The coexistence of leishmaniasis, Chagas disease, and neoplasia in endemic areas has been extensively documented. The use of common drugs in the treatment of these pathologies invites us to search for new molecules with these characteristics. In this research, we report 16 synthetic chalcone derivatives that were investigated for leishmanicidal and trypanocidal activities as well as for antiproliferative potential on eight human cancers and two nontumor cell lines. The final compounds 8−23 were obtained using the classical base-catalyzed Claisen−Schmidt condensation. The most potent compounds as parasiticidal were found to be 22 and 23, while compounds 18 and 22 showed the best antiproliferative activity and therapeutic index against CCRF-CEM, K562, A549, and U2OS cancer cell lines and non-toxic VERO, BMDM, MRC-5, and BJ cells. In the case of K562 and the corresponding drug-resistant K562-TAX cell lines, the antiproliferative activity has shown a more significant difference for compound 19 having 10.3 times higher activity against the K562-TAX than K562 cell line. Flow cytometry analysis using K562 and A549 cell lines cultured with compounds 18 and 22 confirmed the induction of apoptosis in treated cells after 24 h. Based on the structural analysis, these chalcones represent new compounds potentially useful for Leishmania, Trypanosoma cruzi, and some cancer treatments.

Biotechnology Unit Faculty of Pharmacy Central University of Venezuela Los Chaguaramos 1041 A Caracas 47206 Venezuela

Escuela de Medicina Universidad Espíritu Santo Samborondón 092301 Ecuador

Grupo de Investigación en Moléculas y Materiales Funcionales Dirección de Investigación Universidad Central del Ecuador Jerónimo Leiton s n y Gilberto Gatto Sobral Quito 170521 Ecuador

Institute of Immunology Faculty of Medicine Central University of Venezuela Los Chaguaramos 1050 A Caracas 50109 Venezuela

Institute of Molecular and Translational Medicine Faculty of Medicine Palacky University Hněvotínská 1333 5 77900 Olomouc Czech Republic

Laboratorio de Síntesis Orgánica y Diseño de Fármacos Department de Química Facultad Experimental de Ciencias Universidad del Zulia Maracaibo 4001 Venezuela

Laboratory of Biology and Chemotherapy of Tropical Parasitosis of the Foundation Institute for Advanced Studies Health Area Caracas 1080 Venezuela

Organic Synthesis Laboratory Faculty of Pharmacy Central University of Venezuela Los Chaguaramos 1041 A Caracas 47206 Venezuela

Universidad ECOTEC Km 13 5 Vía Samborondón Guayaquil 092302 Ecuador

Zobrazit více v PubMed

Leishmaniasis OPS/OMS. Jan, 2022. [(accessed on 25 February 2022)]. Available online: https://www.paho.org/es/temas/leishmaniasis.

Mann S., Frasca K., Scherrer S., Henao-Martínez A., Newman S., Ramanan P., Suarez J.A. A review of Leishmaniasis: Current knowledge and future directions. Curr. Trop. Med. Rep. 2021;8:121–132. doi: 10.1007/s40475-021-00232-7. PubMed DOI PMC

Rashidi S., Fernández-Rubio C., Manzano-Román R., Mansouri R., Shafiei R., Ali-Hassanzadeh M., Barazesh A., Karimazar M., Hatam G., Nguewa P. Potential therapeutic targets shared between leishmaniasis and cancer. Parasitology. 2021;148:655–671. doi: 10.1017/S0031182021000160. PubMed DOI PMC

Chagas C. Nova tripanozomiaze humana: Estudos sobre a morfolojia e o ciclo evolutivo do schizotrypanum cruzi n. gen., n. sp., ajente etiolojico de nova entidade morbida do homem. Mem. Inst. Oswaldo Cruz. 1909;1:159–218. doi: 10.1590/S0074-02761909000200008. DOI

Echeverria L., Morillo C. American trypanosomiasis (Chagas disease) Infect. Dis. Clin. N. Am. 2019;33:119–134. doi: 10.1016/j.idc.2018.10.015. PubMed DOI

WHO Chagas Disease. Apr, 2021. [(accessed on 31 August 2021)]. Available online: https://www.who.int/news-room/fact-sheets/detail/chagas-disease-(american-trypanosomiasis)

Lidani K.C.F., Andrade F.A., Bavia L., Damasceno F.S., Beltrame M.H., Messias-Reason I.J., Sandri T.L. Chagas disease: From discovery to a worldwide health problem. Front. Public Health. 2019;7:166. doi: 10.3389/fpubh.2019.00166. PubMed DOI PMC

World Health Organization . WHO Report on Cancer: Setting Priorities, Investing Wisely and Providing Care for All. World Health Organization; Geneva, Switzerland: 2020.

Siegel R., Miller K., Fuchs H., Jemal A. Cancer Statistics, 2022. CA Cancer J. Clin. 2022;72:7–33. doi: 10.3322/caac.21708. PubMed DOI

Blagosklonny M.V. Immunosuppressants in cancer prevention and therapy. Oncoimmunology. 2013;2:e26961. doi: 10.4161/onci.26961. PubMed DOI PMC

Liao J.B. Cancer issue: Viruses and human cancer. Yale J. Biol. Med. 2006;79:115–122. PubMed PMC

De Martel C., Ferlay J., Franceschi S., Vignat J., Bray F., Forman D., Plummer M. Global burden of cancers attributable to infections in 2008: A review and synthetic analysis. Lancet Oncol. 2012;13:607–615. doi: 10.1016/S1470-2045(12)70137-7. PubMed DOI

Tretina K., Gotia H.T., Mann D.J., Silva J.C. Theileria-transformed bovine leukocytes have cancer hallmarks. Trends Parasitol. 2015;31:306–314. doi: 10.1016/j.pt.2015.04.001. PubMed DOI

Nguewa P.A., Villa T.G., Notario V. Microbiome control in the prevention and early management of cancer. In: Villa T.G., Vinas M., editors. New Weapons to Control Bacterial Growth. Springer; Cham, Switzerland: 2016. pp. 219–237.

Cheeseman K., Weitzman J. Comment et pourquoi un parasite peut-il être ‘transformant’? Apports d’agents de zoonoses exotiques, Theileria spp., à l’étude du cancer. Bull. Société Pathol. Exot. 2017;110:55–60. doi: 10.1007/s13149-017-0551-4. PubMed DOI

Kopterides P., Mourtzoukou E., Skopelitis E., Tsavaris N., Falagas M. Aspects of the association between leishmaniasis and malignant disorders. Trans. R. Soc. Trop. Med. Hyg. 2007;101:1181–1189. doi: 10.1016/j.trstmh.2007.08.003. PubMed DOI

Ferro S., Palmieri C., Cavicchioli L., De Zan G., Aresu L., Benali S.L. Leishmania amastigotes in neoplastic cells of 3 nonhistiocytic canine tumors. Vet. Pathol. 2013;50:749–752. doi: 10.1177/0300985813480192. PubMed DOI

Al-Kamel M.A.N. Leishmaniasis and malignancy: A review and perspective. Clin. Skin Cancer. 2017;2:54–58. doi: 10.1016/j.clsc.2017.10.003. DOI

Sarkar D., Leung E.Y., Baguley B.C., Finlay G.J., Askarian-Amiri M.E. Epigenetic regulation in human melanoma: Past and future. Epigenetics. 2015;10:103–121. doi: 10.1080/15592294.2014.1003746. PubMed DOI PMC

Afrin F., Khan I., Hemeg H.A. Leishmania-host interactions-an epigenetic paradigm. Front. Immunol. 2019;10:492. doi: 10.3389/fimmu.2019.00492. PubMed DOI PMC

Dacher M., Tachiwana H., Horikoshi N., Kujirai T., Taguchi H., Kimura H., Kurumizaka H. Incorporation and influence of Leishmania histone H3 in chromatin. Nucleic Acids Res. 2019;47:11637–11648. doi: 10.1093/nar/gkz1040. PubMed DOI PMC

Ferreira M.S., Borges A.S. Some aspects of protozoan infections in immunocompromised patients—A Review. Mem. Inst. Oswaldo Cruz. 2002;97:443–457. doi: 10.1590/S0074-02762002000400001. PubMed DOI

Viccoa M.H., César L.I., Musacchio H.M., Bar D.O., Marcipar L.S., Bottasso O.A. Chagas disease reactivation in a patient non-Hodgkin’s lymphoma. Rev. Clin. Esp. 2014;214:e83–e85. doi: 10.1016/j.rce.2014.04.006. PubMed DOI

D’Avila Rosenthal L., Rios Petrarca C., Arndt Mesenburg M., Marreiro Villela M. Trypanosoma cruzi seroprevalence and associated risk factors in cancer patients from Southern Brazil. Rev. Soc. Bras. Med. Trop. 2016;49:768–771. doi: 10.1590/0037-8682-0202-2016. PubMed DOI

Van Tong H., Brindley P.J., Meyer C.G., Velavan T.P. Parasite infection, carcinogenesis and human malignancy. EBioMedicine. 2017;15:12–23. doi: 10.1016/j.ebiom.2016.11.034. PubMed DOI PMC

Rocha Martins P., Duarte Nascimento R., Tomaz dos Santos A., Chaves de Oliveira E., Massara Martinelli P., d’Ávila Reis D. Mast cell-nerve interaction in the colon of Trypanosoma cruzi-infected individuals with chagasic megacolon. Parasitol. Res. 2018;117:1147–1158. doi: 10.1007/s00436-018-5792-z. PubMed DOI

Garcia Duarte J., Duarte Nascimento R., Rocha Martins P., d’Ávila Reis D. Evaluation of the immunoreactivity of nerve growth factor and tropomyosin receptor kinase A in the esophagus of noninfected and infected individuals with Trypanosoma cruzi. Parasitol. Res. 2018;117:1647–1655. doi: 10.1007/s00436-018-5838-2. PubMed DOI

Soto J., Toledo J., Gutierrez P., Nicholls R., Padilla J., Engel J., Fischer C., Voss A., Berman J. Treatment of American cutaneous leishmaniasis with miltefosine, an oral agent. Clin. Infect. Dis. 2001;33:E57–E61. doi: 10.1086/322689. PubMed DOI

Agrawal V., Singh Z. Miltefosine: First oral drug for treatment of visceral leishmaniasis. Med. J. Armed Forces India. 2006;62:66–67. doi: 10.1016/S0377-1237(06)80162-0. PubMed DOI PMC

Sangshetti J., Kalam F., Kulkarni A., Rohidas A., Patilc R. Antileishmanial drug discovery: Comprehensive review of the last 10 years. RSC. Adv. 2015;5:32376–32415. doi: 10.1039/C5RA02669E. DOI

Monge-Maillo B., Loópez-Veélez R. Miltefosine for visceral and cutaneous leishmaniasis: Drug characteristics and evidence-based treatment recommendations. Clin. Infect. Dis. 2015;60:1398–1404. doi: 10.1093/cid/civ004. PubMed DOI

Singh K., Garg G., Ali V. Current therapeutics, their problems and thiol metabolism as potential drug targets in Leishmaniasis. Curr. Drug Metab. 2016;17:897–919. doi: 10.2174/1389200217666160819161444. PubMed DOI

Ribeiro V., Dias N., Paiva T., Hagström-Bex L., Nitz N., Pratesi R., Hecht M. Current trends in the pharmacological management of Chagas disease. Int. J. Parasitol. Drugs Drug Resist. 2020;12:7–17. doi: 10.1016/j.ijpddr.2019.11.004. PubMed DOI PMC

Pérez-Molina J.A., Molina I. Chagas disease. Lancet. 2018;391:82–94. doi: 10.1016/S0140-6736(17)31612-4. PubMed DOI

Njogu P.M., Chibale K. Recent developments in rationally designed multitarget antiprotozoan agents. Curr. Med. Chem. 2013;20:1715–1742. doi: 10.2174/0929867311320130010. PubMed DOI

Prati F., Uliassi E., Bolognesi M.L. Two diseases, one approach: Multitarget drug discovery in Alzheimer’s and neglected tropical diseases. MedChemComm. 2014;5:853–861. doi: 10.1039/C4MD00069B. DOI

Prati P., Bergamini C., Molina M.T., Falchi F., Cavalli A., Kaiser M., Brun R., Fato R., Bolognesi M.L. 2-Phenoxy-1,4-naphthoquinones: From a multitarget antitrypanosomal to a potential antitumor profile. J. Med. Chem. 2015;58:6422–6434. doi: 10.1021/acs.jmedchem.5b00748. PubMed DOI

Venkateswararao E., Sharma V.K., Lee K.-C., Sharma N., Park S.-H., Kim Y., Jung S.-H. A SAR study on a series of synthetic lipophilic chalcones as Inhibitor of transcription factor NF-kB. Eur. J. Med. Chem. 2012;54:379–386. doi: 10.1016/j.ejmech.2012.05.019. PubMed DOI

Zhuang C., Zhang W., Sheng C., Zhang W., Xing C., Miao Z. Chalcone: A privileged structure in medicinal chemistry. Chem. Rev. 2017;117:7762–7810. doi: 10.1021/acs.chemrev.7b00020. PubMed DOI PMC

Qin H.-L., Zhang Z.-W., Lekkala R., Alsulami H., Rakesh K.P. Chalcone hybrids as privileged scaffolds in antimalarial drug discovery: A key review. Eur. J. Med. Chem. 2010;193:112215. doi: 10.1016/j.ejmech.2020.112215. PubMed DOI

Kraus J.M., Verlinde C.L., Karimi M., Lepesheva G.I., Gelb M.H., Buckner F.S. Rational modification of a candidate cancer drug for use against chagas disease. J. Med. Chem. 2009;52:1639–1647. doi: 10.1021/jm801313t. PubMed DOI PMC

Ciccone Miguel D., Lencine Ferraz M., de Oliveira Alves R., Yokoyama-Yasunaka J., Torrecilhas A.C., Romanha A.J., Uliana S.R. The anticancer drug tamoxifen is active against Trypanosoma cruzi in vitro but ineffective in the treatment of the acute phase of Chagas disease in mice. Mem. Inst. Oswaldo Cruz. 2010;105:945–948. doi: 10.1590/S0074-02762010000700021. PubMed DOI

Beckmann S., Grevelding C.G. Imatinib makes a fatal impact on morphology, pairing stability, and survival of adult Schistosoma mansoni in vitro. Int. J. Parasitol. 2010;40:521–526. doi: 10.1016/j.ijpara.2010.01.007. PubMed DOI

Sueth-Santiago V., Decote-Ricardo D., Morrot A., Freire-de-Lima C.G., Freire Lima M.E. Challenges in the chemotherapy of Chagas disease: Looking for possibilities related to the differences and similarities between the parasite and host. World J. Biol. Chem. 2017;8:57–80. doi: 10.4331/wjbc.v8.i1.57. PubMed DOI PMC

Armando R.G., Gómez D.L., Gomez D.E. New drugs are not enough-drug repositioning in oncology: An update. Int. J. Oncol. 2020;56:651–684. doi: 10.3892/ijo.2020.4966. PubMed DOI PMC

Kim J.H., Ryu H.W., Shim J.H., Park K.H., Withers S.G. Development of new and selective Trypanosoma cruzi trans-sialidase inhibitors from sulfonamide chalcones and their derivatives. ChemBioChem. 2009;10:2475–2479. doi: 10.1002/cbic.200900108. PubMed DOI

Ahn S.H., Jang S.S., Han E.G., Lee K.J. A new synthesis of methyl 7H-dibenz [b,g] oxocin-6-carboxylates from Morita–Baylis–Hillman adducts of 2-phenoxybenzaldehydes. Synthesis. 2011;3:377–386. doi: 10.1055/s-0030-1258392. DOI

Dimmock J.R., Zello G.A., Oloo E.O., Quail W., Kraatz H.B., Perjési P., Aradi F., Takács-Novák K., Allen T.M., Santos C.L., et al. Correlations between cytotoxicity and topography of some 2-arylidenebenzocycloalkanones determined by X-ray crystallography. J. Med. Chem. 2002;45:3103–3111. doi: 10.1021/jm010559p. PubMed DOI

Charris J.E., Domínguez J.N., Gamboa N., Rodrigues J.R., Angel J.E. Synthesis and antimalarial activity of E-2-quinolinylbenzocycloalcanones. Eur. J. Med. Chem. 2005;40:875–881. doi: 10.1016/j.ejmech.2005.03.013. PubMed DOI

Choi E., Bae S., Ahn W. Antiproliferative effects of quercetin through cell cycle arrest and apoptosis in human breast cancer MDA-MB-453 cells. Arch. Pharm. Res. 2008;31:1281–1285. doi: 10.1007/s12272-001-2107-0. PubMed DOI

Wei Y., Zhao X., Kariya Y., Fukata H., Teshigawara K., Uchida A. Induction of apoptosis by quercetin: Involvement of heat shock protein. Cancer Res. 1994;54:4952–4957. PubMed

Chen D., Daniel K., Chen M., Kuhn D., Landis-Piwowar K., Dou Q. Dietary flavonoids as proteasome inhibitors and apoptosis inducers in human leukemia cells. Biochem. Pharmacol. 2005;69:1421–1432. doi: 10.1016/j.bcp.2005.02.022. PubMed DOI

Baran I., Ganea C., Scordino A., Musumeci F., Barresi V., Tudisco S., Privitera S., Grasso R., Condorelli D., Ursu I., et al. Effects of menadione, hydrogen peroxide, and quercetin on apoptosis and delayed luminescence of human leukemia Jurkat T-cells. Cell Biochem. Biophys. 2010;58:169–179. doi: 10.1007/s12013-010-9104-1. PubMed DOI

Martínez A., Rajapakse C., Varela-Ramírez A., Lema C., Aguilera R., Sánchez-Delgado R. Arene-Ru(II)-chloroquine complexes interact with DNA, induce apoptosis on human lymphoid cell lines and display low toxicity to normal mammalian cells. J. Inorg. Biochem. 2010;104:967–977. doi: 10.1016/j.jinorgbio.2010.05.002. PubMed DOI PMC

Maso V., Calgarotto A., Franchi G., Nowill A., Filho P., Vassallo J., Olalla S. Multitarget effects of quercetin in leukemia. Cancer Prev. Res. 2014;7:1240–1250. doi: 10.1158/1940-6207.CAPR-13-0383. PubMed DOI

Santos G., Almeida M., Antunes L., Bianchi M. Effect of bixin on DNA damage and cell death induced by doxorubicin in HL60 cell line. Hum. Exp. Toxicol. 2016;35:1319–1327. doi: 10.1177/0960327116630352. PubMed DOI

Leañez J., Nuñez J., García-Marchan Y., Sojo F., Arvelo F., Rodriguez D., Buscema I., Alvarez-Aular A., Bello J., Kouznetsov V., et al. Anti-leishmanial effect of spiro dihydroquinoline-oxindoles on volumen regulation decrease and sterol biosynthesis of Leishmania braziliensis. Exp. Parasitol. 2019;198:31–38. doi: 10.1016/j.exppara.2019.01.011. PubMed DOI

Ammerman N.C., Beier-Sexton M., Azad A.F. Growth and maintenance of Vero cell lines. Curr. Protoc. Microbiol. 2008;11:A.4E.1–A.4E.7. doi: 10.1002/9780471729259.mca04es11. PubMed DOI PMC

Saint-Pierre-Chazalet M., Ben Brahim M., Le Moyec L., Bories C., Rakotomanga M., Loiseau P.M. Membrane sterol depletion impairs miltefosine action in wild-type and miltefosine-resistant Leishmania donovani promastigotes. J. Antimicrob. Chemother. 2009;64:993–1001. doi: 10.1093/jac/dkp321. PubMed DOI

Serrano-Martín X., Payares G., Mendoza-León A. Glibenclamide, a blocker of K +ATP channels, shows antileishmanial activity in experimental murine cutaneous leishmaniasis. Antimicrob. Agents Chemother. 2006;4:4214–4216. doi: 10.1128/AAC.00617-06. PubMed DOI PMC

Nosková V., Džubák P., Kuzmina G., Ludková A., Stehlik D., Trojanec R., Janošáková A., Kořínková G., Mihal V., Hajduch M. In vitro chemoresistance profile and expression/function of MDR associated proteins in resistant cell lines derived from CCRF-CEM, K562, A549 and MDA MB 231 parental cells. Neoplasma. 2002;49:418–425. PubMed

Perlíková P., Rylová G., Nauš P., Elbert T., Tloušóvá E., Bourderioux A., Slavětánská L.P., Motyka K., Doležal D., Znojek P., et al. 7-(2-Thienyl)-7-Deazaadenosine (AB61), a New Potent Nucleoside Cytostatic with a Complex Mode of Action. Mol. Cancer Ther. 2016;15:922–937. doi: 10.1158/1535-7163.MCT-14-0933. PubMed DOI

Džubák P., Gurská S., Bogdanová K., Uhríková D., Kanjaková N., Combet S., Klunda T., Kolář M., Hajdúch M., Poláková M. Antimicrobial and cytotoxic activity of (thio)alkyl hexopyranosides, nonionic glycolipid mimetics. Carbohydr. Res. 2020;488:107905. doi: 10.1016/j.carres.2019.107905. PubMed DOI

Mijares M., Ochoa M., Barroeta A., Martínez G., Suárez A., Compagnone R., Chirinos P., Avila R., De Sanctis J. Cytotoxic effets of fisturalin-3 and 11-deoxyfisturalin-3 on jurkat and U937 cell lines. Biomed. Pap. 2013;157:222–226. doi: 10.5507/bp.2012.089. PubMed DOI

Romero J., Acosta M., Gamboa N., Mijares M., De Sanctis J., Charris J. Optimization of antimalarial, and anticancer activities of (E)-methyl 2-(7-chloroquinolin-4-ylthio)-3-(4-hydroxyphenyl) acrylate. Bioorg. Med. Chem. 2018;26:815–823. doi: 10.1016/j.bmc.2017.12.022. PubMed DOI

Romero J., Acosta M., Gamboa N., Mijares M., De Sanctis J., Llovera L., Charris J. Synthesis, antimalarial, antiproliferative, and apoptotic activities of benzimidazole-5-carboxamide derivatives. Med. Chem. Res. 2019;28:13–27. doi: 10.1007/s00044-018-2258-x. DOI