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.
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References
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
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
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
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
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
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
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
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
Finney JD (1978) Statistical method in biological assay, 3rd edn. Charles Griffin & Co, London, UK, p 508. https://doi.org/10.1002/bimj.4710210714
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
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
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
Kalinski P (2012) Regulation of immune responses by prostaglandin E2. J Immunol 1(188):21–28. https://doi.org/10.4049/jimmunol.1101029
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
Kapoor M, Shaw O, Appleton I (2005) Possible anti-inflammatory role of COX-2-derived prostaglandins: implications for inflammation research. Curr Opin Investig Drugs 6:461–466
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):2430–2431
Mathur S, Hoskins C (2017) Drug development: Lessons from nature. Biomed Rep 6:612–614. https://doi.org/10.3892/br.2017.909
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
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
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 13:5–12
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
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
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.
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
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
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 152:1265–1276
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
Saengchantara ST, Wallace TW (1986) Chromanols, chromanones, and chromones. Nat Prod Rep 3:465–475. https://doi.org/10.1039/NP9860300465
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
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):113–121
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
Wyler DJ, Beller DI, Sypek JP (1987) Macrophage activation for antileishmanial defense by an apparently novel mechanism. J Immunol 138:1246–1249
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.
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Upegui, Y., Rios, K., Quiñones, W. et al. Chroman-4-one hydrazones derivatives: synthesis, characterization, and in vitro and in vivo antileishmanial effects. Med Chem Res 28, 2184–2199 (2019). https://doi.org/10.1007/s00044-019-02446-x
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DOI: https://doi.org/10.1007/s00044-019-02446-x