Chroman-4-one hydrazones derivatives: synthesis, characterization, and in vitro and in vivo antileishmanial effects
- 98 Downloads
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.
KeywordsChromans Hydrazones Ointment Cutaneous leishmaniasis Animal model cure Healing
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.
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.
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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. CrossRefPubMedGoogle Scholar
- 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
- 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
- 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