Skip to content
2000
image of Novel 2-Acetanilide 2-Arylquinoline-4-carboxylates as Antileishmanial Agents: From Prediction to In Vitro Activity/Toxicity

Abstract

Alarming data on the neglected tropical disease leishmaniasis, especially for global visceral cases, have motivated the development of novel drugs to overcome the emergence of resistance. In this context, quinoline derivatives, especially quinoline-4-carboxylic acids, have shown promising antileishmanial activity. More recently, acetanilide linked quinoline derivatives revealed selective antileishmanial activity. Now, we are motivated to investigate the influence of the substituent group on antileishmanial and toxicity properties of sixteen 2-acetanilide 2-arylquinoline-4-carboxylates. To this end, the precursors, 2-arylquinoline-4-carboxylic acids, prepared from isatin through the Pfitzinger reaction, and 2-chloroacetanilides were used in an alkylation reaction to obtain the final products () in yields of 40-88%. Next, 2-acetanilide 2-arylquinoline-4-carboxylates () had their activity evaluated against promastigotes. From the MolPredictX program, all compounds were predicted to be active, and only four halogenated compounds (, , , ) were active by assays, with the best result for the compound (R/R’ = Br/Cl), IC = 17.08 ± 1.09 µM. From the pkCSM program, these compounds were predicted as non-mutagenic, hepatotoxic, and highly cytotoxic on Flathead Minnows. On the other hand, compounds showed moderate ecotoxicity on , with IC = 256-297 µg.mL-1. Finally, in contrast of Amphotericin B which caused relevant erythrocyte lysis starting from 50 μM, none of the compounds showed hemolytic activity. Furthermore, compounds were more selective against promastigotes than against human erythrocytes, with a selectivity index (HC/IC) > 15.63, which demonstrates a promising therapeutic window for 2-acetanilide 2-arylquinoline-4-carboxylates.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/coc/10.2174/0113852728371713250529122641
2025-06-19
2025-09-16

  • From This Site

    /content/journals/coc/10.2174/0113852728371713250529122641
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. The 2030 Agenda for Sustainable Development in the new global and regional context: scenarios and projections in the current crisis (LC/PUB.2020/5) Santiago Available from: https://sustainable-development.un.org/content/documents/26088ECLAC_contribution_ 2020.pdf
    [Google Scholar]
  2. Hotez P.J. Aksoy S. Brindley P.J. Kamhawi S. What constitutes a neglected tropical disease? PLoS Negl. Trop. Dis. 2020 14 1 e0008001 10.1371/journal.pntd.0008001 31999732
    [Google Scholar]
  3. Leishmaniasis 2023 Available from: https://www.who.int/data/gho/data/themes/topics/gho-ntd-leishmaniasis
  4. Mann S. Frasca K. Scherrer S. Henao-Martínez A.F. Newman S. Ramanan P. Suarez J.A. A review of leishmaniasis: Current knowledge and future directions. Curr. Trop. Med. Rep. 2021 8 2 121 132 10.1007/s40475‑021‑00232‑7 33747716
    [Google Scholar]
  5. de Freitas Milagres T. López-de-Felipe M. da Silva W.J. Martín-Martín I. Gálvez R. da Silva O.S. Same parasite, different outcomes: Unraveling the epidemiology of Leishmania infantum infection in Brazil and Spain. Trends Parasitol. 2023 39 9 774 785 10.1016/j.pt.2023.06.008 37442747
    [Google Scholar]
  6. Wijnant G.J. Dumetz F. Dirkx L. Bulté D. Cuypers B. Van Bocxlaer K. Hendrickx S. Tackling drug resistance and other causes of treatment failure in leishmaniasis. Front Trop. Dis. 2022 3 837460 10.3389/fitd.2022.837460
    [Google Scholar]
  7. 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]
  8. Ferreira D.S.P. Murie V.E. Santos T. Vieira P.C. Clososki G.C. Recent advances in selective functionalization of quinolines. Quim. Nova 2021 44 5 599 615 10.21577/0100‑4042.20170701
    [Google Scholar]
  9. Matada B.S. Pattanashettar R. Yernale N.G. A comprehensive review on the biological interest of quinoline and its derivatives. Bioorg. Med. Chem. 2021 32 115973 10.1016/j.bmc.2020.115973 33444846
    [Google Scholar]
  10. 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]
  11. 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]
  12. Silva C.F.M. Pinto D.C.G.A. Fernandes P.A. Silva A.M.S. Evolution of the quinoline scaffold for the treatment of leishmaniasis: A structural perspective. Pharmaceuticals 2024 17 3 285 10.3390/ph17030285 38543071
    [Google Scholar]
  13. Sangshetti J.N. Zambare A.S. Gonjari I. Shinde D.B. Pfitzinger reaction in the synthesis of bioactive compounds – A review. Mini Rev. Org. Chem. 2014 11 2 225 250 10.2174/1570193X113106660020
    [Google Scholar]
  14. Saha S. Pathak D. Shah K. Recent advances in the synthesis and applications of phenylquinoline-4-carboxylic acid derivatives: A comprehensive review. Curr. Org. Chem. 2024 28 1 9 20 10.2174/0113852728279082231226061243
    [Google Scholar]
  15. Abdelwahid M.A.S. Elsaman T. Mohamed M.S. Latif S.A. Mukhtar M.M. Mohamed M.A. Synthesis, characterization, and antileishmanial activity of certain quinoline-4-carboxylic acids. J. Chem. 2019 2019 1 1 9 10.1155/2019/2859637
    [Google Scholar]
  16. Muscia G.C. Carnevale J.P. Bollini M. Asís S.E. Microwave‐assisted döbner synthesis of 2‐phenylquinoline‐4‐carboxylic acids and their antiparasitic activities. J. Heterocycl. Chem. 2008 45 2 611 614 10.1002/jhet.5570450251
    [Google Scholar]
  17. Huang M.F. Luis J. da Silva A. Rocha J. Lima T. Scotti M. Scotti L. de Oliveira R. Souza H. de Athayde-Filho P. Barbosa-Filho J. Synthesis, in silico study and antileishmanial evaluation of new selenides derived from 7-chloro-quinoline and N-phenylacetamides. J. Braz. Chem. Soc. 2021 32 4 712 721 10.21577/0103‑5053.20200223
    [Google Scholar]
  18. Abdel-Latif E. Fahad M.M. Ismail M.A. Synthesis of N -aryl 2-chloroacetamides and their chemical reactivity towards various types of nucleophiles. Synth. Commun. 2020 50 3 289 314 10.1080/00397911.2019.1692225
    [Google Scholar]
  19. Pfitzinger W. Quinoline derivatives from isatinic acid. J. Prakt. Chem. 1886 33 1 100 10.1002/prac.18850330110
    [Google Scholar]
  20. Rashid M. Rafique H. Roshan S. Shamas S. Iqbal Z. Ashraf Z. Abbas Q. Hassan M. Qureshi Z.U.R. Asad M.H.H.B. Enzyme inhibitory kinetics and molecular docking studies of halo-substituted mixed ester/amide-based derivatives as jack bean urease inhibitors. BioMed Res. Int. 2020 2020 1 8867407 10.1155/2020/8867407 33426080
    [Google Scholar]
  21. Tullius Scotti M. Herrera-Acevedo C. Barros de Menezes R.P. Martin H.J. Muratov E.N. Ítalo de Souza Silva Á. Faustino Albuquerque E. Ferreira Calado L. Coy-Barrera E. Scotti L. MolPredictX: Online biological activity predictions by machine learning models. Mol. Inform. 2022 41 12 2200133 10.1002/minf.202200133 35961924
    [Google Scholar]
  22. Almeida F.S. Moreira V.P. Silva E.S. Cardoso L.L. de Sousa Palmeira P.H. Cavalcante-Silva L.H.A. Araújo D.A.M. Amaral I.P.G. González E.R.P. Keesen T.S.L. Leishmanicidal activity of guanidine derivatives against Leishmania infantum. Trop. Med. Infect. Dis. 2023 8 3 141 10.3390/tropicalmed8030141 36977142
    [Google Scholar]
  23. de Morais M.C. Medeiros G.A. Almeida F.S. Rocha J.C. Perez-Castillo Y. Keesen T.S.L. de Sousa D.P. Antileishmanial activity of cinnamic acid derivatives against Leishmania infantum. Molecules 2023 28 6 2844 10.3390/molecules28062844 36985814
    [Google Scholar]
  24. 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]
  25. 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]
  26. 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]
  27. 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]
  28. 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]
  29. Carolus H. Pierson S. Lagrou K. Van Dijck P. Amphotericin B and other polyenes – discovery, clinical use, mode of action and drug resistance. J. Fungi 2020 6 4 321 10.3390/jof6040321 33261213
    [Google Scholar]
  30. Patel G.P. Crank C.W. Leikin J.B. An evaluation of hepatotoxicity and nephrotoxicity of liposomal amphotericin B (L-AMB). J. Med. Toxicol. 2011 7 1 12 15 10.1007/s13181‑010‑0120‑8 21057910
    [Google Scholar]
  31. Serrano D.R. Hernández L. Fleire L. González-Alvarez I. Montoya A. Ballesteros M.P. Dea-Ayuela M.A. Miró G. Bolás-Fernández F. Torrado J.J. Hemolytic and pharmacokinetic studies of liposomal and particulate amphotericin B formulations. Int. J. Pharm. 2013 447 1-2 38 46 10.1016/j.ijpharm.2013.02.038 23438978
    [Google Scholar]
  32. Soares J.R. Nunes M.C.P. Leite A.F. Falqueto E.B. Lacerda B.E.R.A. Ferrari T.C.A. Reversible dilated cardiomyopathy associated with amphotericin B therapy. J. Clin. Pharm. Ther. 2015 40 3 333 335 10.1111/jcpt.12237 25487534
    [Google Scholar]
  33. Upadhyay A. Chandrakar P. Gupta S. Parmar N. Singh S.K. Rashid M. Kushwaha P. Wahajuddin M. Sashidhara K.V. Kar S. Synthesis, biological evaluation, structure–activity relationship, and mechanism of action studies of quinoline–metronidazole derivatives against experimental visceral leishmaniasis. J. Med. Chem. 2019 62 11 5655 5671 10.1021/acs.jmedchem.9b00628 31124675
    [Google Scholar]
  34. Patel D.B. Rajani D.P. Rajani S.D. Patel H.D. A green synthesis of quinoline‐4‐carboxylic derivatives using p ‐toluenesulfonic acid as an efficient organocatalyst under microwave irradiation and their docking, molecular dynamics, ADME‐Tox and biological evaluation. J. Heterocycl. Chem. 2020 57 4 1524 1544 10.1002/jhet.3848
    [Google Scholar]
  35. 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 1285 1296 10.2174/0113852728310711240525123954
    [Google Scholar]
/content/journals/coc/10.2174/0113852728371713250529122641
Loading
Novel 2-Acetanilide 2-Arylquinoline-4-carboxylates as Antileishmanial Agents: From Prediction to In Vitro Activity/Toxicity
Bentham Science Publishers ; https://doi.org/10.2174/0113852728371713250529122641
/content/journals/coc/10.2174/0113852728371713250529122641
/content/journals/coc/10.2174/0113852728371713250529122641
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: pfitzinger reaction ; hemolysis ; bioinformatics ; Leishmania infantum ; Artemia salina ; isatin

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