Activity In Vitro of 2-Chloro-N-[4-(4-Chlorophenyl)-2-Thiazolyl]Acetamide Against Promastigotes of Leishmania mexicana: An Apoptosis Inducer

Abstract

Purpose

Leishmaniasis is an infectious disease transmitted by insects that proliferate mainly in impoverished environments of tropical climates. In the absence of an effective vaccine, pharmacological treatment is the main tool to combat this disease. The objective of this work was to analyze the anti-leishmanial activity of 2-chloro-N-[4-(4-chlorophenyl)-2-thiazolyl] acetamide (AT) in promastigotes of Leishmania mexicana.

Methods

The biological activity of the compound was evaluated using a sulphorhodamine B cytotoxicity test and the integrity of the erythrocytes was evaluated by a lysis test. The anti-trypanosomatid activity was evaluated in vitro, a cell death assay was performed by flow cytometry (IP/Annexin V stain) and a parasite growth recovery assay was performed.

Results

The AT showed a CC50 value of 0.031 µM for HeLa cells after 24 h of exposure, which did not induce erythrocyte lysis. On the other hand, the AT showed an IC50 value of 0.086 µM for L. mexicana (promastigote form) after 24 h of interaction. The compound was capable of inducing apoptosis in the parasites and did not allow recovery after 24 h of exposure.

Conclusion

This study provides valuable information with the objective of developing new drugs for the treatment of this disease, although more research on this molecule is needed to improve its biological activity.

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Data Availability

Data generated and analyzed during this study were included in this published article.

References

  1. 1.

    Savoia D (2015) Recent updates and perspectives on leishmaniasis. J Infect Dev Ctries 9(6):588–596. PMID: 26142667. https://doi.org/10.3855/jidc.6833.

    CAS  Article  Google Scholar 

  2. 2.

    Chatelain E (2015) Chagas disease drug discovery: toward a new era. J Biomol Screen 20(1):22–35. Epub 22 Sep 2014. PMID: 25245987. https://doi.org/10.1177/1087057114550585

    Article  Google Scholar 

  3. 3.

    Ghorbani M, Farhoudi R (2017) Leishmaniasis in humans: drug or vaccine therapy? Drug Des Dev Ther 12:25–40. PMID: 29317800; PMCID: PMC5743117. https://doi.org/10.2147/DDDT.S146521

    Article  Google Scholar 

  4. 4.

    Rouf A, Tanyeli C (2015) Bioactive thiazole and benzothiazole derivatives. Eur J Med Chem 97:911–927. Epub 22 Oct 2014. PMID: 25455640. https://doi.org/10.1016/j.ejmech.2014.10.058

    CAS  Article  Google Scholar 

  5. 5.

    Lu Y, Li CM, Wang Z, Ross CR 2nd, Chen J, Dalton JT et al (2009) Discovery of 4-substituted methoxybenzoyl-aryl-thiazole as novel anticancer agents: synthesis, biological evaluation, and structure-activity relationships. J Med Chem 52(6):1701–1711. PMID: 19243174; PMCID: PMC2760094. https://doi.org/10.1021/jm801449a

    CAS  Article  Google Scholar 

  6. 6.

    Barreca ML, Balzarini J, Chimirri A, De Clercq E, De Luca L, Höltje HD et al (2002) Design, synthesis, structure-activity relationships, and molecular modeling studies of 2,3-diaryl-1,3-thiazolidin-4-ones as potent anti-HIV agents. J Med Chem 45(24):5410–5413. PMID: 12431069. https://doi.org/10.1021/jm020977+

    CAS  Article  Google Scholar 

  7. 7.

    Cuenca-Estrella M, Gomez-Lopez A, Mellado E, Garcia-Effron G, Rodriguez-Tudela JL (2004) In vitro activities of ravuconazole and four other antifungal agents against fluconazole-resistant or -susceptible clinical yeast isolates. Antimicrob Agents Chemother 48:3107–3111. PMID: 15273127; PMCID: PMC478504. https://doi.org/10.1128/AAC.48.8.3107-3111.2004

    CAS  Article  Google Scholar 

  8. 8.

    Mohareb RM, Zaki MY, Abbas NS (2015) Synthesis, anti-inflammatory and anti-ulcer evaluations of thiazole, thiophene, pyridine and pyran derivatives derived from androstenedione. Steroids 98:80–91. Epub 07 Mar 2015. PMID: 25759119. https://doi.org/10.1016/j.steroids.2015.03.001

    CAS  Article  Google Scholar 

  9. 9.

    Papadopoulou MV, Trunz BB, Bloomer BW, McKenzie C, Wilkinson SR, Prasittichai C et al (2011) Novel 3-nitro-1H-1,2,4-triazole-based aliphatic and aromatic amines as anti-Chagasic agents. J Med Chem 54(23):8214–8223. Epub 04 Nov 2011. PMID: 22023653; PMCID: PMC3258117. https://doi.org/10.1021/jm201215n

    CAS  Article  Google Scholar 

  10. 10.

    Papadopoulou MV, Bloomer BW, Rosenzweig HS, Wilkinson SR, Kaiser M, Chatelain E et al (2015) Discovery of potent nitrotriazole-based antitrypanosomal agents: in vitro and in vivo evaluation. Bioorg Med Chem 23(19):6467–6476. Epub 24 Aug 2015. PMID: 26344593. https://doi.org/10.1016/j.bmc.2015.08.014

    CAS  Article  Google Scholar 

  11. 11.

    Ramos-Ligonio A, López-Monteon A, Trigos A (2012) Trypanocidal activity of ergosterol peroxide from Pleurotus ostreatus. Phytother Res 26(6):938–943. Epub 14 Nov 2011. PMID: 22083593. https://doi.org/10.1002/ptr.3653.

    CAS  Article  Google Scholar 

  12. 12.

    Papazisis KT, Geromichalos GD, Dimitriadis KA, Kortsaris AH (1997) Optimization of the sulforhodamine B colorimetric assay. J Immunol Methods 208(2):151–158. PMID: 9433470. https://doi.org/10.1016/s0022-1759(97)00137-3

    CAS  Article  Google Scholar 

  13. 13.

    Nwaka S, Ramirez B, Brun R, Maes L, Douglas F, Ridley R (2009) Advancing drug innovation for neglected diseases—criteria for lead progression. PLoS Negl Trop Dis 3(8):e440. PMID: 19707561; PMCID: PMC2727960. https://doi.org/10.1371/journal.pntd.0000440

    Article  Google Scholar 

  14. 14.

    Yurttas L, Özkay Y, Gençer HK, Acar U (2015) Synthesis of some new thiazole derivatives and their biological activity evaluation. J Chem ID 464379. https://doi.org/10.1155/2015/464379

  15. 15.

    Nava-Zuazo C, Chávez-Silva F, Moo-Puc R, Chan-Bacab MJ, Ortega-Morales BO, Moreno-Díaz H et al (2014) 2-acylamino-5-nitro-1,3-thiazoles: preparation and in vitro bioevaluation against four neglected protozoan parasites. Bioorg Med Chem 22(5):1626–1633. Epub 31 Jan 2014. PMID: 24529307. https://doi.org/10.1016/j.bmc.2014.01.029

    CAS  Article  Google Scholar 

  16. 16.

    Serban G (2019) Future prospects in the treatment of parasitic diseases: 2-amino-1,3,4-thiadiazoles in leishmaniasis. Molecules 24(8):1557. PMID: 31010226; PMCID: PMC6514673. https://doi.org/10.3390/molecules24081557

    CAS  Article  Google Scholar 

  17. 17.

    Bestgen B, Kufareva I, Seetoh W, Abell C, Hartmann RW, Abagyan R et al (2019) 2-Aminothiazole derivatives as selective allosteric modulators of the protein kinase CK2. 2. Structure-based optimization and investigation of effects specific to the allosteric mode of action. J Med Chem 62(4):1817–1836. Epub 13 Feb 2019. PMID: 30689946; PMCID: PMC7579840. https://doi.org/10.1021/acs.jmedchem.8b01765

    CAS  Article  Google Scholar 

  18. 18.

    Jiang FC, Cheng CY (2006) The design and synthesis of 2-aminothiazole derivatives and their inhibitory activity on apoptosis. Yao Xue Xue Bao 41(8):727–734. PMID: 17039777.

    CAS  PubMed  Google Scholar 

  19. 19.

    Fietta P (2006) Many ways to die: passive and active cell death styles. Riv Biol 99(1):69–83. PMID: 16791791.

    PubMed  Google Scholar 

  20. 20.

    Da Silva EB, Silva OEDA, Oliveira AR, da Silva Mendes CH, Dos Santos TA, da Silva AC et al (2017) Design and synthesis of potent anti-trypanosoma cruzi agents new thiazoles derivatives which induce apoptotic parasite death. Eur J Med Chem 130:39–50. Epub 2017 Feb 16. PMID: 28242550. https://doi.org/10.1016/j.ejmech.2017.02.026

    Article  Google Scholar 

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Acknowledgements

The authors thanks to Estefanía Ramos-López, Roberto Meza-Romero and Eric Dumonteil for her appreciation of the manuscript. Mario Daniel Caba-Flores was a recipient of a Ph.D. fellowship from CONACyT, Mexico (451898).

Funding

This research was funded by the Universidad Veracruzana (Prize for interdisciplinary research 2019–2020).

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Authors

Contributions

Conceptualization: AR-L, DHR; Data curation: AR-L; Formal analysis: MDC-F, VAR-C, JL-D; Funding acquisition: DHR; Investigation: VAR-C, JL-D, DCV-O, ÁT, AYLF, ES-P, MDC-F; Project administration: AR-L, DHR; Resources: DHR, ES-P; Supervision: DHR, AL-M, AR-L; Validation: MDC-F, DHR, AL-M, ES-P, DCV-O, JL-D, VAR-C, AYLF, ÁT, AR-L; Visualization: DHR, AL-M, AR-L; Writing—original draft: MDC-F, DHR; Writing—review and editing: AL-M, AR-L.

Corresponding author

Correspondence to Angel Ramos-Ligonio.

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Conflict of Interest

The authors have no conflict of interest to declare.

Ethical Approval

The project was reviewed and approved by the Ethical Committee of the Faculty of Chemical Sciences (FCQ/057/08/2019).

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Caba-Flores, M.D., Hernández-Romero, D., López-Monteon, A. et al. Activity In Vitro of 2-Chloro-N-[4-(4-Chlorophenyl)-2-Thiazolyl]Acetamide Against Promastigotes of Leishmania mexicana: An Apoptosis Inducer. Acta Parasit. (2021). https://doi.org/10.1007/s11686-020-00328-6

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Keywords

  • Neglected tropical diseases
  • Aminothiazole derivatives
  • Leishmaniasis
  • Apoptosis
  • Infectious disease