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Letters in Drug Design & Discovery

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ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

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Research Article

Discovery of 2-aminopyridine Derivatives with Antichagasic and Antileishmanial Activity Using Phenotypic Assays

Author(s): Daiane Yukie Tezuka, Sergio de Albuquerque, Carlos Alberto Montanari and Andrei Leitão*

Volume 17, Issue 7, 2020

Page: [867 - 872] Pages: 6

DOI: 10.2174/1570180816666191204105232

Price: $65

Abstract

Background: Compounds previously studied as anticancer were screened against trypomastigotes to access the bioactivity. The epimastigote form of Trypanosoma cruzi Y strain and the promastigote form of Leishmania amazonensis and Leishmania infantum were used in this work.

Methods: Cell-based assays were performed to access the bioactivity of the compounds using MTT and the flow cytometry methods.

Results: Neq0438, Neq0474 and Neq0440 had the highest potency, with EC50 of 39 μM (L. amazonensis), 52 μM (T. cruzi) and 81 μM (T. cruzi), respectively. These molecules were inactive for Balb/C fibroblast cell line at concentrations above 250 μM, showing selectivity for the parasites.

Conclusion: This is the first report that demonstrates antiparasitic activity for the 2-aminopyridine scaffold, with cross-activity against cancer cells.

Keywords: Trypanosoma cruzi, Leishmania infantum, Leishmania amazonensis, cell-based assays, selectivity index, antiparasitic compounds.

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[1]
Salomao, K.; Menna-Barreto, R.F.; de Castro, S.L. Stairway to heaven or hell? perspectives and limitations of Chagas disease chemotherapy. Curr. Top. Med. Chem., 2016, 16(20), 2266-2289.
[http://dx.doi.org/10.2174/1568026616666160413125049] [PMID: 27072716]
[2]
Gaspar, L.; Moraes, C.B.; Freitas-Junior, L.H.; Ferrari, S.; Costantino, L.; Costi, M.P.; Coron, R.P.; Smith, T.K.; Siqueira-Neto, J.L.; McKerrow, J.H.; Cordeiro-da-Silva, A. Current and future chemotherapy for Chagas disease. Curr. Med. Chem., 2015, 22(37), 4293-4312.
[http://dx.doi.org/10.2174/0929867322666151015120804] [PMID: 26477622]
[3]
Steverding, D. The history of leishmaniasis. Parasit. Vectors, 2017, 10(1), 82.
[http://dx.doi.org/10.1186/s13071-017-2028-5] [PMID: 28202044]
[4]
World Health Organization https://www.who.int/en/news-room/fact-sheets/detail/leishmaniasis[Accessed: July 30 2019]..
[5]
World Health Organization https://www.who.int/en/news-room/fact-sheets/detail/chagas-disease-(american-trypanosomiasis)[Accessed: July 30 2019]..
[6]
Pérez-Molina, J.A.; Pérez-Ayala, A.; Moreno, S.; Fernández-González, M.C.; Zamora, J.; López-Velez, R. Use of benznidazole to treat chronic Chagas’ disease: a systematic review with a meta-analysis. J. Antimicrob. Chemother., 2009, 64(6), 1139-1147.
[http://dx.doi.org/10.1093/jac/dkp357] [PMID: 19819909]
[7]
Laniado-Laborín, R.; Cabrales-Vargas, M.N. Amphotericin B: side effects and toxicity. Rev. Iberoam. Micol., 2009, 26(4), 223-227.
[http://dx.doi.org/10.1016/j.riam.2009.06.003] [PMID: 19836985]
[8]
Silva, B.V.; Silva, B.N.M. Thio- and semicarbazones: hope in the search for treatment of leishmaniasis and Chagas disease. Med. Chem., 2017, 13(2), 110-126.
[http://dx.doi.org/10.2174/1573406412666160909152614] [PMID: 27629824]
[9]
Balaña-Fouce, R.; Pérez Pertejo, M.Y.; Domínguez-Asenjo, B.; Gutiérrez-Corbo, C.; Reguera, R.M. Walking a tightrope: drug discovery in visceral leishmaniasis. Drug Discov. Today, 2019, 24(5), 1209-1216.
[http://dx.doi.org/10.1016/j.drudis.2019.03.007] [PMID: 30876846]
[10]
Fumarola, L.; Spinelli, R.; Brandonisio, O. In vitro assays for evaluation of drug activity against Leishmania spp. Res. Microbiol., 2004, 155(4), 224-230.
[http://dx.doi.org/10.1016/j.resmic.2004.01.001] [PMID: 15142618]
[11]
Shan, Z-Z.; Masuko-Hongo, K.; Dai, S-M.; Nakamura, H.; Kato, T.; Nishioka, K. A potential role of 15-deoxy-delta(12,14)-prostaglandin J2 for induction of human articular chondrocyte apoptosis in arthritis. J. Biol. Chem., 2004, 279(36), 37939-37950.
[http://dx.doi.org/10.1074/jbc.M402424200] [PMID: 15213234]
[12]
Mu, Y.; Liu, Y.; Li, L.; Tian, C.; Zhou, H.; Zhang, Q.; Yan, B. The novel tubulin polymerization inhibitor MHPT exhibits selective anti-tumor activity against rhabdomyosarcoma in vitro and in vivo. PLoS One, 2015, 10(3) e0121806
[http://dx.doi.org/10.1371/journal.pone.0121806] [PMID: 25811876]
[13]
Saidel, M.É.; Dos Santos, K.C.; Nagano, L.F.P.; Montanari, C.A.; Leitão, A. Novel anti-prostate cancer scaffold identified by the combination of in silico and cell-based assays targeting the PI3K-AKT-mTOR pathway. Bioorg. Med. Chem. Lett., 2017, 27(17), 4001-4006.
[http://dx.doi.org/10.1016/j.bmcl.2017.07.061] [PMID: 28774426]
[14]
Ashall, F. Cancer cells and parasites: two of a kind. Trends Biochem. Sci., 1986, 11, 518-520.
[http://dx.doi.org/10.1016/0968-0004(86)90087-3]
[15]
Priotti, J.; Baglioni, M.V.; García, A.; Rico, M.J.; Leonardi, D.; Lamas, M.C.; Menacho Márquez, M. Repositioning of antiparasitic drugs in cyclodextrin inclusion complexes for treatment of triple-negative breast cancer. AAPS PharmSciTech, 2018, 19(8), 3734-3741.
[http://dx.doi.org/10.1208/s12249-018-1169-y] [PMID: 30255471]
[16]
Juarez, M.; Schcolnik-Cabrera, A.; Dueñas-Gonzalez, A. The multitargeted drug ivermectin: from an antiparasitic agent to a repositioned cancer drug. Am. J. Cancer Res., 2018, 8(2), 317-331.
[PMID: 29511601]
[17]
Silva-Jardim, I.; Thiemann, O.H.; Anibal, F.F. Leishmaniasis and Chagas disease chemotherapy: a critical review. J. Braz. Chem. Soc., 2014, 25, 1810-1823.
[http://dx.doi.org/10.5935/0103-5053.20140229]
[18]
Bourguignon, S.C.; Mello, C.B.; Santos, D.O.; Gonzalez, M.S.; Souto-Padron, T. Biological aspects of the Trypanosoma cruzi (Dm28c clone) intermediate form, between epimastigote and trypomastigote, obtained in modified liver infusion tryptose (LIT) medium. Acta Trop., 2006, 98(1), 103-109.
[http://dx.doi.org/10.1016/j.actatropica.2006.02.006] [PMID: 16574051]
[19]
de Azevedo, A.F.; Dutra, J.L.L.; Santos, M.L. Santos, Dde.A.; Alves, P.B.; de Moura, T.R.; de Almeida, R.P.; Fernandes, M.F.; Scher, R.; Fernandes, R.P. Fatty acid profiles in Leishmania spp. isolates with natural resistance to nitric oxide and trivalent antimony. Parasitol. Res., 2014, 113(1), 19-27.
[http://dx.doi.org/10.1007/s00436-013-3621-y] [PMID: 24096610]
[20]
Han, J.; Talorete, T.P.; Yamada, P.; Isoda, H. Anti-proliferative and apoptotic effects of oleuropein and hydroxytyrosol on human breast cancer MCF-7 cells. Cytotechnology, 2009, 59(1), 45-53.
[http://dx.doi.org/10.1007/s10616-009-9191-2] [PMID: 19353300]
[21]
Muelas-Serrano, S.; Nogal-Ruiz, J.J.; Gómez-Barrio, A. Setting of a colorimetric method to determine the viability of Trypanosoma cruzi epimastigotes. Parasitol. Res., 2000, 86(12), 999-1002.
[http://dx.doi.org/10.1007/PL00008532] [PMID: 11133116]
[22]
Paloque, L.; Vidal, N.; Casanova, M.; Dumètre, A.; Verhaeghe, P.; Parzy, D.; Azas, N. A new, rapid and sensitive bioluminescence assay for drug screening on Leishmania. J. Microbiol. Methods, 2013, 95(3), 320-323.
[http://dx.doi.org/10.1016/j.mimet.2013.09.006] [PMID: 24055386]
[23]
Sereno, D.; Lemesre, J-L. Axenically cultured amastigote forms as an in vitro model for investigation of antileishmanial agents. Antimicrob. Agents Chemother., 1997, 41(5), 972-976.
[http://dx.doi.org/10.1128/AAC.41.5.972] [PMID: 9145854]
[24]
Moreno, M.; D’ávila, D.A.; Silva, M.N.; Galvão, L.M.C.; Macedo, A.M.; Chiari, E.; Gontijo, E.D.; Zingales, B. Trypanosoma cruzi benznidazole susceptibility in vitro does not predict the therapeutic outcome of human Chagas disease. Mem. Inst. Oswaldo Cruz, 2010, 105(7), 918-924.
[http://dx.doi.org/10.1590/S0074-02762010000700014] [PMID: 21120364]
[25]
Abate, C.; Ferorelli, S.; Niso, M.; Lovicario, C.; Infantino, V.; Convertini, P.; Perrone, R.; Berardi, F. 2-Aminopyridine derivatives as potential σ(2) receptor antagonists. ChemMedChem, 2012, 7(10), 1847-1857.
[http://dx.doi.org/10.1002/cmdc.201200246] [PMID: 22890883]
[26]
Chacko, S.; Samanta, S. A novel approach towards design, synthesis and evaluation of some Schiff base analogues of 2-aminopyridine and 2-aminobezothiazole against hepatocellular carcinoma. Biomed. Pharmacother., 2017, 89, 162-176.
[http://dx.doi.org/10.1016/j.biopha.2017.01.108] [PMID: 28222397]
[27]
Vodnala, S.K.; Lundbäck, T.; Sjöberg, B.; Svensson, R.; Rottenberg, M.E.; Hammarström, L.G. In vitro and in vivo activities of 2-aminopyrazines and 2-aminopyridines in experimental models of human African trypanosomiasis. Antimicrob. Agents Chemother., 2013, 57(2), 1012-1018.
[http://dx.doi.org/10.1128/AAC.01870-12] [PMID: 23254423]
[28]
Brunschwig, C.; Lawrence, N.; Taylor, D.; Abay, E.; Njoroge, M.; Basarab, G.S.; Le Manach, C.; Paquet, T.; Cabrera, D.G.; Nchinda, A.T.; de Kock, C.; Wiesner, L.; Denti, P.; Waterson, D.; Blasco, B.; Leroy, D.; Witty, M.J.; Donini, C.; Duffy, J.; Wittlin, S.; White, K.L.; Charman, S.A.; Jiménez-Díaz, M.B.; Angulo-Barturen, I.; Herreros, E.; Gamo, F.J.; Rochford, R.; Mancama, D.; Coetzer, T.L.; van der Watt, M.E.; Reader, J.; Birkholtz, L.M.; Marsh, K.C.; Solapure, S.M.; Burke, J.E.; McPhail, J.A.; Vanaerschot, M.; Fidock, D.A.; Fish, P.V.; Siegl, P.; Smith, D.A.; Wirjanata, G.; Noviyanti, R.; Price, R.N.; Marfurt, J.; Silue, K.D.; Street, L.J.; Chibale, K. UCT943, a next-generation Plasmodium falciparum PI4K inhibitor preclinical candidate for the treatment of malaria. Antimicrob. Agents Chemother., 2018, 62(9), e00012-e00018.
[http://dx.doi.org/10.1128/AAC.00012-18] [PMID: 29941635]
[29]
Paquet, T.; Le Manach, C.; Cabrera, D.G.; Younis, Y.; Henrich, P.P.; Abraham, T.S.; Lee, M.C.S.; Basak, R.; Ghidelli-Disse, S.; Lafuente-Monasterio, M.J.; Bantscheff, M.; Ruecker, A.; Blagborough, A.M.; Zakutansky, S.E.; Zeeman, A.M.; White, K.L.; Shackleford, D.M.; Mannila, J.; Morizzi, J.; Scheurer, C.; Angulo-Barturen, I.; Martínez, M.S.; Ferrer, S.; Sanz, L.M.; Gamo, F.J.; Reader, J.; Botha, M.; Dechering, K.J.; Sauerwein, R.W.; Tungtaeng, A.; Vanachayangkul, P.; Lim, C.S.; Burrows, J.; Witty, M.J.; Marsh, K.C.; Bodenreider, C.; Rochford, R.; Solapure, S.M.; Jiménez-Díaz, M.B.; Wittlin, S.; Charman, S.A.; Donini, C.; Campo, B.; Birkholtz, L.M.; Hanson, K.K.; Drewes, G.; Kocken, C.H.M.; Delves, M.J.; Leroy, D.; Fidock, D.A.; Waterson, D.; Street, L.J.; Chibale, K. Antimalarial efficacy of MMV390048, an inhibitor of Plasmodium phosphatidylinositol 4-kinase Sci. Transl. Med., 2017, 9(387)eaad 9735.
[http://dx.doi.org/10.1126/scitranslmed.aad9735] [PMID: 28446690]

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