from natural methoxystilbene as oxidative stress-related disease alleviators: synthesis and in vitro-in silico study. J Mol Struct 1302:137471
Mustafa YF (2024c) Synthesis, in silico analysis, and biomedical effects of coumarins derived from resveratrol. Phytomedicine plus 3(4):100501
Mustafa YF (2024d) Coumarins from carcinogenic phenol: synthesis, characterization, in silico, biosafety, anticancer, antioxidant, and anti-inflammatory assessments. Chem Pap 78:493–504
Mustafa YF, Oglah MK, Bashir MK, Mohammed ET, Khalil RR (2021) Mutual prodrug of 5-ethynyluracil and 5-fluorouracil: synthesis and pharmacokinetic profile. Clin Schizophr Relat Psychoses 15(5):1–6
Mustafa YF, Kasim SM, Al-Dabbagh BM, Al-Shakarchi W (2023a) Synthesis, characterization and biological evaluation of new azo-coumarinic derivatives. Appl Nanosci (switzerland) 13:1095–1102
Mustafa YF, Zain Al-Abdeen SH, Khalil RR, Mohammed ET (2023b) Novel functionalized phenyl acetate derivatives of benzo [e]-bispyrone fused hybrids: synthesis and biological activities. Results in Chemistry 5:100942
Mustafa YF, Ismael RN, Jebir RM (2024) Natural coumarins from two cultivars of watermelon seeds as biosafe anticancer agents, an algorithm for their isolation and evaluation. J Mol Struct 1295(P1):136644
Mustafa YF (2024a) Harmful free radicals in aging: a narrative review of their detrimental effects on health. Indian J Clin Biochem 39(2):154-167
Mustafa YF (2024b) Combretastatin A4–based coumarins: synthesis, anticancer, oxidative stress–relieving, anti–inflammatory, biosafety, and in silico analysis. Chem Pap. https://doi.org/10.1007/s11696-024-03341-5
Naik NS, Shastri LA, Joshi SD, Dixit SR, Chougala BM, Samundeeswari S et al (2017) 3,4-Dihydropyrimidinone-coumarin analogues as a new class of selective agent against S. aureus: synthesis, biological evaluation and molecular modelling study. Bioorganic Med Chem 25(4):1413–1422
Nguyen HT, Vu TY, Chandi V, Polimati H, Tatipamula VB (2020) Dual COX and 5-LOX inhibition by clerodane diterpenes from seeds of Polyalthia longifolia (Sonn.) Thwaites. Scientific Rep 10(1):1–10
Oglah MK, Mustafa YF (2020) Synthesis, antioxidant, and preliminary antitumor activities of new curcumin analogues. J Glob Pharma Technol 12(2):854–862
Oglah MK, Kahtan Bashir M, Fakri Mustafa Y, Mohammed ET, Khalil RR (2020) Synthesis and biological activities of 3,5-disubstituted-4-hydroxycinnamic acids linked to a functionalized coumarin. Syst Rev Pharm 11(6):717–725
Patra P (2022) A short review on the synthesis of pyrrolo[3,4-c ]coumarins an isolamellarin-B scaffolds. Synth Commun 52(21):1999–2018
Potapov AY, Paponov BV, Podoplelova NA, Panteleev MA, Potapov MA, Ledenyova IV et al (2021) Synthesis of 2H-pyrano[3,2-g]quinolin-2-ones containing a pyrimidinone moiety and characterization of their anticoagulant activity via inhibition of blood coagulation factors Xa and XIa. Chem Heterocycl Compd 57(5):574–580
Prasanna S, Doerksen R (2009) Topological polar surface area: a useful descriptor in 2D-QSAR. Curr Med Chem 16(1):21–41
Prateeptongkum S, Mahavorasirikul W, Duangdee N (2018) Synthesis and anti-proliferative activity of novel oxepin-annulated coumarins. ARKIVOC 2018(7):73–85
Ramsis TM, Ebrahim MA, Fayed EA (2023) Synthetic coumarin derivatives with anticoagulation and antiplatelet aggregation inhibitory effects. Med Chem Res 32(9):2269–2278
Ransy C, Vaz C, Lombès A, Bouillaud F (2020) Use of H2O2 to cause oxidative stress, the catalase issue. Int J Mol Sci 21(23):9149
Rim KT (2020) In silico prediction of toxicity and its applications for chemicals at work. Toxicol Environ Heal Sci 12(3):191–202
Rioux B, Mention MM, Alarcan J, Abiola TT, Peyrot C, Brunissen F et al (2022) Sustainable synthesis, in silico evaluation of potential toxicity and environmental fate, antioxidant and UV-filtering/photostability activity of phenolic-based thiobarbituric derivatives. Green Chem Lett Rev 15(1):116–127
Roomi AB, Widjaja G, Savitri D, Jalil AT, Mustafa YF, Thangavelu L et al (2021) SnO2:Au/Carbon quantum dots nanocomposites: synthesis, characterization, and antibacterial activity. J Nanostruct 11(3):514–523
Shinada NK, de Brevern AG, Schmidtke P (2019) Halogens in protein–ligand binding mechanism: a structural perspective. J Med Chem 62(21):9341–9356
Tiwari R, Mishra S, Danaboina G, Pratap Singh Jadaun G, Kalaivani M, Kalaiselvan V et al (2023) Comprehensive chemo-profiling of coumarins enriched extract derived from Aegle marmelos (L.) Correa fruit pulp, as an anti-diabetic and anti-inflammatory agent. Saudi Pharmaceutical J 31(9):101708
Trainor GL (2007) The importance of plasma protein binding in drug discovery. Expert Opin Drug Discov 2(1):51–64
Vlachou EN, Armatas GS, Litinas KE (2017) Synthesis of Fused Oxazolocoumarins from o—Hydroxynitrocoumarins and Benzyl Alcohol Under Gold Nanoparticles or FeCl 3 Catalysis. J Heterocycl Chem 54(4):2447–2453
Waheed SA, Mustafa YF (2022) Synthesis and evaluation of new coumarins as antitumor and antioxidant applicants. Journal of Medicinal and Chemical Sciences 5(5):808–819
Waheed SA, Mustafaa YF (2022) Novel naphthalene-derived coumarin composites: synthesis, antibacterial, and antifungal activity assessments. Eurasian Chem Commun 4(8):709–724
Wei Z (2001) Neurotoxicology of the brain barrier system: new implications. J Toxicol Clin Toxicol 39(7):711–719
Widjaja G, Doewes RI, Rudiansyah M, Sultan MQ, Ansari MJ, Izzat SE et al (2022) Effect of tomato consumption on inflammatory markers in health and disease status: a systematic review and meta-analysis of clinical trials. Clin Nutr ESPEN 50:93–100
Yang XC, Zeng CM, Avula SR, Peng XM, Geng RX, Zhou CH (2023) Novel coumarin aminophosphonates as potential multitargeting antibacterial agents against Staphylococcus aureus. Eur J Med Chem 245:114891
Zeki NM, Mustafa YF (2023) Synthesis and pharmacological profiles of 6,7-dihydroxycoumarin and its derivatives: a concise review. Iraqi J Pharm 20(Supplementary Issue 1):174–188
Zeki NM, Mustafa YF (2024) Annulated heterocyclic[g]coumarin composites: synthetic approaches and bioactive profiling. Chem Biodivers 21(3):202301855
Zeki NM, Mustafa YF (2024a) Coumarin hybrids for targeted therapies: a promising approach for potential drug candidates. Phytochem Lett 60:117–133
Zeki NM, Mustafa YF (2024b) 6,7-Coumarin-heterocyclic hybrids: a comprehensive review of their natural sources, synthetic approaches, and bioactivity. J Mol Struct 1303:137601
Zhou ZW, Zhou SF (2009) Application of mechanism-based CYP inhibition for predicting drug–drug interactions. Expert Opin Drug Metab Toxicol 5(6):579–605
Zhou S, Zhao FL, Wang SH, Wang YR, Hong Y, Zhou Q et al (2023) Assessments of CYP-inhibition-based drug–drug interaction between vonoprazan and poziotinib in vitro and in vivo. Pharm Biol 61(1):356–361
Zi Y, Zhu M, Li X, Xu Y, Wei H, Li D et al (2018) Effects of carboxyl and aldehyde groups on the antibacterial activity of oxidized amylose. Carbohyd Polym 192:118–125
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Zeki, N.M., Mustafa, Y.F. Novel heterocyclic coumarin annulates: synthesis and figuring their roles in biomedicine, bench-to-bedside investigation. Chem. Pap. (2024). https://doi.org/10.1007/s11696-024-03441-2
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DOI: https://doi.org/10.1007/s11696-024-03441-2