Skip to content
2000
image of Side Chain Effects on the ipophilicity-antimicrobial-toxicity Correlation of Greener 4-Alkoxy/Amino-7-Chloroquinolines
file format pdf download PDF

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.

© 2025 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
2025-10-18

  • 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/10.2174/0109298673372039250614231629/BMS-CMC-2024-HT139-6061-15.html?itemId=/content/journals/cmc/10.2174/0109298673372039250614231629&mimeType=html&fmt=ahah

References

  1. Behera S. Mohanty P. Behura R. Barick A.K. Jali B.R. Antibacterial properties of quinoline derivatives: A mini-review. Biointerface Res. Appl. Chem. 2021 12 5 6078 6092 10.33263/BRIAC125.60786092
    [Google Scholar]
  2. Li J. Gu A. Nong X.M. Zhai S. Yue Z.Y. Li M.Y. Liu Y. Six-membered aromatic nitrogen heterocyclic anti-tumor agents: Synthesis and applications. Chem. Rec. 2023 23 12 202300293 10.1002/tcr.202300293 38010365
    [Google Scholar]
  3. Nitrogen Heterocyclic Compounds. 2023 Available from: https://oec.world/en/profile/hs/nitrogen-heterocyclic-compounds (accessed December 4, 2023).
  4. Kerru N. Gummidi L. Maddila S. Gangu K.K. Jonnalagadda S.B. A review on recent advances in nitrogen-containing molecules and their biological applications. Molecules 2020 25 8 1909 10.3390/molecules25081909 32326131
    [Google Scholar]
  5. Dib M. Ouchetto H. Ouchetto K. Hafid A. Khouili M. Recent developments of quinoline derivatives and their potential biological activities. Curr. Org. Synth. 2021 18 3 248 269 10.2174/1570179417666201216162055 33327918
    [Google Scholar]
  6. Moor L.F.E. Vasconcelos T.R.A. da R Reis R. Pinto L.S.S. da Costa T.M. Quinoline: An attractive scaffold in drug design. Mini Rev. Med. Chem. 2021 21 16 2209 2226 10.2174/1389557521666210210155908 33568032
    [Google Scholar]
  7. da Silva S.E.B. da Silva Moura J.A. de Sousa Nunes T.R. da Rocha Pitta I. da Rocha Pitta M.G. New trends in biological activities and clinical studies of quinolinic analogues: A review. Curr. Drug Targets 2022 23 5 441 457 10.2174/1389450122666210415100151 33858312
    [Google Scholar]
  8. Sharma S. Singh K. Singh S. Synthetic strategies for quinoline based derivatives as potential bioactive heterocycles. Curr. Org. Synth. 2023 20 6 606 629 10.2174/1570179420666221004143910 36200204
    [Google Scholar]
  9. Egan T.J. Hunter R. Kaschula C.H. Marques H.M. Misplon A. Walden J. 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. 2000 43 2 283 291 10.1021/jm990437l 10649984
    [Google Scholar]
  10. Natarajan J.K. Alumasa J.N. Yearick K. Ekoue-Kovi K.A. Casabianca L.B. de Dios A.C. Wolf C. Roepe P.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. 2008 51 12 3466 3479 10.1021/jm701478a 18512900
    [Google Scholar]
  11. Pallaval V.B. Kanithi M. Meenakshisundaram S. Jagadeesh A. Alavala M. Pillaiyar T. Manickam M. Chidipi B. Chloroquine analogs: An overview of natural and synthetic quinolines as broad spectrum antiviral agents. Curr. Pharm. Des. 2021 27 9 1185 1193 10.2174/1381612826666201211121721 33308117
    [Google Scholar]
  12. Chiodi D. Ishihara Y. “Magic chloro”: Profound effects of the chlorine atom in drug discovery. J. Med. Chem. 2023 66 8 5305 5331 10.1021/acs.jmedchem.2c02015 37014977
    [Google Scholar]
  13. Kaiser C.R. Pais K.C. de Souza M.V.N. Wardell J.L. Wardell S.M.S.V. Tiekink E.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. CrystEngComm 2009 11 6 1133 1140 10.1039/b823058g
    [Google Scholar]
  14. Copetti J.P.P. Salbego P.R.S. Orlando T. Rosa J.M.L. Fiss G.F. Oliveira J.P.G. Vasconcellos M.L.A.A. Zanatta N. Bonacorso H.G. Martins M.A.P. Substituent effects on the crystallization mechanisms of 7-chloro-4-substituted-quinolines. CrystEngComm 2020 22 24 4094 4107 10.1039/D0CE00214C
    [Google Scholar]
  15. Taramelli D. Tognazioli C. Ravagnani F. Leopardi O. Giannulis G. Boelaert J.R. Inhibition of intramacrophage growth of Penicillium marneffei by 4-aminoquinolines. Antimicrob. Agents Chemother. 2001 45 5 1450 1455 10.1128/AAC.45.5.1450‑1455.2001 11302809
    [Google Scholar]
  16. Devi K. Asmat Y. Jain S. Sharma S. Dwivedi J. An efficient approach to the synthesis of novel oxazolidinones as potential antimicrobial agents. J. Chem. 2013 2013 1 252187 10.1155/2013/252187
    [Google Scholar]
  17. Perković I. Poljak T. Savijoki K. Varmanen P. Maravić-Vlahoviček G. Beus M. Kučević A. Džajić I. Rajić Z. Synthesis and biological evaluation of new quinoline and anthranilic acid derivatives as potential quorum sensing inhibitors. Molecules 2023 28 15 5866 10.3390/molecules28155866 37570836
    [Google Scholar]
  18. Harrold M.W. Zavod R.M. Basic concepts in medicinal chemistry. Drug Dev. Ind. Pharm. 2014 40 7 988 10.3109/03639045.2013.789908
    [Google Scholar]
  19. Nogueira L.J. Montanari C.A. Donnici C.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 Química 2009 1 3 227 240 10.5935/1984‑6835.20090023
    [Google Scholar]
  20. Lipinski C.A. Lombardo F. Dominy B.W. Feeney P.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev. 2001 46 1-3 3 25 10.1016/S0169‑409X(96)00423‑1
    [Google Scholar]
  21. Lipinski C.A. Lombardo F. Dominy B.W. Feeney P.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev. 2012 64 Suppl. 4 17 10.1016/j.addr.2012.09.019 11259830
    [Google Scholar]
  22. Lipinski C.A. Lead- and drug-like compounds: The rule-of-five revolution. Drug Discov. Today. Technol. 2004 1 4 337 341 10.1016/j.ddtec.2004.11.007 24981612
    [Google Scholar]
  23. Veber D.F. Johnson S.R. Cheng H.Y. Smith B.R. Ward K.W. Kopple K.D. Molecular properties that influence the oral bioavailability of drug candidates. J. Med. Chem. 2002 45 12 2615 2623 10.1021/jm020017n 12036371
    [Google Scholar]
  24. Lipinski C.A. Reaume A.G. Phenotypic screening of low molecular weight compounds is rich ground for repurposed, on-target drugs. Front. Pharmacol. 2022 13 917968 10.3389/fphar.2022.917968 36003497
    [Google Scholar]
  25. Yu E. Mangunuru H.P.R. Telang N.S. Kong C.J. Verghese J. Gilliland S.E. III Ahmad S. Dominey R.N. Gupton B.F. High-yielding continuous-flow synthesis of antimalarial drug hydroxychloroquine. Beilstein J. Org. Chem. 2018 14 583 592 10.3762/bjoc.14.45 29623120
    [Google Scholar]
  26. Shaik R. Rao H.S.P. Hydroxychloroquine (HCQ) and its synthetic precursors: A review. Mini Rev. Org. Chem. 2022 19 1 111 124 10.2174/1570193X18666210204113412
    [Google Scholar]
  27. Alves F. Oliveira R. Souza H. Lima P. Farias F. Marzari B. Coelho H. Luis J. Athayde-Filho P. Fiss G. Cleaner approach and antimicrobial screening of 2-selenoacetanilides: Emergence of potential agents against co-infection. J. Sulfur Chem. 2025 46 2 212 225 10.1080/17415993.2024.2449383
    [Google Scholar]
  28. Alves F.S. Sousa A.P. Almeida-Júnior A. Lima P.S.V. Silva M.F.R. Galvão J.L.F.M. Lima E.O. Souza H.D.S. Luis J.A.S. Athayde-Filho P.F. Fiss G.F. Antimicrobial investigation of phthalimide and N-phthaloylglycine esters: Activity, mechanism of action, synergism and ecotoxicity. Life 2025 15 4 518 10.3390/life15040518
    [Google Scholar]
  29. Almeida-Júnior A. Souza H.D.S. Sousa A.P. Dantas M.V.O. Sampaio F.C. Luis J.A.S. Rodrigues-Junior V.S. Barbosa-Filho J.M. Fiss G.F. Athayde-Filho P.F. In silico/vitro study of antibacterial effects of non-toxic cinnamic amidoesters on Artemia salina. Curr. Org. Chem. 2025 29 16 10.2174/0113852728310711240525123954
    [Google Scholar]
  30. Craig J.C. Jr Pearson D.E. NMR proof of the structure of 4-aminoquinolines and pyridines. J. Heterocycl. Chem. 1968 5 5 631 637 10.1002/jhet.5570050508
    [Google Scholar]
  31. Bolte J. Demuynck C. Lhomme J. Synthetic models of DNA complexes with antimalarial compounds. 2. The problem of guanine specificity in chloroquine binding. J. Med. Chem. 1977 20 1 106 113 10.1021/jm00211a022 833808
    [Google Scholar]
  32. Michne W.F. Guiles J.W. Treasurywala A.M. Castonguay L.A. Weigelt C.A. Oconnor B. Volberg W.A. Grant A.M. Chadwick C.C. Krafte D.S. Hill R.J. Novel inhibitors of potassium ion channels on human T lymphocytes. J. Med. Chem. 1995 38 11 1877 1883 10.1021/jm00011a007 7540207
    [Google Scholar]
  33. Kitel R. Surmiak E. Borggräfe J. Kalinowska-Tluscik J. Golik P. Czub M. Uzar W. Musielak B. Madej M. Popowicz G.M. Dubin G. Holak T.A. Discovery of inhibitory fragments that selectively target Spire2–FMN2 interaction. J. Med. Chem. 2023 66 23 15715 15727 10.1021/acs.jmedchem.3c00877 38039505
    [Google Scholar]
  34. Gallo S. Atifi S. Mahamoud A. Santelli-Rouvier C. Wolfárt K. Molnar J. Barbe J. Synthesis of aza mono, bi and tricyclic compounds. Evaluation of their anti MDR activity. Eur. J. Med. Chem. 2003 38 1 19 26 10.1016/S0223‑5234(02)01422‑8 12593913
    [Google Scholar]
  35. Facchinetti V. Gomes C.R. Aboud K. Fiorot R. de Carvalho G. Paier C.R. do Ó Pessoa C. Gomes A.C. de Souza M.V. Vasconcelos T. Design, synthesis, and molecular docking studies of new quinoline-thiazole hybrids, potential leads in the development of novel antileukemic agents. J. Braz. Chem. Soc. 2024 35 2 e-20230139 10.21577/0103‑5053.20230139
    [Google Scholar]
  36. de Souza M.V. Pais K.C. Kaiser C.R. Peralta M.A. de L Ferreira M. Lourenço M.C.S. Synthesis and in vitro antitubercular activity of a series of quinoline derivatives. Bioorg. Med. Chem. 2009 17 4 1474 1480 10.1016/j.bmc.2009.01.013 19188070
    [Google Scholar]
  37. Feng Y.Y. Dong C.E. Li R. Zhang X.Q. Wang W. Zhang X.R. Liu W.W. Shi D.H. Design, synthesis and biological evaluation of quinoline-1,2,4-triazine hybrids as antimalarial agents. J. Mol. Struct. 2023 1271 133982 10.1016/j.molstruc.2022.133982
    [Google Scholar]
  38. Steck E.A. Hallock L.L. Suter C.M. Quinolines V.L. Quinolines; some 4-aminoquinoline derivatives. J. Am. Chem. Soc. 1948 70 12 4063 4065 10.1021/ja01192a030 18105939
    [Google Scholar]
  39. Heindel N.D. Fine S.A. Acid catalyzed alcoholysis of 4,7-dichloroquinoline. J. Heterocycl. Chem. 1969 6 6 961 10.1002/jhet.5570060635
    [Google Scholar]
  40. Bauer A.W. Kirby W.M.M. Sherris J.C. Turck M. Antibiotic susceptibility testing by a standardized single disk method. Am. J. Clin. Pathol. 1966 45 4_ts 493 496 10.1093/ajcp/45.4_ts.493 5325707
    [Google Scholar]
  41. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts; Approved Standard Second Ed USA West Valley Road 2002
    [Google Scholar]
  42. de Sousa A.P. Souza H.D.S. Almeida-Júnior A. da Silva M.F.R. Cordeiro L.V. Lima E.O. Fiss G.F. de Athayde-Filho P.F. Novel esters derived from 4-hydroxychalcones as potential sunscreens with antimicrobial action. Synth. Commun. 2024 54 12 973 991 10.1080/00397911.2024.2356641
    [Google Scholar]
  43. Neco G.L.P.L. Santana A.R. Silva D.F. Costa D.M. Alves C.Q. Brandão H.N. Jesus O.N. Atividade biológica e toxicidade frente à Artemia salina do acesso BGP 152 de Passiflora suberosa L. Revista RG News 2022 8 2 1 8
    [Google Scholar]
  44. Barros A.G. Avaliação ADMET de substâncias. BIOINFO 2023 3 1 25 10.51780/bioinfo‑03‑25
    [Google Scholar]
  45. Daina A. Michielin O. Zoete V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep. 2017 7 1 42717 10.1038/srep42717 28256516
    [Google Scholar]
  46. Pires D.E.V. Blundell T.L. Ascher D.B. pkCSM: Predicting small-molecule pharmacokinetic and toxicity properties using graph-based signatures. J. Med. Chem. 2015 58 9 4066 4072 10.1021/acs.jmedchem.5b00104 25860834
    [Google Scholar]
  47. Nguta J.M. Mbaria J.M. Gakuya D.W. Gathumbi P.K. Kabasa J.D. Kiama S.G. Biological screening of Kenyan medicinal plants using Artemia salina L. (Artemiidae). Pharmacologyonline 2011 2 458 478
    [Google Scholar]
  48. Sharma A. Wakode S. Sharma S. Fayaz F. Pottoo F.H. Methods and strategies used in green chemistry: A review. Curr. Org. Chem. 2020 24 22 2555 2565 10.2174/1385272824999200802025233
    [Google Scholar]
  49. Grover T. Singh N. Vaja M. Insights into quinoline in context of conventional versus green synthesis. Curr. Org. Chem. 2023 27 16 1381 1392 10.2174/0113852728268691231009063856
    [Google Scholar]
  50. Martins M.A.P. Pereira C.M.P. Moura S. Fiss G.F. Frizzo C.P. Emmerich D.J. Zanatta N. Bonacorso H.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. ARKIVOC 2006 2006 13 187 194 10.3998/ark.5550190.0007.d20
    [Google Scholar]
  51. Gonçalves L.C. Fiss G.F. Perin G. Alves D. Jacob R.G. Lenardão E.J. Glycerol as a promoting medium for cross-coupling reactions of diaryl diselenides with vinyl bromides. Tetrahedron Lett. 2010 51 51 6772 6775 10.1016/j.tetlet.2010.10.107
    [Google Scholar]
  52. Frizzo C.P. Moreira D.N. Guarda E.A. Fiss G.F. Marzari M.R.B. Zanatta N. Bonacorso H.G. Martins M.A.P. Ionic liquid as catalyst in the synthesis of N-alkyl trifluoromethyl pyrazoles. Catal. Commun. 2009 10 8 1153 1156 10.1016/j.catcom.2008.12.030
    [Google Scholar]
  53. Martins M.A.P. Peres R.L. Frizzo C.P. Scapin E. Moreira D.N. Fiss G.F. Zanatta N. Bonacorso H.G. Solvent-free route to β-enamino dichloromethyl ketones and application in the synthesis of novel 5-dichloromethyl-1 H -pyrazoles. J. Heterocycl. Chem. 2009 46 6 1247 1251 10.1002/jhet.227
    [Google Scholar]
  54. Martins M.A.P. Peres R.L. Fiss G.F. Dimer F.A. Mayer R. Frizzo C.P. Marzari M.R.B. Zanatta N. Bonacorso H.G. A solvent-free synthesis of β-enamino trihalomethyl ketones. J. Braz. Chem. Soc. 2007 18 8 1486 1491 10.1590/S0103‑50532007000800006
    [Google Scholar]
  55. Rosa F. Bonacorso H. Zanatta N. Flores A. Fiss G. Emmerich D. Scapin E. Martins M. Cunico W. Microwave-assisted regiospecific synthesis of 2-trifluoromethyl-7-trihalomethylated pyrazolo[1,5-a]pyrimidines. Lett. Org. Chem. 2006 3 5 358 362 10.2174/157017806776611962
    [Google Scholar]
  56. WHO fungal priority pathogens list to guide research, development and public health action. 2022 Available from: https://www.who.int/publications/i/item/9789240060241
  57. Hotez P.J. Aksoy S. Brindley P.J. Kamhawi S. What constitutes a neglected tropical disease? PLoS Negl. Trop. Dis. 2020 14 1 0008001 10.1371/journal.pntd.0008001 31999732
    [Google Scholar]
  58. Usman M. Markus A. Fatima A. Aslam B. Zaid M. Khattak M. Bashir S. Masood S. Rafaque Z. Dasti J.I. Synergistic effects of gentamicin, cefepime, and ciprofloxacin on biofilm of Pseudomonas aeruginosa. Infect. Drug Resist. 2023 16 5887 5898 10.2147/IDR.S426111 37692466
    [Google Scholar]
  59. Ammazzalorso A. Granese A. De Filippis B. Recent trends and challenges to overcome Pseudomonas aeruginosa infections. Expert Opin. Ther. Pat. 2024 34 6 493 509 10.1080/13543776.2024.2348602 38683024
    [Google Scholar]
  60. Pasternak B. Inghammar M. Svanström H. Fluoroquinolone use and risk of aortic aneurysm and dissection: Nationwide cohort study. BMJ 2018 360 k678 10.1136/bmj.k678 29519881
    [Google Scholar]
  61. Feng X. Zhang Z. Li X. Song Y. Kang J. Yin D. Gao Y. Shi N. Duan J. Mutations in gyrB play an important role in ciprofloxacin-resistant Pseudomonas aeruginosa. Infect. Drug Resist. 2019 12 261 272 10.1136/bmj.k678 30804676
    [Google Scholar]
  62. da Rosa Monte Machado G. Diedrich D. Ruaro T.C. Zimmer A.R. Lettieri Teixeira M. de Oliveira L.F. Jean M. Van de Weghe P. de Andrade S.F. Baggio Gnoatto S.C. Fuentefria A.M. Quinolines derivatives as promising new antifungal candidates for the treatment of candidiasis and dermatophytosis. Braz. J. Microbiol. 2020 51 4 1691 1701 10.1007/s42770‑020‑00348‑4 32737869
    [Google Scholar]
  63. Olmedo D.A. Vásquez Y. Morán J.A. De León E.G. Caballero-George C. Solís P.N. Understanding the Artemia salina (brine shrimp) test: Pharmacological significance and global impact. Comb. Chem. High Throughput Screen. 2024 27 4 545 554 10.2174/1386207326666230703095928 37403396
    [Google Scholar]
/content/journals/cmc/10.2174/0109298673372039250614231629
Loading
Side Chain Effects on the ipophilicity-antimicrobial-toxicity Correlation of Greener 4-Alkoxy/Amino-7-Chloroquinolines
Bentham Science Publishers ; 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
Keywords: Artemia salina ; drug research ; fungicides ; green chemistry ; 7-chloroquinolines ; Antibiotics

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