Exploration of Chalcones as Antimicrobial agents: Synthesis, Characterization, Antimicrobial Evaluation and Molecular Docking studies Synthesis , charactrization , antimicirobial and docking evaluation of some new chalcones
Iranian Journal of Pharmaceutical Sciences,
Vol. 21 No. 1 (2025),
21 Bahman 2025
,
Page 430-447
https://doi.org/10.22037/ijps.v21i1.46927
Abstract
Although many medications are available to treat infectious infections, their therapeutic efficacy is hampered by systemic toxicities, drug resistance, hypersensitivity, and a narrow antibacterial spectrum. Based on the above facts, we synthesized and evaluated some new chalcones' antibacterial and antifungal properties. A group of natural compounds called chalcones has a broad spectrum of biological activity. The Claisen-Schmidt condensation of 4-tert-butyl-2,6-dimethyl-3,5-dinitro acetophenone with a variety of substituted aromatic and heteroaromatic aldehydes yielded some new chalcones with different substituents in consideration of the wide range of biological activities related to chalcones. Column chromatography and recrystallization techniques were used to purify the produced chalcones. IR, 1H NMR, and elemental analysis data characterized the purified chalcones. These substances underwent additional testing for antimicrobial activity using the serial tube dilution technique. Antibacterial testing revealed potent activity for chalcones R1, R5, R6, and R18 (MIC: 32 µg/mL), attributed to electron-withdrawing groups like dichloro, nitro, and difluoro substituents. Antifungal studies identified R1, R3, and R18 as the most effective (MIC: 16 µg/mL against Aspergillus niger and Candida tropicalis), with SAR analysis emphasizing the roles of halogens and methoxy groups in enhancing activity. Quality evaluation of the protein PDB: 4AMV confirmed its suitability for molecular docking studies using the SAVES server and binding pocket analysis using CASTp and BIOVIA Discovery studio. Docking of chalcones against PDB: 4AMV using Auto Dock Vina module of PyRx 0.8 revealed binding affinities ranging from −7.2 to −8.4 kcal/mol, with ciprofloxacin (standard) showing −8.3 kcal/mol. Chalcone R6 exhibited the greatest affinity for binding (-8.4 kcal/mol) and robust interactions, including hydrogen bonds and hydrophobic contacts. R1, R5, and R9 also demonstrated significant affinities (−8.2 to −8.0 kcal/mol). These findings highlight chalcones, particularly R6, as promising candidates for further antimicrobial development.
- Chalcones
- Claisen-Shmidt reaction
- Antimicrobial Evaluation
- Molecular Docking
How to Cite
References
1. Richard JF, Yitzhak T. Antibiotics and bacterial resistance in the 21st century. Perspect Med Chem. 2014; 6:S14459.
2. Halling-Sørensen B. Inhibition of aerobic growth and nitrification of bacteria in sewage sludge by antibacterial agents. Arch Environ Contam Toxicol. 2001; 40:451–60.
3. Harish C, Parul B, Archana Y, Babita P, Abhay PM, Anant RN. Antimicrobial resistance and the alternative resources with special emphasis on plant-based antimicrobials—a review. Plants. 2017; 6:16.
4. Francesca P, Patrizio P, Annalisa P. Antimicrobial resistance: A global multifaceted phenomenon. Pathog Glob Health. 2015; 109:309–18.
5. Bingyun L, Thomas JW. Bacteria antibiotic resistance: New challenges and opportunities for implant-associated orthopedic infections. J Orthop Res. 2018; 36:22–32.
6. U.S. Food and Drug Administration. Novel Drug Approvals for 2017. Available from: https://www.fda.gov/drugs/new-drugs-fda-cdersnew-molecular-entities-and-new-therapeutic-biological-products/novel-drug-approvals-2017
7. U.S. Food and Drug Administration. Novel Drug Approvals for 2018. Available from: https://www.fda.gov/drugs/new-drugs-fda-cdersnew-molecular-entities-and-new-therapeutic-biological-products/novel-drug-approvals-2018
8. Wang W, Sun Q. Novel targeted drugs approved by the NMPA and FDA in 2019. Signal Transduct Target Ther. 2020;5(65):1–4.
9. Nurken B, Mohamad A. An overview of drug discovery and development. Future Med Chem. 2020; 12:939–47.
10. Alam MS, Rahman SM, Lee DU. Synthesis, biological evaluation, quantitative-SAR, and docking studies of novel chalcone derivatives as antibacterial and antioxidant agents. Chem Pap. 2015; 69(8):1118–29. https://doi.org/10.1515/chempap-2015-0113
11. Singh P, Anand A, Kumar V. Recent developments in biological activities of chalcones: A mini review. Eur J Med Chem. 2014; 85:758–77. DOI:10.1016/j.ejmech.2014.08.033.
12. Wadleigh RW, Yu SJ. Glutathione transferase activity of fall armyworm larvae toward α, β-unsaturated carbonyl allelochemicals and its induction by allelochemicals. Insect Biochem. 1987; 17(5):759–64. DOI: 10.1016/0020-1790(87)90046-1.
13. Karthikeyan C, Narayana Moorthy NSH, Ramasamy S, Vanam U, Manivannan E, Karunagaran D, et al. Advances in chalcones with anticancer activities. Recent Pat Anticancer Drug Discov. 2014; 10(1):97–115. DOI: 10.2174/1574892809666140819153902.
14. Dhar K, Saxena A, Kumar S, Sapra S, Sweety, Nepali K, et al. Synthesis and biological evaluation of chalcones having heterosubstituent(s). Indian J Pharm Sci. 2010; 72(6):801. DOI:10.4103/0250-474X.84602.
15. Ninomiya M, Koketsu M. In: Ramawat KG, editor. Natural Products. Berlin: Springer Verlag; 2013.
16. Okolo EN, Ugwu DI, Ezema BE, Ndefo JC, Eze FU, Ezema CG, et al. New chalcone derivatives as potential antimicrobial and antioxidant agents. Sci Rep. 2021; 11:21871. DOI: 10.1038/s41598-021-01292-5.
17. Henry EJ, Bird SJ, Gowland P, Collins M, Cassella JP. Ferrocenyl chalcone derivatives as possible antimicrobial agents. J Antibiot. 2020; 73(5):299–308. DOI: 10.1038/s41429-020-0280-y.
18. Benouda H, Bouchal B, Challioui A, Oulmidi A, Harit T, Malek F, et al. Synthesis of a series of chalcones and related flavones and evaluation of their antibacterial and antifungal activities. Lett Drug Des Discov. 2018; 16(1):93–100. DOI: 10.2174/1570180815666180404130430.
19. ur Rashid H, Xu Y, Ahmad N, Muhammad Y, Wang L. Promising anti-inflammatory effects of chalcones via inhibition of cyclooxygenase, prostaglandin E2, inducible NO synthase and nuclear factor KB activities. Bioorg Chem. 2019; 87:335–65. DOI:10.1016/j.bioorg.2019.03.033.
20. Nurkenov O, Ibraev M, Schepetkin I, Khlebnikov A, Seilkhanov T, Arinova A, et al. Synthesis, structure, and anti-inflammatory activity of functionally substituted chalcones and their derivatives. Russ J Gen Chem. 2019;89(7):1360–7. DOI: 10.1134/S1070363219070028.
21. Ibrahim TS, Moustafa AH, Almalki AJ, Allam RM, Althagafi A, Md S, et al. Novel chalcone/aryl carboximidamide hybrids as potent anti-inflammatory agents via inhibition of prostaglandin E2 and inducible NO synthase activities: design, synthesis, molecular docking studies and ADMET prediction. J Enzyme Inhib Med Chem. 2021; 36(1):1067–78. DOI:10.1080/14756366.2021.1929201.
22. Lakshminarayanan B, Kannappan N, Subburaju T. Synthesis and biological evaluation of novel chalcones with methanesulfonyl end as potent analgesic and anti-inflammatory agents. Int J Pharm Res Biosci. 2020;11(10):4974–81. DOI:10.13040/IJPSR.0975-8232.11 (10).4974-81.
23. Higgs J, Wasowski C, Marcos A, Jukič M, Paván CH, Gobec S, et al. Chalcone derivatives: synthesis, in vitro and in vivo evaluation of their anti-anxiety, anti-depression and analgesic effects. Heliyon. 2019; 5(3):e01376. DOI:10.1016/j.heliyon.2019.e01376.
24. Murtaza S, Mir KZ, Tatheer A, Ullah RS. Synthesis and evaluation of chalcone and its derivatives as potential anticholinergic agents. Lett Drug Des Discov. 2019; 16(3):322–32. DOI: 10.2174/1570180815666180523085436.
25. Fakhrudin N, Pertiwi KK, Takubessi MI, Susiani EF, Nurrochmad A, Widyarini S, et al. A geranylated chalcone with antiplatelet activity from the leaves of breadfruit (Artocarpus altilis). Pharmacia. 2020;67:173. DOI:10.3897/pharmacia.67.e56788.
26. Choudhary AN, Kumar A, Juy V. Design, synthesis and evaluation of chalcone derivatives as anti-inflammatory, antioxidant and antiulcer agents. Lett Drug Des Discov. 2012; 9(5):479–88. DOI: 10.2174/157018012800389368.
27. Bale AT, Salar U, Khan KM, Chigurupati S, Fasina T, Ali F, et al. Chalcones and bis-chalcone analogs as DPPH and ABTS radical scavengers. Lett Drug Des Discov. 2021; 18(3):249–57. DOI: 10.2174/1570180817999201001155032.
28. Al Zahrani NA, El-Shishtawy RM, Elaasser MM, Asiri AM. Synthesis of novel chalcone-based phenothiazine derivatives as antioxidant and anticancer agents. Molecules. 2020; 25(19):4566. DOI: 10.3390/molecules25194566.
29. Qin HL, Zhang ZW, Lekkala R, Alsulami H, Rakesh K. Chalcone hybrids as privileged scaffolds in antimalarial drug discovery: a key review. Eur J Med Chem. 2020; 193:112215. DOI:10.1016/j.ejmech.2020.112215.
30. Ouyang Y, Li J, Chen X, Fu X, Sun S, Wu Q. Chalcone derivatives: role in anticancer therapy. Biomolecules. 2021;11(6):894. DOI: 10.3390/biom11060894.
31. Čižmáriková M, Takáč P, Spengler G, Kincses A, Nové M, Vilková M, et al. New chalcone derivative inhibits ABCB1 in multidrug-resistant T-cell lymphoma and colon adenocarcinoma cells. Anticancer Res. 2019;39(12):6499–505. DOI:10.21873/anticanres.13864.
32. Fu Y, Liu D, Zeng H, Ren X, Song B, Hu D, et al. New chalcone derivatives: Synthesis, antiviral activity and mechanism of action. RSC Adv. 2020;10(41):24483–90. DOI: 10.1039/D0RA03684F.
33. Alsafi MA, Hughes DL, Said MA. First COVID-19 molecular docking with a chalcone-based compound: synthesis, single-crystal structure and Hirshfeld surface analysis study. Acta Crystallogr Sect C Struct Chem. 2020;76(12):1043–50. doi:10.1107/S2053229620014217.
34. Duran N, Polat MF, Aktas DA, Alagoz MA, Ay E, Cimen F, et al. New chalcone derivatives as effective against SARS-CoV-2 agent. Int J Clin Pract. 2021; 75:e14846. doi:10.1111/ijcp.14846.
35. Kalirajan R. Activity of some novel chalcone substituted 9-anilinoacridines against coronavirus (COVID-19): a computational approach. Coronaviruses. 2020; 1:13–22. DOI: 10.2174/2666796701999200625210746.
36. Escrivani DO, Charlton RL, Caruso MB, Burle-Caldas GA, Borsodi MP, Zingali RB, et al. Chalcones identify cTXNPx as a potential antileishmanial drug target. PLoS Negl Trop Dis. 2021; 15(11):e0009951. doi:10.1371/journal.pntd.0009951.
37. Welday Kahssay S, Hailu GS, Taye Desta K. Design, synthesis, characterization and in vivo antidiabetic activity evaluation of some chalcone derivatives. Drug Des Devel Ther. 2021; 15:3119–29. DOI:10.2147/DDDT.S316185.
38. Jain A, Jain D. Synthesis, characterization and biological evaluation of some new heterocyclic derivatives of chalcone as antihyperglycemic agents. Int J Pharm Sci Res. 2019; 10(12):5700–6. DOI:10.13040/IJPSR.0975-8232.10 (12).5700-06.
39. Bhoj P, Togre N, Bahekar S, Goswami K, Chandak H, Patil M. Immunomodulatory activity of sulfonamide chalcone compounds in mice infected with filarial parasite, Brugia malayi. Indian J Clin Biochem. 2019; 34(2):225–9. DOI: 10.1007/s12291-017-0727-5.
40. Lee JS, Bukhari SNA, Fauzi NM. Effects of chalcone derivatives on players of the immune system. Drug Des Devel Ther. 2015; 9:4761. DOI:10.2147/DDDT.S86242.
41. Reddy MR, Aidhen IS, Reddy UA, Reddy GB, Ingle K, Mukhopadhyay S. Synthesis of 4-C-β-D-glucosylated isoliquiritigenin and analogues for aldose reductase inhibition studies. Eur J Org Chem. 2019; 2019(24):3937–48. DOI:10.1002/ejoc.201900413.
42. Shah U, Patel S, Patel M, Gandhi K, Patel A. Identification of chalcone derivatives as putative non-steroidal aromatase inhibitors potentially useful against breast cancer by molecular docking and ADME prediction. Indian J Chem. 2020; B59:283–9.
43. Aljohani G, Al-Sheikh Ali A, Alraqa SY, Itri Amran S, Basar N. Synthesis, molecular docking and biochemical analysis of aminoalkylated naphthalene-based chalcones as acetylcholinesterase inhibitors. J Taibah Univ Sci. 2021; 15(1):781–97. DOI:10.1080/16583655.2021.2005921.
44. Bui TH, Nguyen NT, Dang PH, Nguyen HX, Nguyen MTT. Design and synthesis of chalcone derivatives as potential non-purine xanthine oxidase inhibitors. SpringerPlus.2016; 5(1):1789. DOI: 10.1186/s40064-016-3485-6.
45. Claisen L, Claparede B. Condensationen von Ketonen mit Aldehyden. Ber Dtsch Chem Ges. 1881; 14:2463.
46. Shaik AB, Bhandare RR, Nissankararao S, Edis Z, Tangirala NR, Shahanaaz S, et al. Design, facile synthesis and characterization of dichloro substituted chalcones and dihydropyrazole derivatives for their antifungal, antitubercular and antiproliferative activities. Molecules. 2020; 25:3188. DOI: 10.3390/molecules25143188.
47. Dassault Systèmes . BIOVIA Discovery Studio Visualizr; Dassault Systèmes: San Diego, 2020.
48. Rathod S, Shinde K, Porlekar J, Choudhari P, Dhavale R, Mahuli D, et al. Computational Exploration of Anticancer Potential of Flavonoids against Cyclin-Dependent Kinase 8: An In Silico Molecular Docking and Dynamic Approach. ACS Omega. 2022 Dec 21;8(1):391-409. DOI: 10.1021/acsomega.2c04837. PMID: 36643495; PMCID: PMC9835631.
49. Dym O, Eisenberg D, Yeates TO. Detection of errors in protein models. In: International Tables for Crystallography Volume F: Crystallography of Biological Macromolecules. Springer; 2006.
50. Bhowmik D, Nandi R, Prakash A, Kumar D. Evaluation of flavonoids as 2019-NCoV cell entry inhibitors through molecular docking and pharmacological analysis. Heliyon. 2021; 7:e06515. https://doi.org/10.1016/j.heliyon.2021.e06515.
51. Wiederstein M, Sippl MJ. ProSA-Web: Interactive web service for the recognition of errors in three-dimensional structures of proteins. Nucleic Acids Res. 2007; 35:W407–W410. https://doi.org/10.1093/nar/gkm290.
52. Laskowski RA, Macarthur MW, Thornton JM. PROCHECK: A program to check the stereochemical quality of protein structures. J Appl Cryst. 1993; 26:283–91. https://doi.org/10.1107/S0021889892009944.
53. Tian et al. Nucleic Acids Res. 2018. PMID: 29860391. https://doi.org/10.1093/nar/gky473.
54. Eberhardt J, Santos-Martins D, Tillack AF, Forli S. AutoDock Vina 1.2.0: New docking methods, expanded force field, and Python bindings. J Chem Inf Model. 2021;61:3891–8. https://doi.org/10.1021/acs.jcim.1c00203.
55. Stanzione F, Giangreco I, Cole JC. Use of molecular docking computational tools in drug discovery. Prog Med Chem. 2021; 60:273–343. https://doi.org/10.1016/bs.pmch.2021.01.004.
56. Ikwu FA, Isyaku Y, Obadawo BS, Lawal HA, Ajibowu SA. In silico design and molecular docking study of CDK2 inhibitors with potent cytotoxic activity against HCT116 colorectal cancer cell line. J Genet Eng Biotechnol. 2020;18:51. https://doi.org/10.1186/s43141-020-000662.
57. Dallakyan S, Olson AJ. Small-molecule library screening by docking with PyRx. Methods Mol Biol. 2015; 1263:243–50. https://doi.org/10.1007/978-1-4939-2269-7_19.
58. Vanangamudi G, Subramanian M, Jayanthi P, Arulkumaran R, Kamalakkannan D, Thirunarayanan G. IR and NMR spectral studies of some 2-hydroxy-1-naphthylchalcones: Assessment of substituent effects. Arab J Chem. 2011. doi:10.1016/j.arabjc.2011.07.019.
59. Mala V, Sathiyamoorthi K, Sakthinathan SP, Kamalakkannan D, Suresh R, Vanangamudi G, Thirunarayanan G. Solvent-free synthesis, spectral correlations and antimicrobial activities of some 3,4-dimethoxychalcones. Q-Science Connect. 2013. DOI:10.5339/connect.2013.7.
60. Opletalova V, Hartl J, Palat K Jr, Patel A. Conformational analysis of 2-hydroxy-2′,5′-diazachalcones. J Pharm Biomed Anal. 2000; 23:55–59.
61. Rao MLN, Houjou H, Hiratani K. Novel synthesis of macrocycles with chalcone moieties through mixed aldol reaction. Tetrahedron Lett. 2001; 42:8351–8355.
62. Jung YJ, Son KI, Oh YE, Noh DY. Ferrocenyl chalcones containing anthracenyl group: Synthesis, X-ray crystal structures and electrochemical properties.
63. Immadisetty SK, Saravanan G, Vamsi J, et al. Synthesis, characterization and antimicrobial activity of some novel N-((1H-benzoimidazol-1-yl)methyl)-4-(1-phenyl-5-substituted-4,5-dihydro-1H-pyrazol-3-yl)benzenamine derivatives. Pharmacognosy Res. 2014; 6(1):40–49.
64. Kucerova-Chlupacova M, Kunes J, Buchta V, et al. Novel halogenated pyrazine-based chalcones as potential antimicrobial agents. Molecules. 2016; 21(11):1421.
65. da Silva DL, de Souza MV, Frugulhetti IC, et al. Antimicrobial and cytotoxicity potential of acetamido, amino and nitrochalcones. Planta Med. 2012; 78(18):1863–1868.
66. Zhan W, Zhou R, Mao P, et al. Synthesis, antifungal activity and mechanism of action of novel chalcone derivatives containing 1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazole. Mol Divers. 2024; 28(2):461–474.
67. Marques BC, Santos MB, Anselmo DB, et al. Methoxychalcones: effect of methoxyl group on the antifungal, antibacterial, and antiproliferative activities. Med Chem. 2020; 16(7):881–891.
- Abstract Viewed: 84 times
- IJPS_Volume21_Issue1_Pages430-447 Downloaded: 71 times