Advertisement

Medicinal Chemistry Research

, Volume 28, Issue 12, pp 2184–2199 | Cite as

Chroman-4-one hydrazones derivatives: synthesis, characterization, and in vitro and in vivo antileishmanial effects

  • Yulieth Upegui
  • Karina Rios
  • Wiston Quiñones
  • Fernando EcheverriEmail author
  • Rosendo Archbold
  • Javier D. Murillo
  • Fernando Torres
  • Gustavo Escobar
  • Iván D. Vélez
  • Sara M. RobledoEmail author
Original Research
  • 98 Downloads

Abstract

In searching for better therapeutic alternatives to treat cutaneous leishmaniasis (CL), this study aimed to obtain and evaluate the efficacy and toxicity of new chroman-4-one hydrazones derivatives. Compounds were prepared and characterized, and then transformed into hydrazonas for molecular optimization. Their cytotoxicity was tested in different cell types using an in vitro MTT assay and the efficacy was evaluated using an in vitro macrophage intracellular amastigotes of Leishmania (Viannia) panamensis and L. (V) braziliensis by flow cytometry. The therapeutic effect of two formulations of chroman-4-one hydrazones on the CL induced by L. (V) braziliensis in golden hamsters was determined according to the size of lesions after treatment. The effect of these compounds in the production of inflammatory mediators and cell migration was also determined by in vitro assays using human fibroblasts models. Neither cytotoxicity nor genotoxicity was observed. The benzoic acid hydrazone derivative 2-(2,3-dihydro-4H-1-benzopyran-4-ylidene) hydrazide (4), produced a higher percentage of clinical cures, followed by benzoic acid, 2-(2,3-dihydro-4H-1-benzothiopyran-4-ylidene) hydrazide (3), while benzoic acid, 2-(2,3-dihydro-1,1-dioxide-4H-1-benzothiopyran-4-ylidene) hydrazide (5) and 4-pyridinecarboxylic acid, 2-(4H-1-benzopyran-4-ylidene) hydrazide (6) caused a poor therapeutic response. The compound 4 also showed an effect in the inflammatory and fibroblast migration processes. In conclusion, this is the first report of antileishmanial activity combined with inflammatory and wound healing properties. Results obtained here suggest that this strategy could be a good alternative for development of new drugs for the treatment of CL.

Keywords

Chromans Hydrazones Ointment Cutaneous leishmaniasis Animal model cure Healing 

Notes

Acknowledgements

This work was a cooperative activity within the Temporal Union “Estrategia Integral para el control de la Leishmaniasis en Colombia” (EICOLEISH-UT) with financial support from Colciencias (CT695-2014). Authors also thanks to I. Ortiz, Facultad de Salud, Universidad Pontificia Bolivariana for technical support with the genotoxicity test.

Author contributions

FE and SMR devised the study and wrote the paper. WQ, GE, FT, and RA performed the chemical analyses. YU, KR, IDV, and SMR performed the in vitro and in vivo experiments.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. Alvar J, Vélez ID, Bern C, Herrero M, Desjeux P, Cano J, Jannin J, den Boer M, WHO Leishmaniasis Control Team (2012) Leishmaniasis worldwide and global estimates of its incidence PLoS ONE 7:e35671.  https://doi.org/10.1371/journal.pone.0035671 CrossRefPubMedPubMedCentralGoogle Scholar
  2. Bogdan C, Nathan C (1993) Modulation of macrophage function by transforming growth factor beta, interleukin-4, and interleukin-10. Ann N Y Acad Sci 685:713–739.  https://doi.org/10.1111/j.1749-6632.1993.tb35934.x CrossRefPubMedGoogle Scholar
  3. Borges F, Roleira F, Milhazes N, Santana L, Uriarte E (2005) Simple coumarins and analogues in medicinal chemistry: occurrence, synthesis and biological activity. Curr Med Chem 12:887–916.  https://doi.org/10.2174/0929867053507315 CrossRefPubMedGoogle Scholar
  4. Cywin CL, Firestone RA, McNeil DW, Grygon CA, Crane KM, White DM, Kinkade PR, Hopkins JL, Davidson W, Labadia ME, Wildeson J, Morelock MM, Peterson JD, Raymond EL, Brown ML, Spero DM (2003) The design of potent hydrazones and disulfides as cathepsin S inhibitors. Bioorg Med Chem 6:733–740.  https://doi.org/10.1016/S0968-0896(02)00468-6 CrossRefGoogle Scholar
  5. Den Boer M, Argaw D, Jannin J, Alvar J (2011) Leishmaniasis impact and treatment access. Clin Microbiol Infect 17:1471–1477.  https://doi.org/10.1111/j.1469-0691.2011.03635.x CrossRefGoogle Scholar
  6. Das P, De T, Chakraborti T (2014) Leishmania donovani secretory serine protease alters macrophage inflammatory response via COX-2 mediated PGE-2 production. Indian J Biochem Biophys 51:542–551. http://nopr.niscair.res.in/handle/123456789/30506 PubMedGoogle Scholar
  7. Desai PV, Patny A, Sabnis Y, Tekwani B, Gut J, Rosenthal P, Shivastava A, Avery M (2004) Identification of novel parasitic cysteine protease inhibitors using virtual screening. 1. The ChemBridge database. J Med Chem 47:6609–6615.  https://doi.org/10.1021/jm0493717 CrossRefGoogle Scholar
  8. Elmekki MA, Elhassan MM, Ozbak HA, Mukhtar MM (2016) Elevated TGF-beta levels in drug-resistant visceral leishmaniasis. Ann Saudi Med 36:73–77.  https://doi.org/10.5144/0256-4947.2016.7310.5144/0256-4947.2016.73
  9. Finney JD (1978) Statistical method in biological assay, 3rd edn. Charles Griffin & Co, London, UK, p 508.  https://doi.org/10.1002/bimj.4710210714 CrossRefGoogle Scholar
  10. Friden-Saxin M, Seifert T, Ryden Landergren M, Suuronen T, Lahtela-Kakkonen M, Jarho EM, Luthman K (2012) Synthesis and evaluation of substituted chroman-4-one and chromone derivatives as sirtuin 2-selective Iinhibitors. J Med Chem 55:7104–7113.  https://doi.org/10.1021/jm3005288 CrossRefGoogle Scholar
  11. Gaspar A, Matos MJ, Garrido J, Uriarte E, Borges F (2014) Chromone: a valid scaffold in medicinal chemistry. Chem Rev 114:4960–4992.  https://doi.org/10.1021/cr400265z CrossRefGoogle Scholar
  12. Gaspar A, Mohabbati M, Cagide F, Razzaghi-Asl N, Miri R, Firuzi O, Borges F (2019) Searching for new cytotoxic agents based on chromen-4-one and chromane-2,4-dione scaffolds. Res Pharma Sci 14:74–83.  https://doi.org/10.4103/1735-5362.251855 CrossRefGoogle Scholar
  13. Kalinski P (2012) Regulation of immune responses by prostaglandin E2. J Immunol 1(188):21–28.  https://doi.org/10.4049/jimmunol.1101029 CrossRefGoogle Scholar
  14. Kanbe Y, Kim MH, Nishimoto M, Ohtake Y, Kato N, Tsunenari T, Taniguchi K, Ohizumi I, Kaiho S, Morikawa K, Jo JC, Lim HS, Kim HY (2006) Discovery of thiochroman and chroman derivatives as pure antiestrogens and their structure-activity relationship. Bioorg Med Chem 14:4803–4819.  https://doi.org/10.1016/j.bmc.2006.03.020 CrossRefGoogle Scholar
  15. Kapoor M, Shaw O, Appleton I (2005) Possible anti-inflammatory role of COX-2-derived prostaglandins: implications for inflammation research. Curr Opin Investig Drugs 6:461–466PubMedGoogle Scholar
  16. Limoncu ME, Balcioğlu IC, Yereli K, Ozbel Y, Ozbilgin A (1997) A new experimental in vitro culture medium for cultivation of Leishmania species. J Clin Microbiol 35(9):2430–2431PubMedPubMedCentralGoogle Scholar
  17. Mathur S, Hoskins C (2017) Drug development: Lessons from nature. Biomed Rep 6:612–614.  https://doi.org/10.3892/br.2017.909 CrossRefPubMedPubMedCentralGoogle Scholar
  18. Mesa C, Blandón GA, Muñoz DL, Muskus CE, Flórez AF, Ochoa R, Vélez ID, Robledo SM (2015) In silico screening of potential drug with anti-leishmanial activity and validation of their activity by in vitro and in vivo studies. J Chem Chem Eng 9:375–402.  https://doi.org/10.17265/1934-7375/2015.06.002 CrossRefGoogle Scholar
  19. Montoya A, Daza A, Muñoz D, Ríos K, Taylor V, Cedeño D, Vélez ID, Echeverri F, Robledo SM (2015) Development of a novel formulation with hypericin to treat cutaneous leishmaniasis based on photodynamic therapy in in vitro and in vivo studies. Antimicrob Agents Chemother 59:5804–5813.  https://doi.org/10.1128/AAC.00545-15 CrossRefPubMedPubMedCentralGoogle Scholar
  20. Muñoz DL, Cardona D, Cardona A, Carrillo LM, Quiñones W, Echeverri F, Vélez ID, Robledo SM (2006) Efecto de hidrazonas sobre amastigotes intracelulares de Leishmania panamensis y una proteasa de cisteína parasitaria. Vitae 13:5–12Google Scholar
  21. Nicolaou KC, Pfefferkorn JA, Roecker AJ, Cao G-Q, Barluenga S, Mitchell HJ (2000) Natural Product-like combinatorial libraries based on privileged structures. 1. General principles and solid-phase synthesis of benzopyrans. J Am Chem Soc 122:9939–9953.  https://doi.org/10.1021/ja002033k CrossRefGoogle Scholar
  22. OECD (2016) Test No. 473: in vitro mammalian chromosomal aberration test, OECD guidelines for the testing of chemicals, section 4. OECD Publishing, Paris.  https://doi.org/10.1787/9789264264649-en
  23. Pulido SA, Muñoz DL, Restrepo AM, Mesa CV, Alzate JF, Vélez ID, Robledo SM (2012) Improvement of the green fluorescent protein reporter system in Leishmania spp. for the in vitro and in vivo screening of anti-leishmanial drugs. Acta Trop 122:36–45.  https://doi.org/10.1016/j.actatropica.2011.11.015. CrossRefPubMedGoogle Scholar
  24. Ramendra P, Vishnu P, Ram J (2014) Natural and synthetic chromenes, fused chromenes, and versatility of dihydrobenzo[h]chromenes in organic synthesis. Chem Rev 114:10476–10526.  https://doi.org/10.1021/cr500075s CrossRefGoogle Scholar
  25. Rawat P, Manaswita Verma S (2016) Design and synthesis of chroman derivatives with dual anti-breast cancer and antiepileptic activities. Drug Des Devel Ther 10:2779–2788.  https://doi.org/10.2147/DDDT.S111266 CrossRefPubMedPubMedCentralGoogle Scholar
  26. Robledo S, Wozencraft A, Valencia AZ, Saravia N (1994) Human monocyte infection by Leishmania (Viannia) panamensis. Role of complement receptors and correlation of susceptibility in vitro with clinical phenotype. J Immunol 152:1265–1276PubMedGoogle Scholar
  27. Robledo SM, Carrillo LM, Daza A, Restrepo AM, Muñoz DL, Tobón J, Murillo JD, López A, Ríos C, Mesa CV, Upegui YA, Valencia-Tobón A, Mondragón-Shem K, Rodríguez B, Vélez ID (2012) Cutaneous leishmaniasis in the dorsal skin of hamsters: a useful model for the screening of antileishmanial drugs. J Vis Exp (62). 3533.  https://doi.org/10.3791/3533
  28. Saengchantara ST, Wallace TW (1986) Chromanols, chromanones, and chromones. Nat Prod Rep 3:465–475.  https://doi.org/10.1039/NP9860300465 CrossRefGoogle Scholar
  29. Sharma SK, Kumar S, Chand K, Kathuria A, Gupta A, Jain R (2011) An update on natural occurrence and biological activity of chromones. Curr Med Chem 18:3825–3852.  https://doi.org/10.2174/092986711803414359 CrossRefPubMedGoogle Scholar
  30. Tsatsop RK, Djiobie GE, Regonne K, Bama VS, Mbawala A, Benoît NM (2017) Optimization of rheological properties in the formulation of an ointment base from natural ingredients. Inter J Sci Tech Res 2017(6):113–121Google Scholar
  31. WHO Expert Committee on the Control of the Leishmaniases and World Health Organization (2010) Control of the leishmaniases: report of a meeting of the WHO Expert Commitee on the Control of Leishmaniases. World Health Organization, Geneva, 22–26 March. http://www.who.int/iris/handle/10665/44412
  32. Wyler DJ, Beller DI, Sypek JP (1987) Macrophage activation for antileishmanial defense by an apparently novel mechanism. J Immunol 138:1246–1249PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Yulieth Upegui
    • 1
  • Karina Rios
    • 2
  • Wiston Quiñones
    • 3
  • Fernando Echeverri
    • 3
    Email author
  • Rosendo Archbold
    • 3
  • Javier D. Murillo
    • 1
  • Fernando Torres
    • 3
  • Gustavo Escobar
    • 3
  • Iván D. Vélez
    • 1
  • Sara M. Robledo
    • 1
    Email author
  1. 1.PECET-School of MedicineUniversidad de AntioquiaMedellinColombia
  2. 2.Biogen-Universidad de SantanderCúcutaColombia
  3. 3.Química Orgánica de Productos Naturales-Institut of ChemistryUniversidad de AntioquiaMedellinColombia

Personalised recommendations