Abstract
The physicochemical properties of four N-halomethylated and one non-halomethylated ammonium salts, with proven in vitro antileishmanial activity, were determined according to pharmaceutical standard procedures. The effectiveness and toxicity of these compounds were assessed in hamsters infected with Leishmania (Viannia) braziliensis and compared to that showed by meglumine antimoniate. Animals were followed during 90 days after the completion of treatment. Therapeutic response was determined according to the reduction of size of skin lesions. Toxicity was determined by the effect of compounds on body weight changes and serum levels of renal and hepatic metabolites. The effectiveness of compound 4 was similar to that showed by intralesional administration of meglumine antimoniate and better than that of the other ammonium salts. Levels of creatinine, alanine amino transferase, and blood urea nitrogen in serum were not significantly different between treatment groups, including healthy or untreated hamsters. Results imply that compound 4 has potential as a pharmaceutical active ingredient in the development of new and better formulations for the treatment of cutaneous leishmaniasis.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Albert A, Serjeant EP (1984) The determination of ionization constants: a laboratory manual, 3rd edn. Springer, Netherlands. https://doi.org/10.1007/978-94-009-5548-6
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(5):e35671. https://doi.org/10.1371/journal.pone.0035671
Avlonitis N, Lekka E, Detsi A, Koufaki M, Calogeropoulou T, Scoulica E, Siapi E, Kyrikou I, Mavromoustakos T, Tsotinis A, Grdadolnik SG, Makriyannis A (2003) Antileishmanial ring-substituted ether phospholipids. J Med Chem 46(5):755–767. https://doi.org/10.1021/jm020972c
Azzouz S, Maache M, Garcia RG, Osuna A (2005) Leishmanicidal activity of edelfosine, miltefosine, and ilmofosine. Basic Clin Pharmacol Toxicol 96(1):60–65. https://doi.org/10.1111/j.1742-7843.2005.pto960109.x
Basilico N, Migotto M, Ilboudo DP, Taramelli D, Stradi R, Pini E (2015) Modified quaternary ammonium salts as potential antimalarial agents. Bioorg Med Chem 23(15):4681–4687. https://doi.org/10.1016/j.bmc.2015.05.055
Calas M, Cordina G, Bompart J, Ben Bari M, Jei T, Ancelin ML, Vial H (1997) Antimalarial activity of molecules interfering with Plasmodium falciparum phospholipid metabolism. Structure-Activity Relationship analysis. J Med Chem 40(22):3557–3566. https://doi.org/10.1021/jm9701886
Calvani M, Critelli L, Gallo G, Giorgi F, Gramiccioli G, Santaniello M, Scafetta N, Tinti MO, De Angelis F (1998) L-Carnitine esters as “soft”, broad-spectrum antibacterial amphiphiles. J Med Chem 41(13):2227–2233. https://doi.org/10.1021/jm970305x
Clarissa KL, Obando D, Widmer F, Wright LC, Sorrell TC, Jolliffe KA (2006) Correlation of antifungal activity with fungal phospholipase inhibition using a series of bisquaternary ammonium salts. J Med Chem 49(2):811–816. https://doi.org/10.1021/jm0508843
Croft SL, Yardley V (2002) Chemotherapy of leishmaniasis. Curr Pharm Des 8(4):319–342. https://doi.org/10.2174/1381612023396258
Decuypere S, Vanaerschot M, Brunker K, Imamura H, Müller S, Khanal B, Rijal S, Dujardin JC, Coombs GH (2012) Molecular mechanisms of drug resistance in natural Leishmania populations vary with genetic background. PLoS Negl Trop Dis 6(2):e1514. https://doi.org/10.1371/journal.pntd.0001514
Duque-Benítez SM, Ríos-Vásquez LA, Ocampo-Cardona R, Cedeño DL, Jones MA, Vélez ID, Robledo SM (2016) Synthesis of novel quaternary ammonium salts and their in vitro antileishmanial activity and U937 cell cytotoxicity. Molecules 21(4):381. https://doi.org/10.3390/molecules21040381
Egorova KS, Gordeev EG, Ananikov VP (2017) Biological activity of ionic liquids and their application in pharmaceutics and medicine. Chem Rev 117(10):7132–7189. https://doi.org/10.1021/acs.chemrev.6b00562
Jennings MG, Minbiole KPC, Wuest WM (2015) Quaternary ammonium compounds: an antimicrobial mainstay and platform for innovation to address bacterial resistance. ACS Infect Dis 1(7):288–303. https://doi.org/10.1021/acsinfecdis.5b00047
Lozoya-Agullo I, González-Álvarez I, González-Álvarez M (2015) In situ perfusion model in rat colon for drug absorption studies: comparison with small intestine and Caco-2 cell model. J Pharm Sci 104(9):3136–3145. https://doi.org/10.1002/jps.24447
Mora CP, Lozano HR, Martinez F (2005) Aspectos termodinámicos de la miscibilidad parcial entre el noctanol y el agua. Braz J Pharm Sci 41(1):13–26. https://doi.org/10.1590/S1516-93322005000100003
Oblak E, Piecuch A, Maciaszczyk-Dziubinska E, Wawrzycka D (2016) Quaternary ammonium salt N-(dodecyloxycarboxymethyl)-N,N,Ntrimethyl ammonium chloride induced alterations in Saccharomyces cerevisiae physiology. J Biosci 41(4):601–614. https://doi.org/10.1007/s12038-016-9644-7
Organization for Economic Co-operation and Development (OECD) (2015) Test No. 105: Water Solubility, Paris. https://doi.org/10.1787/9789264069589-en. Accessed 13 May
Pearson RG (1997) The HSAB principle, in chemical hardness. Wiley-VCH Verlag GmbH & Co KGaA, Weinheim. https://doi.org/10.1002/3527606173.ch1
Pham TT, Loiseau PM, Barratt G (2013) Strategies for the design of orally bioavailable antileishmanial treatments. Int J Pharm 454(1):539–552. https://doi.org/10.1016/j.ijpharm.2013.07.035
Prince SJ, McLaury HJ, Allen LV, McLaury P (1999) Analysis of benzalkonium chloride and its homologs: HPLC versus HPCE. J Pharm Biomed Anal 19:877–882. https://doi.org/10.1016/S0731-7085(98)00187-3
Pulido SA, Nguyen VH, Alzate JF, Cedeño DL, Makurath MA, Ríos-Vásquez A, Duque-Benítez SM, Jones MA, Robledo SM, Friesen JA (2017) Insights into the phosphatidylcholine and phosphatidylethanolamine biosynthetic pathways in Leishmania parasites and characterization of a choline kinase from Leishmania infantum. Comp Biochem Physiol B 213:45–54. https://doi.org/10.1016/j.cbpb.2017.07.008
Rego P, Casas O, Gallardo CS, Rodriguez LA, Pombar A (2005) Evaluación de la eficacia de detergentes a base de amonio cuaternario frente a cepas de Salmonella y E. coli aisladas de alimentos. Aliment: Rev Tec Hig Aliment 364:114–122
Ríos LA, Ocampo R, Duque SM, Robledo SM, Vèlez ID, Cedeño DL, Jones MA (2015) Quaternary N-(halomethyl) ammonium salts as therapeutic agents. Patent US 9145352 B2
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(62):3533. https://doi.org/10.3791/3533
Sangster J (1997) Octanol-water partition coefficients: fundamentals and physical chemistry Chichester. John Wiley & Sons, Hoboken
Shao J, Zhang F, Bai Z, Wang C, Yuan Y, Wang W (2012) Synthesis and antitumor activity of emodin quaternary ammonium salt derivatives. Eur J Med Chem 56:308–319. https://doi.org/10.1016/j.ejmech.2012.07.047
Shiraishi M, Aramaki Y, Seto M, Imoto H, Nishikawa Y, Kanzaki N, Okamoto M, Sawada H, Nishimura O, Baba M, Fujino M (2000) Discovery of novel, potent, and selective small-molecule CCR5 antagonists as anti-HIV-1 agents: synthesis and biological evaluation of anilide derivatives with a quaternary ammonium. J Med Chem 43(10):2049–2063. https://doi.org/10.1021/jm9906264
Song D, Yang JS, Kim SJ, Kim BK, Park SK, Won M, Lee K, Kim HM, Choi KY, Lee K, Han G (2013) Design, synthesis and biological evaluation of novel aliphatic amido/sulfonamido-quaternary ammonium salts as antitumor agents. Bioorg Med Chem 21(3):788–794. https://doi.org/10.1016/j.bmc.2012.11.027
Titus RG, Marchand M, Boon T, Louis JA (1985) A limiting dilution assay for quantifying Leishmania major in tissues of infected mice. Parasite Immunol 7(5):545–555. https://doi.org/10.1111/j.1365-3024.1985.tb00098.x
Unger C, Sindermann H, Peukert M, Hilgard P, Engel J, Eibl H (1992) Hexadecylphosphocholine in the topical treatment of skin metastases in breast cancer patients. Prog Exp Tumor Res 34(2–3):153–159. https://doi.org/10.1016/0305-7372(90)90054-J
United States Pharmacopeial Convention Pharmacopeia USP32 (2010) USP32-NF27 ed. Rockville: Pharmacopoeial Convention. Inc. http://www.uspbpep.com/usp32/pub/data/v32270/usp32nf27s0_c776.html. Accessed 20 Jan 2017
Williams HD, Trevaskis NL, Charman SA, Shanker RM, Charman WN, Pouton CW, Porter CJ (2013) Strategies to address low drug solubility in discovery and development. Pharmacol Rev 65(1):315–499. https://doi.org/10.1124/pr.112.005660
World Health Organization (2010) Control of the leishmaniasis: report of a meeting of the WHO Expert Committee on the Control of Leishmaniases. World Health Organ Tech Rep Ser 949:1–186
Yang JS, Song D, Lee B, Ko WJ, Park SK, Won M, Lee K, Kim HM, Han G (2011) Synthesis and biological evaluation of novel aliphatic amido-quaternary ammonium salts for anticancer chemotherapy: part I. Eur J Med Chem 46(7):2861–2866. https://doi.org/10.1016/j.ejmech.2011.04.009
Yang JS, Song D, Ko WJ, Kim B, Kim BK, Park SK, Won M, Lee K, Lee K, Kim HM, Han G (2013) Synthesis and biological evaluation of novel aliphatic amidoquaternary ammonium salts for anticancer chemotherapy: part II. Eur J Med Chem 63:621–628. doi:https://doi.org/10.1016/j.ejmech.2012.12.063
Yip KW, Mao X, Au PY, Hedley DW, Chow S, Dalili S, Mocanu JD, Bastianutto C, Schimmer A, Liu FF (2006) Benzethonium chloride: a novel anticancer agent identified by using a cell-based small-molecule screen. Clin Cancer Res 12(18):5557–5569. https://doi.org/10.1158/1078-0432.CCR-06-0536
Acknowledgments
Special thanks to D. Muñoz for the technical assistance in the culturing of Leishmania parasites.
Funding
Colciencias (CT-567-2014 and 695-2014) and Universidad de Caldas (Grant 0375813).
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Ethical aspects
The Institutional Ethical Committee for Animal Experimentation at Universidad de Antioquia endorsed all procedures (Act No. 77-2012).
Conflict of interest
The authors declare that they have no conflict of interest.
Rights and permissions
About this article
Cite this article
Fernandez, M., Murillo, J., Ríos-Vásquez, L.A. et al. In vivo studies of the effectiveness of novel N-halomethylated and non-halomethylated quaternary ammonium salts in the topical treatment of cutaneous leishmaniasis. Parasitol Res 117, 273–286 (2018). https://doi.org/10.1007/s00436-017-5702-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00436-017-5702-9