Skip to content
2000
Volume 23, Issue 4
  • ISSN: 2211-3525
  • E-ISSN: 2211-3533

Abstract

Background

The urgent need for new antimicrobial compounds arises from the growing threat of multidrug-resistant human pathogens responsible for infectious diseases. The indole moiety, a prevalent heterocyclic ring system found in nature, is a key structural element in many pharmaceutical agents due to its wide range of biological activities. Bis(indolyl)methanes, in particular, have emerged as promising candidates for antibacterial activity.

Aim

This study aimed to evaluate the antibacterial activity of nine bis(indolyl)methane derivatives against a range of pathogenic bacterial strains responsible for various human diseases.

Methods

The compounds were synthesized using a solvent-free method, and their antibacterial activity was evaluated using the disk diffusion assay. The minimum inhibitory concentration (MIC) of the active compounds identified in the disk diffusion assay was determined by the microtiter broth dilution method in 96-well microtiter plates. Bacterial strains in the mid-log phase of growth were utilized. Bacterial suspensions equivalent to 0.5 McFarland standards were prepared by suspending the bacterial inoculum in sterile water. A working concentration of 100 µg/mL was achieved by diluting the test compounds in 100% DMSO.

Results

The antimicrobial activity of nine synthetic compounds was evaluated against nine medically significant pathogenic strains. These include , , and , known for producing toxins that cause acute foodborne illnesses, as well as K12 and , which can disrupt the intestinal barrier in immunocompromised individuals. The results suggest that these compounds have the potential to be effective antimicrobial agents.

Conclusion

Our findings demonstrate the promising antimicrobial activity of the synthesized compounds, with 1-ethyl-3-((1-ethyl-1-indol-3-yl)(phenyl)methyl)-1-indole emerging as the most potent, significantly inhibiting most tested bacterial strains. These results highlight the potential for developing novel compounds for antibacterial treatment.

Loading

Article metrics loading...

/content/journals/aia/10.2174/0122113525345761241023044441
2024-12-10
2025-09-28
Loading full text...

Full text loading...

References

  1. KoenigX. HilberK. The anti-addiction drug ibogaine and the heart: a delicate relation.Molecules20152022208222810.3390/molecules20022208 25642835
    [Google Scholar]
  2. SeiglerD.S. Plant Secondary Metabolism.New YorkSpringer2001
    [Google Scholar]
  3. WangC. HuangY. Traceless directing strategy: efficient synthesis of N-alkyl indoles via redox-neutral C-H activation.Org. Lett.201315205294529710.1021/ol402523x 24099640
    [Google Scholar]
  4. SuzenS. BuyukbingolE. Anti-cancer activity studies of indolalthiohydantoin (PIT) on certain cancer cell lines.Farmaco200055424624810.1016/S0014‑827X(00)00028‑8 10966154
    [Google Scholar]
  5. HendyM.S. AliA.A. AhmedL. HossamR. MostafaA. ElmazarM.M. NaguibB.H. AttiaY.M. AhmedM.S. Structure-based drug design, synthesis, in vitro, and in vivo biological evaluation of indole-based biomimetic analogs targeting estrogen receptor-α inhibition.Eur. J. Med. Chem.201916628129010.1016/j.ejmech.2019.01.068 30731397
    [Google Scholar]
  6. HanY. DongW. GuoQ. LiX. HuangL. The importance of indole and azaindole scaffold in the development of antitumor agents.Eur. J. Med. Chem.202020311250610.1016/j.ejmech.2020.112506 32688198
    [Google Scholar]
  7. RaniP. SrivastavaV.K. KumarA. Synthesis and antiinflammatory activity of heterocyclic indole derivatives.Eur. J. Med. Chem.200439544945210.1016/j.ejmech.2003.11.002 15110970
    [Google Scholar]
  8. MisraU. HitkariA. SaxenaA.K. GurtuS. ShankerK. Biologically active indolylmethyl-1,3,4-oxadiazoles, 1,3,4-thiadiazoles, 4H--1,3,4-triazoles and 1,2,4-triazines.Eur. J. Med. Chem.1996317-862963410.1016/0223‑5234(96)89559‑6
    [Google Scholar]
  9. AndreaniA. RambaldiM. LocatelliA. PifferiG. Synthesis and antiinflammatory activity of indolylacrylic and methylacrylic acids.Eur. J. Med. Chem.1994291190390610.1016/0223‑5234(94)90115‑5
    [Google Scholar]
  10. DemurtasM. BaldisserottoA. LamprontiI. MoiD. BalboniG. PacificoS. VertuaniS. ManfrediniS. OnnisV. Indole derivatives as multifunctional drugs: Synthesis and evaluation of antioxidant, photoprotective and antiproliferative activity of indole hydrazones.Bioorg. Chem.20198556857610.1016/j.bioorg.2019.02.007 30825715
    [Google Scholar]
  11. DekaB. DebM.L. BaruahP.K. Recent advances on the C2-functionalization of indole via umpolung.Top. Curr. Chem. (Cham)202037822210.1007/s41061‑020‑0287‑7 32030596
    [Google Scholar]
  12. ReddyB.V.S. ReddyM.R. MadanC. KumarK.P. RaoM.S. Indium(III) chloride catalyzed three-component coupling reaction: A novel synthesis of 2-substituted aryl(indolyl)kojic acid derivatives as potent antifungal and antibacterial agents.Bioorg. Med. Chem. Lett.201020247507751110.1016/j.bmcl.2010.10.003 21067928
    [Google Scholar]
  13. ZhuY. ZhaoJ. LuoL. GaoY. BaoH. LiP. ZhangH. Research progress of indole compounds with potential antidiabetic activity.Eur. J. Med. Chem.202122311366510.1016/j.ejmech.2021.113665 34192642
    [Google Scholar]
  14. AgarwalA. SrivastavaK. PuriS.K. ChauhanP.M.S. Synthesis of substituted indole derivatives as a new class of antimalarial agents.Bioorg. Med. Chem. Lett.200515123133313610.1016/j.bmcl.2005.04.011 15925306
    [Google Scholar]
  15. SchuckD.C. JordãoA.K. NakabashiM. CunhaA.C. FerreiraV.F. GarciaC.R.S. Synthetic indole and melatonin derivatives exhibit antimalarial activity on the cell cycle of the human malaria parasite Plasmodium falciparum.Eur. J. Med. Chem.20147837538210.1016/j.ejmech.2014.03.055 24699367
    [Google Scholar]
  16. LiJ.Y. SunX.F. LiJ.J. YuF. ZhangY. HuangX.J. JiangF.X. The antimalarial activity of indole alkaloids and hybrids.Arch. Pharm. (Weinheim)202035311200013110.1002/ardp.202000131 32785974
    [Google Scholar]
  17. KumariA. SinghR.K. Medicinal chemistry of indole derivatives: Current to future therapeutic prospectives.Bioorg. Chem.20198910302110.1016/j.bioorg.2019.103021 31176854
    [Google Scholar]
  18. TiwariR.K. SinghD. SinghJ. YadavV. PathakA.K. DaburR. ChhillarA.K. SinghR. SharmaG.L. ChandraR. VermaA.K. Synthesis and antibacterial activity of substituted 1,2,3,4-tetrahydropyrazino [1,2-a] indoles.Bioorg. Med. Chem. Lett.200616241341610.1016/j.bmcl.2005.09.066 16246547
    [Google Scholar]
  19. WhiteheadC.W. WhitesittC.A. Effect of lipophilic substituents on some biological properties of indoles.J. Med. Chem.197417121298130410.1021/jm00258a014 4214926
    [Google Scholar]
  20. YamamotoY. KurazonoM. A new class of anti-MRSA and anti-VRE agents: Preparation and antibacterial activities of indole-containing compounds.Bioorg. Med. Chem. Lett.20071761626162810.1016/j.bmcl.2006.12.081 17254785
    [Google Scholar]
  21. MahboobiS. EichhornE. PoppA. SellmerA. ElzS. MöllmannU. 3-Bromo-4-(1H-3-indolyl)-2,5-dihydro-1H-2,5-pyrroledione derivatives as new lead compounds for antibacterially active substances.Eur. J. Med. Chem.200641217619110.1016/j.ejmech.2005.10.006 16375991
    [Google Scholar]
  22. RyuC.K. LeeJ.Y. ParkR.E. MaM.Y. NhoJ.H. Synthesis and antifungal activity of 1H-indole-4,7-diones.Bioorg. Med. Chem. Lett.200717112713110.1016/j.bmcl.2006.09.076 17046257
    [Google Scholar]
  23. BolousM. ArumugamN. AlmansourA.I. Suresh KumarR. MaruokaK. AntharamV.C. ThangamaniS. Broad-spectrum antifungal activity of spirooxindolo-pyrrolidine tethered indole/imidazole hybrid heterocycles against fungal pathogens.Bioorg. Med. Chem. Lett.201929162059206310.1016/j.bmcl.2019.07.022 31320146
    [Google Scholar]
  24. Hidalgo-RomanoB. GolliharJ. BrownS.A. WhiteleyM. ValenzuelaE. KaplanH.B. WoodT.K. McLeanR.J.C. Indole inhibition of N-acylated homoserine lactone-mediated quorum signalling is widespread in Gram-negative bacteria.Microbiology (Reading)2014160112464247310.1099/mic.0.081729‑0 25165125
    [Google Scholar]
  25. FuS.F. WeiJ.Y. ChenH.W. LiuY.Y. LuH.Y. ChouJ.Y. Indole-3-acetic acid: A widespread physiological code in interactions of fungi with other organisms.Plant Signal. Behav.2015108e104805210.1080/15592324.2015.1048052 26179718
    [Google Scholar]
  26. ZhangM.Z. ChenQ. YangG.F. A review on recent developments of indole-containing antiviral agents.Eur. J. Med. Chem.201589142144110.1016/j.ejmech.2014.10.065 25462257
    [Google Scholar]
  27. SantosA.S. FerroR.D. ViduedoN. MaiaL.B. SilvaA.M.S. MarquesM.M.B. Synthesis of Bis(3‐indolyl)methanes mediated by potassium tert‐butoxide.ChemistryOpen2023121e20220026510.1002/open.202200265 36650736
    [Google Scholar]
  28. PatilS.A. PatilR. MillerD.D. Indole molecules as inhibitors of tubulin polymerization: Potential new anticancer agents.Future Med. Chem.20124162085211510.4155/fmc.12.141 23157240
    [Google Scholar]
  29. SarvaS. HarinathJ.S. SthanikamS.P. EthirajS. VaithiyalingamM. CirandurS.R. Synthesis, antibacterial and anti-inflammatory activity of bis(indolyl)methanes.Chin. Chem. Lett.2016271162010.1016/j.cclet.2015.08.012
    [Google Scholar]
  30. NemallapudiB.R. ZyryanovG.V. AvulaB. GudaM.R. GundalaS. An effective green and ecofriendly catalyst for synthesis of bis(indolyl)methanes as promising antimicrobial agents.J. Heterocycl. Chem.201956123324333210.1002/jhet.3729
    [Google Scholar]
  31. BiswalS. SahooU. SethyS. KumarH.K.S. BanerjeeM. Indole: the molecule of diverse biological activities.Asian J. Pharm. Clin. Res.20125116
    [Google Scholar]
  32. ShaikhT.M. DebebeH. Synthesis and evaluation of antimicrobial activities of novel N-substituted indole derivatives.J. Chem.202020201910.1155/2020/1543081
    [Google Scholar]
  33. BandiniM. EichholzerA. Catalytic functionalization of indoles in a new dimension.Angew. Chem. Int. Ed.200948519608964410.1002/anie.200901843 19946913
    [Google Scholar]
  34. SandtorvA.H. Transition metal‐catalyzed C-H activation of indoles.Adv. Synth. Catal.2015357112403243510.1002/adsc.201500374
    [Google Scholar]
  35. AllenJ.R. BahamondeA. FurukawaY. SigmanM.S. Enantioselective N-alkylation of indoles via an intermolecular Aza-wacker-Type Reaction.J. Am. Chem. Soc.2019141228670867410.1021/jacs.9b01476 31117643
    [Google Scholar]
  36. KarchavaA.V. MelkonyanF.S. YurovskayaM.A. New strategies for the synthesis of N-alkylated indoles (Review).Chem. Heterocycl. Compd.201248339140710.1007/s10593‑012‑1006‑2
    [Google Scholar]
  37. KarchavaA.V. ShulevaI.S. OvcharenkoA.A. YurovskayaM.A. 2- and 3-phenylsulfonylindoles – synthetic equivalents of unsubstituted indole in N-alkylation reactions.Chem. Heterocycl. Compd.201046329130110.1007/s10593‑010‑0504‑3
    [Google Scholar]
  38. SukataK. N -Alkylation of pyrrole, indole, and several other nitrogen heterocycles using potassium hydroxide as a base in the presence of polyethylene glycols or their dialkyl ethers.Bull. Chem. Soc. Jpn.198356128028410.1246/bcsj.56.280
    [Google Scholar]
  39. GuidaW.C. MathreD.J. Phase-transfer alkylation of heterocycles in the presence of 18-crown-6 and potassium tert-butoxide.J. Org. Chem.198045163172317610.1021/jo01304a006
    [Google Scholar]
  40. TejchmanW. Korona-GlowniakI. MalmA. ZylewskiM. SuderP. Antibacterial properties of 5-substituted derivatives of rhodanine-3-carboxyalkyl acids.Med. Chem. Res.20172661316132410.1007/s00044‑017‑1852‑7 28515623
    [Google Scholar]
  41. LelarioF. ScranoL. De FranchiS. BonomoM.G. SalzanoG. MilanS. MilellaL. BufoS.A. Identification and antimicrobial activity of most representative secondary metabolites from different plant species.Chem. Biol. Technol. Agric.2018511310.1186/s40538‑018‑0125‑0
    [Google Scholar]
  42. SharmaD.K. TripathiA.K. SharmaR. ChibR. ur Rasool, R.; Hussain, A.; Singh, B.; Goswami, A.; Khan, I.A.; Mukherjee, D. A new class of bactericidal agents against S. aureus, MRSA and VRE derived from bisindolylmethane.Med. Chem. Res.20142341643165310.1007/s00044‑013‑0764‑4
    [Google Scholar]
  43. NaikC. P.; G B, A.; Seikh, A.H.; Dutta, S. Synthesis, characterization, and antibacterial activity of novel bis(indolyl)methanes sourced from biorenewable furfurals using gluconic acid aqueous solution (GAAS) as a sustainable catalyst.RSC Advances20241430215532156210.1039/D4RA03905J 38979445
    [Google Scholar]
  44. HidronA.I. EdwardsJ.R. PatelJ. HoranT.C. SievertD.M. PollockD.A. FridkinS.K. NHSN annual update: antimicrobial-resistant pathogens associated with healthcare-associated infections: annual summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2006-2007.Infect. Control Hosp. Epidemiol.20082911996101110.1086/591861 18947320
    [Google Scholar]
  45. GilmoreM.S. LebretonF. van SchaikW. Genomic transition of enterococci from gut commensals to leading causes of multidrug-resistant hospital infection in the antibiotic era.Curr. Opin. Microbiol.2013161101610.1016/j.mib.2013.01.006 23395351
    [Google Scholar]
  46. JettB.D. HuyckeM.M. GilmoreM.S. Virulence of Enterococci.Clin. Microbiol. Rev.19947446247810.1128/CMR.7.4.462 7834601
    [Google Scholar]
  47. RichardsM.J. EdwardsJ.R. CulverD.H. GaynesR.P. Nosocomial infections in combined medical-surgical intensive care units in the United States.Infect. Control Hosp. Epidemiol.200021851051510.1086/501795 10968716
    [Google Scholar]
  48. MakiD.G. AggerW.A. Enterococcal bacteremia.Medicine (Baltimore)198867424826910.1097/00005792‑198807000‑00005 3134590
    [Google Scholar]
  49. ActorJ.K. Clinical Bacteriology.Wiley201210.1016/B978‑0‑323‑07447‑6.00012‑0
    [Google Scholar]
  50. BeecherD.J. WongA.L. Tripartite hemolysin BL from Bacillus cereus. Hemolytic analysis of component interactions and a model for its characteristic paradoxical zone phenomenon.J. Biol. Chem.1997272123323910.1074/jbc.272.1.233 8995253
    [Google Scholar]
  51. KramerJ.M. GilbertR.J. Bacillus cereus and other Bacillus species.In: Foodborne bacterial pathogens. DoyleM.P. New YorkMarcel Dekker, Inc.19892177
    [Google Scholar]
  52. ToddE.C.D. Bacteria: Staphylococcus aureus.Encyclopedia of Food Safety. MotarjemiY. MoyG. ToddE. USAElsevier2014Vol. 153053410.1016/B978‑0‑12‑378612‑8.00115‑3
    [Google Scholar]
  53. FosterT.J. Potential for vaccination against infections caused by Staphylococcus aureus.Vaccine19919422122710.1016/0264‑410X(91)90103‑D 2058264
    [Google Scholar]
  54. BennishM.L. Potentially lethal complications of shigellosis.Clin. Infect. Dis.199113Suppl. 4S319S32410.1093/clinids/13.Supplement_4.S319 2047657
    [Google Scholar]
  55. KotloffK.L. WinickoffJ.P. IvanoffB. ClemensJ.D. SwerdlowD.L. SansonettiP.J. AdakG.K. LevineM.M. Global burden of Shigella infections: implications for vaccine development and implementation of control strategies.Bull. World Health Organ.1999778651666 10516787
    [Google Scholar]
  56. BennishM.L. WojtyniakB.J. Mortality due to shigellosis: Community and hospital data.Clin. Infect. Dis.199113Suppl. 4S245S25110.1093/clinids/13.Supplement_4.S245 2047645
    [Google Scholar]
  57. AshkenaziS. LevyI. KazaronovskiV. SamraZ. Growing antimicrobial resistance of Shigella isolates.J. Antimicrob. Chemother.200351242742910.1093/jac/dkg080 12562716
    [Google Scholar]
  58. DuPontH.L. LevineM.M. HornickR.B. FormalS.B. Inoculum size in shigellosis and implications for expected mode of transmission.J. Infect. Dis.198915961126112810.1093/infdis/159.6.1126 2656880
    [Google Scholar]
  59. SmallP. BlankenhornD. WeltyD. ZinserE. SlonczewskiJ.L. Acid and base resistance in Escherichia coli and Shigella flexneri: role of rpoS and growth pH.J. Bacteriol.199417661729173710.1128/jb.176.6.1729‑1737.1994 8132468
    [Google Scholar]
  60. HetemD.J. RooijakkersS.H.M. EkkelenkampM.B. Staphylococci and Micrococci.Infectious diseases. CohenJ. PowderlyW.G. OpalS.M. Elsevier2017Vol. 115091522.e210.1016/B978‑0‑7020‑6285‑8.00176‑3
    [Google Scholar]
  61. FosseT. TogaB. PelouxY. GranthilC. BertrandoJ. SethianM. Meningitis due to Micrococcus luteus.Infection198513628028110.1007/BF01645439 4077270
    [Google Scholar]
  62. WuW. JinY. BaiF. Pseudomonas aeruginosa.Molecular Medical Microbiology. TangY.W. SussmanM. LiuD. PoxtonI. SchwartzmanJ. Elsevier2015Vol. 2753767
    [Google Scholar]
  63. PlanetP.J. Pseudomonas aeruginosa.Principles and Practice of Pediatric Infectious Diseases. LongS.S. ProberC.G. FischerM. KimberlinD. Elsevier201886687010.1016/B978‑0‑323‑40181‑4.00155‑9
    [Google Scholar]
  64. RadoshevichL. CossartP. Listeria monocytogenes: Towards a complete picture of its physiology and pathogenesis.Nat. Rev. Microbiol.2018161324610.1038/nrmicro.2017.126 29176582
    [Google Scholar]
  65. DebM.L. BhuyanP.J. Uncatalysed Knoevenagel condensation in aqueous medium at room temperature.Tetrahedron Lett.200546386453645610.1016/j.tetlet.2005.07.111
    [Google Scholar]
  66. DekaB. BaruahP.K. DebM.L. Multi-component synthesis of 3-substituted indoles and their cyclisation to α-carbolines via I2-promoted intramolecular C2 oxidative amination/aromatisation at room temperature.Org. Biomol. Chem.201816427806781010.1039/C8OB02362J 30328453
    [Google Scholar]
  67. DekaB. ThakuriaR. DebM.L. BaruahP.K. A revisit to the multi-component reaction of indole, aldehyde, and N-substituted aniline catalyzed by PMA–SiO2.Monatsh. Chem.2018149122245225210.1007/s00706‑018‑2290‑z
    [Google Scholar]
  68. DekaB. DebM.L. ThakuriaR. BaruahP.K. I2/TBHP/cyclohexanone a novel catalyst system for the oxidative dearomatization of indoles to indolin-3-ones at room temperature under solvent-free condition.Catal. Commun.2018106687210.1016/j.catcom.2017.12.015
    [Google Scholar]
  69. DebM.L. DekaB. SaikiaP.J. BaruahP.K. Base-promoted three-component cascade approach to unsymmetrical bis(indolyl)methanes.Tetrahedron Lett.201758201999200310.1016/j.tetlet.2017.04.032
    [Google Scholar]
  70. DebM.L. BorpatraP.J. SaikiaP.J. BaruahP.K. Introducing tetramethylurea as a new methylene precursor: A microwave-assisted RuCl3-catalyzed cross dehydrogenative coupling approach to bis(indolyl)methanes.Org. Biomol. Chem.20171561435144310.1039/C6OB02671K 28102407
    [Google Scholar]
  71. DebM. BaruahP. DasC. DekaB. SaikiaP. Hydrogen-bond-catalyzed arylation of 3-(aminoalkyl)indoles via C–N bond cleavage with thiourea under microwave irradiation: An Approach to 3-(α,α-Diarylmethyl)indoles.Synlett201627202788279410.1055/s‑0036‑1588887
    [Google Scholar]
  72. RahmanI. DekaB. DebM.L. BaruahP.K. C‐C bond cleavage by the reaction of cyclic amines or indoles with activated olefins: A redox‐neutral mechanism for the reducing action of tetrahydroisoquinolines.ChemistrySelect2019435104251042910.1002/slct.201902655
    [Google Scholar]
  73. DebM.L. PeguC.D. DekaB. DuttaP. KotmaleA.S. BaruahP.K. Brønsted-Acid-mediated divergent reactions of betti bases with indoles: an approach to chromeno[2,3-b]indoles through intramolecular dehydrogenative C2-alkoxylation of indole.Eur. J. Med. Chem.201620162034413448
    [Google Scholar]
  74. GopalaiahK. ChandruduS. DeviA. Iron-catalyzed oxidative coupling of benzylamines and indoles: Novel approach for synthesis of bis(indolyl)methanes.Synthesis201547121766177410.1055/s‑0034‑1380012
    [Google Scholar]
  75. BhatM.I. SowmyaK. KapilaS. KapilaR. Escherichia coli K12: An evolving opportunistic commensal gut microbe distorts barrier integrity in human intestinal cells.Microb. Pathog.201913310354510.1016/j.micpath.2019.103545 31112772
    [Google Scholar]
  76. SteckN. HoffmannM. SavaI.G. KimS.C. HahneH. TonkonogyS.L. MairK. KruegerD. PruteanuM. ShanahanF. VogelmannR. SchemannM. KusterB. SartorR.B. HallerD. Enterococcus faecalis metalloprotease compromises epithelial barrier and contributes to intestinal inflammation.Gastroenterology2011141395997110.1053/j.gastro.2011.05.035 21699778
    [Google Scholar]
/content/journals/aia/10.2174/0122113525345761241023044441
Loading
/content/journals/aia/10.2174/0122113525345761241023044441
Loading

Data & Media loading...

Supplements

Supplementary material is available on the publisher’s website along with the published article.

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test