Review Article

Hybrid-Compounds Against Trypanosomiases

Author(s): Jessica Alves Nunes and Edeildo Ferreira da Silva-Júnior*

Volume 23, Issue 14, 2022

Published on: 28 June, 2022

Page: [1319 - 1329] Pages: 11

DOI: 10.2174/1389450123666220509202352

Price: $65

Abstract

Neglected tropical diseases (NTDs) are a global public health problem associated with approximately 20 conditions. Among these, Chagas disease (CD), caused by Trypanosoma cruzi, and human African trypanosomiasis (HAT), caused by T. brucei gambiense or T. brucei rhodesiense, affect mainly the populations of the countries from the American continent and sub- Saharan Africa. Pharmacological therapies used for such illnesses are not yet fully effective. In this context, the search for new therapeutic alternatives against these diseases becomes necessary. A drug design tool, recently recognized for its effectiveness in obtaining ligands capable of modulating multiple targets for complex diseases, concerns molecular hybridization. Therefore, this review aims to demonstrate the importance of applying molecular hybridization in facing the challenges of developing prototypes as candidates for the treatment of parasitic diseases. Therefore, studies involving different chemical classes that investigated and used hybrid compounds in recent years were compiled in this work, such as thiazolidinones, naphthoquinones, quinolines, and others. Finally, this review covers several applications of the exploration of molecular hybridization as a potent strategy in the development of molecules potentially active against trypanosomiases, in order to provide information that can help in designing new drugs with trypanocidal activity.

Keywords: Neglected tropical diseases, Chagas disease, human African trypanosomiasis, molecular hybridization, rational drug design, trypanocidal activity.

Graphical Abstract
[1]
Bodimeade C, Marks M, Mabey D. Neglected tropical diseases: Elimination and eradication. Clin Med (Northfield Il) 2019; 19: 157-60.
[2]
Moloo A. Neglected tropical diseases Available from: https://www.who.int/news-room/questions-and-answers/item/neglected-tropical-diseases (Accessed on Dec 26, 2021).
[3]
Engels D, Zhou X-N. Neglected tropical diseases: An effective global response to local poverty-related disease priorities. Infect Dis Poverty 2020; 9(1): 10.
[http://dx.doi.org/10.1186/s40249-020-0630-9] [PMID: 31987053]
[4]
Parthasarathy A, Kalesh K. Defeating the trypanosomatid trio: Proteomics of the protozoan parasites causing neglected tropical diseases. RSC Med Chem 2020; 11(6): 625-45.
[http://dx.doi.org/10.1039/D0MD00122H] [PMID: 33479664]
[5]
Ribeiro V, Dias N, Paiva T, et al. Current trends in the pharmacological management of Chagas disease. Int J Parasitol Drugs Drug Resist 2020; 12: 7-17.
[http://dx.doi.org/10.1016/j.ijpddr.2019.11.004] [PMID: 31862616]
[6]
Lidani KCF, Andrade FA, Bavia L, et al. Chagas Disease: From Discovery to a Worldwide Health Problem. Front Public Health 2019; 7: 166.
[http://dx.doi.org/10.3389/fpubh.2019.00166] [PMID: 31312626]
[7]
Varikuti S, Jha BK, Volpedo G, et al. Host-directed drug therapies for neglected tropical diseases caused by protozoan parasites. Front Microbiol 2018; 9: 2655.
[http://dx.doi.org/10.3389/fmicb.2018.02655] [PMID: 30555425]
[8]
Ivasiv V, Albertini C, Gonçalves AE, Rossi M, Bolognesi ML. Molecular hybridization as a tool for designing multitarget drug candidates for complex diseases. Curr Top Med Chem 2019; 19(19): 1694-711.
[http://dx.doi.org/10.2174/1568026619666190619115735] [PMID: 31237210]
[9]
Gontijo VS, Viegas FPD, Ortiz CJC, et al. Molecular hybridization as a tool in the design of multi-target directed drug candidates for neurodegenerative diseases. Curr Neuropharmacol 2020; 18(5): 348-407.
[http://dx.doi.org/10.2174/1385272823666191021124443] [PMID: 31631821]
[10]
Holota S, Kryshchyshyn A, Derkach H, et al. Synthesis of 5-enamine-4-thiazolidinone derivatives with trypanocidal and anticancer activity. Bioorg Chem 2019; 86: 126-36.
[http://dx.doi.org/10.1016/j.bioorg.2019.01.045] [PMID: 30690336]
[11]
Du X, Guo C, Hansell E, et al. Synthesis and structure-activity relationship study of potent trypanocidal thio semicarbazone inhibitors of the trypanosomal cysteine protease cruzain. J Med Chem 2002; 45(13): 2695-707.
[http://dx.doi.org/10.1021/jm010459j] [PMID: 12061873]
[12]
Havrylyuk D, Zimenkovsky B, Karpenko O, Grellier P, Lesyk R. Synthesis of pyrazoline-thiazolidinone hybrids with trypanocidal activity. Eur J Med Chem 2014; 85: 245-54.
[http://dx.doi.org/10.1016/j.ejmech.2014.07.103] [PMID: 25089808]
[13]
Moreira DRM, Leite AC, Cardoso MV, et al. Structural design, synthesis and structure-activity relationships of thiazolidinones with enhanced anti-Trypanosoma cruzi activity. ChemMedChem 2014; 9(1): 177-88.
[http://dx.doi.org/10.1002/cmdc.201300354] [PMID: 24203393]
[14]
Haroon M, Akhtar T, Aline AC, et al. Design, synthesis and in vitro trypanocidal and leishmanicidal activities of 2-(2-arylidene)hydrazono-4-oxothiazolidine-5-acetic acid derivatives. ChemistrySelect 2019; 4: 13163-72.
[http://dx.doi.org/10.1002/slct.201902561]
[15]
da Silva CF, Batista MM, Batista DG, et al. In vitro and in vivo. studies of the trypanocidal activity of a diarylthiophene diamidine against Trypanosoma cruzi. Antimicrob Agents Chemother 2008; 52(9): 3307-14.
[http://dx.doi.org/10.1128/AAC.00038-08] [PMID: 18625779]
[16]
Patterson S, Jones DC, Shanks EJ, et al. Synthesis and evaluation of 1-(1-(Benzo[b]thiophen-2-yl)cyclohexyl)piperidine (BTCP) analogues as inhibitors of trypanothione reductase. ChemMedChem 2009; 4(8): 1341-53.
[http://dx.doi.org/10.1002/cmdc.200900098] [PMID: 19557802]
[17]
Silva-Júnior EF, Silva EPS, França PHB, et al. Design, synthesis, molecular docking and biological evaluation of thiophen-2-iminothiazolidine derivatives for use against Trypanosoma cruzi. Bioorg Med Chem 2016; 24(18): 4228-40.
[http://dx.doi.org/10.1016/j.bmc.2016.07.013] [PMID: 27475533]
[18]
Georgiadis M-O, Kourbeli V, Papanastasiou IP, Tsotinis A, Taylor MC, Kelly JM. Synthesis and evaluation of novel 2,4-disubstituted arylthiazoles against T. brucei. RSC Med Chem 2019; 11(1): 72-84.
[http://dx.doi.org/10.1039/C9MD00478E] [PMID: 33479605]
[19]
Kryshchyshyn A, Kaminskyy D, Karpenko O, Gzella A, Grellier P, Lesyk R. Thiazolidinone/thiazole based hybrids - New class of antitrypanosomal agents. Eur J Med Chem 2019; 174: 292-308.
[http://dx.doi.org/10.1016/j.ejmech.2019.04.052] [PMID: 31051403]
[20]
da Silva Júnior EN, de Souza MCBV, Fernandes MC, et al. Synthesis and anti-Trypanosoma cruzi activity of derivatives from nor-lapachones and lapachones. Bioorg Med Chem 2008; 16(9): 5030-8.
[http://dx.doi.org/10.1016/j.bmc.2008.03.032] [PMID: 18378461]
[21]
Cardoso MFDC, Salomão K, Bombaça AC, et al. Synthesis and anti-Trypanosoma cruzi activity of new 3-phenylthio-nor-β-lapachone derivatives. Bioorg Med Chem 2015; 23(15): 4763-8.
[http://dx.doi.org/10.1016/j.bmc.2015.05.039] [PMID: 26118339]
[22]
Cerone M, Uliassi E, Prati F, et al. Discovery of sustainable drugs for neglected tropical diseases: Cashew Nut Shell Liquid (CNSL)-based hybrids target mitochondrial function and ATP production in trypanosoma brucei. ChemMedChem 2019; 14(6): 621-35.
[http://dx.doi.org/10.1002/cmdc.201800790] [PMID: 30664325]
[23]
Silva LR, Guimarães AS, do Nascimento J, et al. Computer-aided design of 1,4-naphthoquinone-based inhibitors targeting cruzain and rhodesain cysteine proteases. Bioorg Med Chem 2021; 41: 116213.
[http://dx.doi.org/10.1016/j.bmc.2021.116213] [PMID: 33992862]
[24]
Fotie J, Kaiser M, Delfín DAD, et al. Antitrypanosomal activity of 1,2-dihydroquinolin-6-ols and their ester derivatives. J Med Chem 2010; 53(3): 966-82.
[http://dx.doi.org/10.1021/jm900723w] [PMID: 20047276]
[25]
Gehrke SS, Pinto EG, Steverding D, et al. Conjugation to 4-aminoquinoline improves the anti-trypanosomal activity of Deferiprone-type iron chelators. Bioorg Med Chem 2013; 21(3): 805-13.
[http://dx.doi.org/10.1016/j.bmc.2012.11.009] [PMID: 23266185]
[26]
Coa JC, Castrillón W, Cardona W, et al. Synthesis, leishmanicidal, trypanocidal and cytotoxic activity of quinoline-hydrazone hybrids. Eur J Med Chem 2015; 101: 746-53.
[http://dx.doi.org/10.1016/j.ejmech.2015.07.018] [PMID: 26218652]
[27]
Leverrier A, Bero J, Cabrera J, Frédérich M, Quetin-Leclercq J, Palermo JA. Structure-activity relationship of hybrids of Cinchona alkaloids and bile acids with in vitro antiplasmodial and antitrypanosomal activities. Eur J Med Chem 2015; 100: 10-7.
[http://dx.doi.org/10.1016/j.ejmech.2015.05.044] [PMID: 26063305]
[28]
Sola I, Artigas A, Taylor MC, et al. Synthesis and biological evaluation of N-cyanoalkyl-, N-aminoalkyl-, and N-guanidinoalkyl-substituted 4-aminoquinoline derivatives as potent, selective, brain permeable antitrypanosomal agents. Bioorg Med Chem 2016; 24(21): 5162-71.
[http://dx.doi.org/10.1016/j.bmc.2016.08.036] [PMID: 27591008]
[29]
Porcal W, Hernández P, Boiani L, et al. New trypanocidal hybrid compounds from the association of hydrazone moieties and benzofuroxan heterocycle. Bioorg Med Chem 2008; 16(14): 6995-7004.
[http://dx.doi.org/10.1016/j.bmc.2008.05.038] [PMID: 18547811]
[30]
Castro D, Boiani L, Benitez D, et al. Anti-trypanosomatid benzofuroxans and deoxygenated analogues: Synthesis using polymer-supported triphenylphosphine, biological evaluation and mechanism of action studies. Eur J Med Chem 2009; 44(12): 5055-65.
[http://dx.doi.org/10.1016/j.ejmech.2009.09.009] [PMID: 19837489]
[31]
Massarico Serafim RA, Gonçalves JE, de Souza FP, et al. Design, synthesis and biological evaluation of hybrid bioisoster derivatives of N-acylhydrazone and furoxan groups with potential and selective anti-Trypanosoma cruzi activity. Eur J Med Chem 2014; 82: 418-25.
[http://dx.doi.org/10.1016/j.ejmech.2014.05.077] [PMID: 24929292]
[32]
Gerpe A, Boiani L, Hernández P, et al. Naftifine-analogues as anti-Trypanosoma cruzi agents. Eur J Med Chem 2010; 45(6): 2154-64.
[http://dx.doi.org/10.1016/j.ejmech.2010.01.052] [PMID: 20163894]
[33]
Freitas M da S, Torrecilhas AC, Xander P, Vasconcelos CI, Menegon RF. Hybrid design as a strategy for development of trypanocidal drugs. J Pharm Res Int 2019; 25(2): 1-15.
[http://dx.doi.org/10.9734/JPRI/2018/46885]
[34]
Ding D, Meng Q, Gao G, et al. Design, synthesis, and structure-activity relationship of Trypanosoma brucei leucyl-tRNA synthetase inhibitors as antitrypanosomal agents. J Med Chem 2011; 54(5): 1276-87.
[http://dx.doi.org/10.1021/jm101225g] [PMID: 21322634]
[35]
Qiao Z, Wang Q, Zhang F, et al. Chalcone-benzoxaborole hybrid molecules as potent antitrypanosomal agents. J Med Chem 2012; 55(7): 3553-7.
[http://dx.doi.org/10.1021/jm2012408] [PMID: 22360533]
[36]
Varghese S, Rahmani R, Russell S, et al. Discovery of potent Nethylurea pyrazole derivatives as dual inhibitors of Trypanosoma brucei and Trypanosoma cruzi. ACS Med Chem Lett 2019; 11(3): 278-85.
[http://dx.doi.org/10.1021/acsmedchemlett.9b00218] [PMID: 32184957]
[37]
de Araújo JS, García-Rubia A, Sebastián-Pérez V, et al. Imidazole derivatives as promising agents for the treatment of Chagas disease. Antimicrob Agents Chemother 2019; 63(4): e02156-18.
[http://dx.doi.org/10.1128/AAC.02156-18] [PMID: 30670432]
[38]
Monteiro ME, Lechuga G, Lara LS, et al. Synthesis, structure-activity relationship and trypanocidal activity of pyrazole-imidazoline and new pyrazole-tetrahydropyrimidine hybrids as promising chemotherapeutic agents for Chagas disease. Eur J Med Chem 2019; 182: 111610.
[http://dx.doi.org/10.1016/j.ejmech.2019.111610] [PMID: 31434040]
[39]
Vieira DF, Choi JY, Calvet CM, et al. Binding mode and potency of N-indolyloxopyridinyl-4-aminopropanyl-based inhibitors targeting Trypanosoma cruzi CYP51. J Med Chem 2014; 57(23): 10162-75.
[http://dx.doi.org/10.1021/jm501568b] [PMID: 25393646]
[40]
Calvet CM, Vieira DF, Choi JY, et al. 4-Aminopyridyl-based CYP51 inhibitors as anti-Trypanosoma cruzi drug leads with improved pharmacokinetic profile and in vivo potency. J Med Chem 2014; 57(16): 6989-7005.
[http://dx.doi.org/10.1021/jm500448u] [PMID: 25101801]
[41]
Otero E, García E, Palacios G, et al. Triclosan-caffeic acid hybrids: Synthesis, leishmanicidal, trypanocidal and cytotoxic activities. Eur J Med Chem 2017; 141: 73-83.
[http://dx.doi.org/10.1016/j.ejmech.2017.09.064] [PMID: 29028533]
[42]
Boudreau PD, Miller BW, McCall L-I, et al. Design of gallinamide a analogs as potent inhibitors of the cysteine proteases human cathepsin L and Trypanosoma cruzi cruzain. J Med Chem 2019; 62(20): 9026-44.
[http://dx.doi.org/10.1021/acs.jmedchem.9b00294 ] [PMID: 31539239]
[43]
Ravaschino EL, Docampo R, Rodriguez JB. Design, synthesis, and biological evaluation of phosphinopeptides against Trypanosoma cruzi targeting trypanothione biosynthesis. J Med Chem 2006; 49(1): 426-35.
[http://dx.doi.org/10.1021/jm050922i] [PMID: 16392828]
[44]
Dardonville C, Rinaldi E, Barrett MP, Brun R, Gilbert IH, Hanau S. Selective inhibition of Trypanosoma brucei 6-phosphogluconate dehydrogenase by high-energy intermediate and transition-state analogues. J Med Chem 2004; 47(13): 3427-37.
[http://dx.doi.org/10.1021/jm031066i] [PMID: 15189039]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy