Skip to content
2000
Volume 33, Issue 5
  • ISSN: 0929-8673
  • E-ISSN: 1875-533X
file format text download EPUB
file format pdf download PDF
side by side viewer icon HTML

Abstract

Background

More robust 4-substituted 7-chloroquinolines have been investigated for their diverse properties. However, there is still no systematic study that correlates the effects of the side chain at the 4-position of chloroquine and hydroxychloroquine derivatives with their lipophilicity, antimicrobial and toxicity properties.

Objective

To this end, a cleaner and facile approach was planned to obtain nineteen 4- substituted 7-chloroquinolines, whose influence of the substituent group and side chain extension at the 4-position on their properties was studied.

Methods

4-Alkoxy/amino-7-chloroquinolines were prepared by a nucleophilic aromatic substitution (SAr) reaction between 4,7-dichloroquinoline and alcohols/amines, evaluated for their ADMET test, antimicrobial activity against Gram-(+) and Gram-(−) bacteria, and fungus, and toxicity on larvae.

Results

4-Alkoxy/amino-7-chloroquinolines were obtained in yields ranging from 81 to 100%. The best results showed antimicrobial activity against for 4-amino-7-chloroquinolines , with halos greater than 20 mm, and against for 4-amino-7-chloroquinolines , with halos close to 30 mm. A correspondence between Minnow toxicity prediction and toxicity on larvae was observed, where compounds and , with R = Pent, were both predicted to have high acute toxicity (log LC < -0.3) and classified as highly toxic (LC < 100 µg mL-1). It seems that increased lipophilicity in the side chain is harmful to larvae.

Conclusion

Considering the results for compounds and with greater activity against and , respectively, especially for 4-amino-7-chloroquinolines and , which are slightly toxic on larvae (LC 500-1000 µg mL-1), their antimicrobial studies deserve to be continued by the determination of Minimum Inhibitory Concentration (MIC) values.

© 2026 The Author(s). Published by Bentham Science Publishers.
This is an open access article published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode
Loading

Article metrics loading...

/content/journals/cmc/10.2174/0109298673372039250614231629
2025-10-08
2026-02-24

  • From This Site

    /content/journals/cmc/10.2174/0109298673372039250614231629
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

/deliver/fulltext/cmc/33/5/CMC-33-5-03.html?itemId=/content/journals/cmc/10.2174/0109298673372039250614231629&mimeType=html&fmt=ahah

References

  1. BeheraS. MohantyP. BehuraR. BarickA.K. JaliB.R. Antibacterial properties of quinoline derivatives: A mini-review.Biointerface Res. Appl. Chem.20211256078609210.33263/BRIAC125.60786092
     [Google Scholar]
  2. LiJ. GuA. NongX.M. ZhaiS. YueZ.Y. LiM.Y. LiuY. Six-membered aromatic nitrogen heterocyclic anti- tumor agents: Synthesis and applications.Chem. Rec.2023231220230029310.1002/tcr.20230029338010365
     [Google Scholar]
  3. Nitrogen Heterocyclic Compounds.2023Available from: https://oec.world/en/profile/hs/nitrogen-heterocyclic-compounds (accessed December 4, 2023).
  4. KerruN. GummidiL. MaddilaS. GanguK.K. JonnalagaddaS.B. A review on recent advances in nitrogen- containing molecules and their biological applications.Molecules2020258190910.3390/molecules2508190932326131
     [Google Scholar]
  5. DibM. OuchettoH. OuchettoK. HafidA. KhouiliM. Recent developments of quinoline derivatives and their potential biological activities.Curr. Org. Synth.202118324826910.2174/157017941766620121616205533327918
     [Google Scholar]
  6. MoorL.F.E. VasconcelosT.R.A. da R ReisR. PintoL.S.S. da CostaT.M. Quinoline: An attractive scaffold in drug design.Mini Rev. Med. Chem.202121162209222610.2174/138955752166621021015590833568032
     [Google Scholar]
  7. da SilvaS.E.B. da Silva MouraJ.A. de Sousa NunesT.R. da Rocha PittaI. da Rocha PittaM.G. New trends in biological activities and clinical studies of quinolinic analogues: A review.Curr. Drug Targets202223544145710.2174/138945012266621041510015133858312
     [Google Scholar]
  8. SharmaS. SinghK. SinghS. Synthetic strategies for quinoline based derivatives as potential bioactive heterocycles.Curr. Org. Synth.202320660662910.2174/157017942066622100414391036200204
     [Google Scholar]
  9. EganT.J. HunterR. KaschulaC.H. MarquesH.M. MisplonA. WaldenJ. Structure-function relationships in aminoquinolines: Effect of amino and chloro groups on quinoline-hematin complex formation, inhibition of β-hematin formation, and antiplasmodial activity.J. Med. Chem.200043228329110.1021/jm990437l10649984
     [Google Scholar]
  10. NatarajanJ.K. AlumasaJ.N. YearickK. Ekoue-KoviK.A. CasabiancaL.B. de DiosA.C. WolfC. RoepeP.D. 4-N-, 4-S-, and 4-O-chloroquine analogues: Influence of side chain length and quinolyl nitrogen pKa on activity vs chloroquine resistant malaria.J. Med. Chem.200851123466347910.1021/jm701478a18512900
     [Google Scholar]
  11. PallavalV.B. KanithiM. MeenakshisundaramS. JagadeeshA. AlavalaM. PillaiyarT. ManickamM. ChidipiB. Chloroquine analogs: An overview of natural and synthetic quinolines as broad spectrum antiviral agents.Curr. Pharm. Des.20212791185119310.2174/138161282666620121112172133308117
     [Google Scholar]
  12. ChiodiD. IshiharaY. “Magic chloro”: Profound effects of the chlorine atom in drug discovery.J. Med. Chem.20236685305533110.1021/acs.jmedchem.2c0201537014977
     [Google Scholar]
  13. KaiserC.R. PaisK.C. de SouzaM.V.N. WardellJ.L. WardellS.M.S.V. TiekinkE.R.T. Assessing the persistence of the N–H-N hydrogen bonding leading to supramolecular chains in molecules related to the anti-malarial drug, chloroquine.CrystEngComm20091161133114010.1039/b823058g
     [Google Scholar]
  14. CopettiJ.P.P. SalbegoP.R.S. OrlandoT. RosaJ.M.L. FissG.F. OliveiraJ.P.G. VasconcellosM.L.A.A. ZanattaN. BonacorsoH.G. MartinsM.A.P. Substituent effects on the crystallization mechanisms of 7-chloro-4-substituted-quinolines.CrystEngComm202022244094410710.1039/D0CE00214C
     [Google Scholar]
  15. TaramelliD. TognazioliC. RavagnaniF. LeopardiO. GiannulisG. BoelaertJ.R. Inhibition of intramacrophage growth of Penicillium marneffei by 4-aminoquinolines.Antimicrob. Agents Chemother.20014551450145510.1128/AAC.45.5.1450‑1455.200111302809
     [Google Scholar]
  16. DeviK. AsmatY. JainS. SharmaS. DwivediJ. An efficient approach to the synthesis of novel oxazolidinones as potential antimicrobial agents.J. Chem.20132013125218710.1155/2013/252187
     [Google Scholar]
  17. PerkovićI. PoljakT. SavijokiK. VarmanenP. Maravić-VlahovičekG. BeusM. KučevićA. DžajićI. RajićZ. Synthesis and biological evaluation of new quinoline and anthranilic acid derivatives as potential quorum sensing inhibitors.Molecules20232815586610.3390/molecules2815586637570836
     [Google Scholar]
  18. HarroldM.W. ZavodR.M. Basic concepts in medicinal chemistry.Drug Dev. Ind. Pharm.201440798810.3109/03639045.2013.789908
     [Google Scholar]
  19. NogueiraL.J. MontanariC.A. DonniciC.L. The history, evolution and importance of lipophilicity in medicinal chemistry: From hippocrates and galeno to paracelsus and the contributions of overton and hansch.Revista Virtual de Química20091322724010.5935/1984‑6835.20090023
     [Google Scholar]
  20. LipinskiC.A. LombardoF. DominyB.W. FeeneyP.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings.Adv. Drug Deliv. Rev.2001461-332510.1016/S0169‑409X(96)00423‑1
     [Google Scholar]
  21. LipinskiC.A. LombardoF. DominyB.W. FeeneyP.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings.Adv. Drug Deliv. Rev.201264Suppl.41710.1016/j.addr.2012.09.01911259830
     [Google Scholar]
  22. LipinskiC.A. Lead- and drug-like compounds: The rule-of-five revolution.Drug Discov. Today. Technol.20041433734110.1016/j.ddtec.2004.11.00724981612
     [Google Scholar]
  23. VeberD.F. JohnsonS.R. ChengH.Y. SmithB.R. WardK.W. KoppleK.D. Molecular properties that influence the oral bioavailability of drug candidates.J. Med. Chem.200245122615262310.1021/jm020017n12036371
     [Google Scholar]
  24. LipinskiC.A. ReaumeA.G. Phenotypic screening of low molecular weight compounds is rich ground for repurposed, on-target drugs.Front. Pharmacol.20221391796810.3389/fphar.2022.91796836003497
     [Google Scholar]
  25. YuE. MangunuruH.P.R. TelangN.S. KongC.J. VergheseJ. GillilandS.E.III AhmadS. DomineyR.N. GuptonB.F. High-yielding continuous-flow synthesis of antimalarial drug hydroxychloroquine.Beilstein J. Org. Chem.20181458359210.3762/bjoc.14.4529623120
     [Google Scholar]
  26. ShaikR. RaoH.S.P. Hydroxychloroquine (HCQ) and its synthetic precursors: A review.Mini Rev. Org. Chem.202219111112410.2174/1570193X18666210204113412
     [Google Scholar]
  27. AlvesF. OliveiraR. SouzaH. LimaP. FariasF. MarzariB. CoelhoH. LuisJ. Athayde-FilhoP. FissG. Cleaner approach and antimicrobial screening of 2-selenoacetanilides: Emergence of potential agents against co-infection.J. Sulfur Chem.202546221222510.1080/17415993.2024.2449383
     [Google Scholar]
  28. AlvesF.S. SousaA.P. Almeida-JúniorA. LimaP.S.V. SilvaM.F.R. GalvãoJ.L.F.M. LimaE.O. SouzaH.D.S. LuisJ.A.S. Athayde-FilhoP.F. FissG.F. Antimicrobial investigation of phthalimide and N-phthaloylglycine esters: Activity, mechanism of action, synergism and ecotoxicity.Life202515451810.3390/life15040518
     [Google Scholar]
  29. Almeida-JúniorA. SouzaH.D.S. SousaA.P. DantasM.V.O. SampaioF.C. LuisJ.A.S. Rodrigues-JuniorV.S. Barbosa-FilhoJ.M. FissG.F. Athayde-FilhoP.F. In silico/vitro study of antibacterial effects of non-toxic cinnamic amidoesters on Artemia salina. Curr. Org. Chem.2025291610.2174/0113852728310711240525123954
     [Google Scholar]
  30. CraigJ.C.Jr PearsonD.E. NMR proof of the structure of 4-aminoquinolines and pyridines.J. Heterocycl. Chem.19685563163710.1002/jhet.5570050508
     [Google Scholar]
  31. BolteJ. DemuynckC. LhommeJ. Synthetic models of DNA complexes with antimalarial compounds. 2. The problem of guanine specificity in chloroquine binding.J. Med. Chem.197720110611310.1021/jm00211a022833808
     [Google Scholar]
  32. MichneW.F. GuilesJ.W. TreasurywalaA.M. CastonguayL.A. WeigeltC.A. OconnorB. VolbergW.A. GrantA.M. ChadwickC.C. KrafteD.S. HillR.J. Novel inhibitors of potassium ion channels on human T lymphocytes.J. Med. Chem.199538111877188310.1021/jm00011a0077540207
     [Google Scholar]
  33. KitelR. SurmiakE. BorggräfeJ. Kalinowska-TluscikJ. GolikP. CzubM. UzarW. MusielakB. MadejM. PopowiczG.M. DubinG. HolakT.A. Discovery of inhibitory fragments that selectively target Spire2–FMN2 interaction.J. Med. Chem.20236623157151572710.1021/acs.jmedchem.3c0087738039505
     [Google Scholar]
  34. GalloS. AtifiS. MahamoudA. Santelli-RouvierC. WolfártK. MolnarJ. BarbeJ. Synthesis of aza mono, bi and tricyclic compounds. Evaluation of their anti MDR activity.Eur. J. Med. Chem.2003381192610.1016/S0223‑5234(02)01422‑812593913
     [Google Scholar]
  35. FacchinettiV. GomesC.R. AboudK. FiorotR. de CarvalhoG. PaierC.R. do Ó PessoaC. GomesA.C. de SouzaM.V. VasconcelosT. Design, synthesis, and molecular docking studies of new quinoline-thiazole hybrids, potential leads in the development of novel antileukemic agents.J. Braz. Chem. Soc.2024352e-2023013910.21577/0103‑5053.20230139
     [Google Scholar]
  36. de SouzaM.V. PaisK.C. KaiserC.R. PeraltaM.A. de L FerreiraM. LourençoM.C.S. Synthesis and in vitro antitubercular activity of a series of quinoline derivatives.Bioorg. Med. Chem.20091741474148010.1016/j.bmc.2009.01.01319188070
     [Google Scholar]
  37. FengY.Y. DongC.E. LiR. ZhangX.Q. WangW. ZhangX.R. LiuW.W. ShiD.H. Design, synthesis and biological evaluation of quinoline-1,2,4-triazine hybrids as antimalarial agents.J. Mol. Struct.2023127113398210.1016/j.molstruc.2022.133982
     [Google Scholar]
  38. SteckE.A. HallockL.L. SuterC.M. QuinolinesV.L. Quinolines; some 4-aminoquinoline derivatives.J. Am. Chem. Soc.194870124063406510.1021/ja01192a03018105939
     [Google Scholar]
  39. HeindelN.D. FineS.A. Acid catalyzed alcoholysis of 4,7-dichloroquinoline.J. Heterocycl. Chem.19696696110.1002/jhet.5570060635
     [Google Scholar]
  40. BauerA.W. KirbyW.M.M. SherrisJ.C. TurckM. Antibiotic susceptibility testing by a standardized single disk method.Am. J. Clin. Pathol.1966454_ts49349610.1093/ajcp/45.4_ts.4935325707
     [Google Scholar]
  41. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts; Approved StandardSecond EdUSAWest Valley Road2002
     [Google Scholar]
  42. de SousaA.P. SouzaH.D.S. Almeida-JúniorA. da SilvaM.F.R. CordeiroL.V. LimaE.O. FissG.F. de Athayde-FilhoP.F. Novel esters derived from 4-hydroxychalcones as potential sunscreens with antimicrobial action.Synth. Commun.2024541297399110.1080/00397911.2024.2356641
     [Google Scholar]
  43. NecoG.L.P.L. SantanaA.R. SilvaD.F. CostaD.M. AlvesC.Q. BrandãoH.N. JesusO.N. Atividade biológica e toxicidade frente à Artemia salina do acesso BGP 152 de Passiflora suberosa L.Revista RG News20228218
     [Google Scholar]
  44. BarrosA.G. Avaliação ADMET de substâncias.BIOINFO2023312510.51780/bioinfo‑03‑25
     [Google Scholar]
  45. DainaA. MichielinO. ZoeteV. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules.Sci. Rep.2017714271710.1038/srep4271728256516
     [Google Scholar]
  46. PiresD.E.V. BlundellT.L. AscherD.B. pkCSM: Predicting small-molecule pharmacokinetic and toxicity properties using graph-based signatures.J. Med. Chem.20155894066407210.1021/acs.jmedchem.5b0010425860834
     [Google Scholar]
  47. NgutaJ.M. MbariaJ.M. GakuyaD.W. GathumbiP.K. KabasaJ.D. KiamaS.G. Biological screening of Kenyan medicinal plants using Artemia salina L. (Artemiidae).Pharmacologyonline20112458478
     [Google Scholar]
  48. SharmaA. WakodeS. SharmaS. FayazF. PottooF.H. Methods and strategies used in green chemistry: A review.Curr. Org. Chem.202024222555256510.2174/1385272824999200802025233
     [Google Scholar]
  49. GroverT. SinghN. VajaM. Insights into quinoline in context of conventional versus green synthesis.Curr. Org. Chem.202327161381139210.2174/0113852728268691231009063856
     [Google Scholar]
  50. MartinsM.A.P. PereiraC.M.P. MouraS. FissG.F. FrizzoC.P. EmmerichD.J. ZanattaN. BonacorsoH.G. Preparation of novel 5-alkoxy-1,1,1,2,2-pentafluoroalk-4-en-3-ones and their application to a one-pot synthesis of azoles.ARKIVOC200620061318719410.3998/ark.5550190.0007.d20
     [Google Scholar]
  51. GonçalvesL.C. FissG.F. PerinG. AlvesD. JacobR.G. LenardãoE.J. Glycerol as a promoting medium for cross-coupling reactions of diaryl diselenides with vinyl bromides.Tetrahedron Lett.201051516772677510.1016/j.tetlet.2010.10.107
     [Google Scholar]
  52. FrizzoC.P. MoreiraD.N. GuardaE.A. FissG.F. MarzariM.R.B. ZanattaN. BonacorsoH.G. MartinsM.A.P. Ionic liquid as catalyst in the synthesis of N-alkyl trifluoromethyl pyrazoles.Catal. Commun.20091081153115610.1016/j.catcom.2008.12.030
     [Google Scholar]
  53. MartinsM.A.P. PeresR.L. FrizzoC.P. ScapinE. MoreiraD.N. FissG.F. ZanattaN. BonacorsoH.G. Solvent-free route to β-enamino dichloromethyl ketones and application in the synthesis of novel 5-dichloromethyl-1 H -pyrazoles.J. Heterocycl. Chem.20094661247125110.1002/jhet.227
     [Google Scholar]
  54. MartinsM.A.P. PeresR.L. FissG.F. DimerF.A. MayerR. FrizzoC.P. MarzariM.R.B. ZanattaN. BonacorsoH.G. A solvent-free synthesis of β-enamino trihalomethyl ketones.J. Braz. Chem. Soc.20071881486149110.1590/S0103‑50532007000800006
     [Google Scholar]
  55. RosaF. BonacorsoH. ZanattaN. FloresA. FissG. EmmerichD. ScapinE. MartinsM. CunicoW. Microwave-assisted regiospecific synthesis of 2-trifluoromethyl-7-trihalomethylated pyrazolo[1,5-a]pyrimidines.Lett. Org. Chem.20063535836210.2174/157017806776611962
     [Google Scholar]
  56. WHO fungal priority pathogens list to guide research, development and public health action.2022Available from: https://www.who.int/publications/i/item/9789240060241
  57. HotezP.J. AksoyS. BrindleyP.J. KamhawiS. What constitutes a neglected tropical disease?PLoS Negl. Trop. Dis.2020141000800110.1371/journal.pntd.000800131999732
     [Google Scholar]
  58. UsmanM. MarkusA. FatimaA. AslamB. ZaidM. KhattakM. BashirS. MasoodS. RafaqueZ. DastiJ.I. Synergistic effects of gentamicin, cefepime, and ciprofloxacin on biofilm of Pseudomonas aeruginosa. Infect. Drug Resist.2023165887589810.2147/IDR.S42611137692466
     [Google Scholar]
  59. AmmazzalorsoA. GraneseA. De FilippisB. Recent trends and challenges to overcome Pseudomonas aeruginosa infections.Expert Opin. Ther. Pat.202434649350910.1080/13543776.2024.234860238683024
     [Google Scholar]
  60. PasternakB. InghammarM. SvanströmH. Fluoroquinolone use and risk of aortic aneurysm and dissection: Nationwide cohort study.BMJ2018360k67810.1136/bmj.k67829519881
     [Google Scholar]
  61. FengX. ZhangZ. LiX. SongY. KangJ. YinD. GaoY. ShiN. DuanJ. Mutations in gyrB play an important role in ciprofloxacin-resistant Pseudomonas aeruginosa. Infect. Drug Resist.20191226127210.1136/bmj.k67830804676
     [Google Scholar]
  62. da Rosa Monte MachadoG. DiedrichD. RuaroT.C. ZimmerA.R. Lettieri TeixeiraM. de OliveiraL.F. JeanM. Van de WegheP. de AndradeS.F. Baggio GnoattoS.C. FuentefriaA.M. Quinolines derivatives as promising new antifungal candidates for the treatment of candidiasis and dermatophytosis.Braz. J. Microbiol.20205141691170110.1007/s42770‑020‑00348‑432737869
     [Google Scholar]
  63. OlmedoD.A. VásquezY. MoránJ.A. De LeónE.G. Caballero-GeorgeC. SolísP.N. Understanding the Artemia salina (brine shrimp) test: Pharmacological significance and global impact.Comb. Chem. High Throughput Screen.202427454555410.2174/138620732666623070309592837403396
     [Google Scholar]
/content/journals/cmc/10.2174/0109298673372039250614231629
Loading
Side Chain Effects on the Lipophilicity-antimicrobial-toxicity Correlation of Greener 4-Alkoxy/Amino-7-Chloroquinolines
Curr. Med. Chem. 33, 924 (2026); https://doi.org/10.2174/0109298673372039250614231629
/content/journals/cmc/10.2174/0109298673372039250614231629
/content/journals/cmc/10.2174/0109298673372039250614231629
Loading

Data & Media loading...

Supplements

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

file format download Download

  • Article Type:     Research Article
Keyword(s): 7-chloroquinolines; Antibiotics; Artemia salina; drug research; fungicides; green chemistry

Most Cited Most Cited RSS feed

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