Natural compounds based chemotherapeutic against Chagas disease and leishmaniasis: mitochondrion as a strategic target

Lazarin-Bidóia, Danielle; Garcia, Francielle Pelegrin; Ueda-Nakamura, Tânia; Silva, Sueli de Oliveira; Nakamura, Celso Vataru

doi:10.1590/0074-02760220396

Acessibilidade / Reportar erro

Brasil

Memórias do Instituto Oswaldo Cruz

Español English

Brasil

Español English

sumário « anterior atual seguinte »

Sumário

PERSPECTIVE • Mem. Inst. Oswaldo Cruz 117 • 2022 • https://doi.org/10.1590/0074-02760220396 copy

Natural compounds based chemotherapeutic against Chagas disease and leishmaniasis: mitochondrion as a strategic target

Authorship SCIMAGO INSTITUTIONS RANKINGS

Over the past years, natural products have been explored in order to find biological active substances to treat various diseases. Regarding their potential action against parasites such as trypanosomatids, specially Trypanosoma cruzi and Leishmania spp., much advance has been achieved. Extracts and purified molecules of several species from genera Piper, Tanacetum, Porophyllum, and Copaifera have been widely investigated by our research group and exhibited interesting antitrypanosomal and antileishmanial activities. These natural compounds affected different structures in parasites, and we believe that the mitochondrion is a strategic target to induce parasite death. Considering that these trypanosomatids have a unique mitochondrion, this cellular target has been extensively studied aiming to find more selective drugs, since the current treatment of these neglected tropical diseases has some challenges such as high toxicity and prolonged treatment time. Here, we summarise some results obtained with natural products from our research group and we further highlighted some strategies that must be considered to finally develop an effective chemotherapeutic agent against these parasites.

Key words:
trypanosomatids; natural products; mitochondrion; new therapeutic alternatives

Instituto Oswaldo Cruz, Ministério da Saúde Av. Brasil, 4365 - Pavilhão Mourisco, Manguinhos, 21040-900 Rio de Janeiro RJ Brazil, Tel.: (55 21) 2562-1222, Fax: (55 21) 2562 1220 - Rio de Janeiro - RJ - Brazil
E-mail: memorias@fiocruz.br

Acompanhe os números deste periódico no seu leitor de RSS

[1] + Corresponding author: cvnakamura@uem.br

Species	Evaluated material	Activity					References
		Trypanosoma cruzi			Leishmania amazonensis
		epimastigote	trypomastigote	amastigote	promastigote	amastigote
Achillea millefolium Anacardium occidentale Baccharis trimera Cymbopogon citratus Erythrina speciosa Eugenia uniflora Lippia alba Matricaria chamomilla Mikania glomerata Ocimum gratissimum Piper regnellii Prunus domestica Psidium guajava Punica granatum Sambucus canadensis Spilanthes acmella Stryphnodendron adstringens Tanacetum parthenium Tanacetum vulgare	hydroalcoholic extract	39.8^a* 9.4^a* 65.8^a* 79.5^a* 26.0^a* 34.3^a* 36.5^a* 95.0^a* 49.5^a* 28.3^a* 89.7^a* 5.9^a* 15.6^a* 11.2^a* 13.8^a* 9.3^a* 51.9^a* 93.0^a* 95.5^a*	- - - - - - - - - - - - - - - - - - -	- - - - - - - - - - - - - - - - - - -	11.6^a* 5.4^a* 58.3^a* 98.0^a* 5.1^a* 38.0^a* 8.5^a* 98.1^a* 52.5^a* 54.7^a* 98.2^a* 42.2^a* 65.4^a* 69.1^a* 65.7^a* 4.3^a* 36.5^a* 96.5^a* 96.4^a*	48.2^a* 32.3^a* 64.6^a* 95.2^a* 28.4^a* 51.6^a* 57.5^a* 92.7^a* 97.5^a* 91.5^a* 96.8^a* 90.0^a* 52.0^a* 9.1^a* 54.9^a* 18.1^a* 21.0^a* 94.3^a* 99.0^a*	³⁴34. Luize PS, Tiuman TS, Morello LG, Maza PK, Ueda-Nakamura T, Dias-Filho BP, et al. Effects of medicinal plant extracts on growth of Leishmania (L.) amazonensis and Trypanosoma cruzi. Braz J Pharm Sci. 2005; 41: 85-94.
Piper regnellii	eupomatenoid-3 eupomatenoid-5 eupomatenoid-6 conocarpan	26.3^b* 7.0^b* 7.5^b* 8.0^b*	- - - -	- - - -	- - - -	- - - -	³⁵35. Luize PS, Ueda-Nakamura T, Dias-Filho BP, Cortez DAG, Nakamura CV. Activity of neolignans isolated from Piper regnellii (MIQ.) C.DC. var. pallescens (C.DC.) Yunk against Trypanosoma cruzi. Biol Pharm Bull. 2006; 10: 2126-30.
Piper regnellii	eupomatenoid-5	-	-	5.0^b+	-	-	³⁶36. Luize PS, Ueda-Nakamura T, Dias-Filho BP, Cortez DAG, Morgado-Diaz JA, De Souza W, et al. Ultrastructural alterations induced by the neolignan dihydrobenzofuranic eupomatenoid-5 on epimastigote and amastigote forms of Trypanosoma cruzi. Parasitol Res. 2006; 100: 31-7.
Piper regnellii	eupomatenoid-5	-	40.5^c#	-	-	-	³⁷37. Pelizzaro-Rocha KJ, Veiga-Santos P, Lazarin-Bidoia D, Ueda-Nakamura T, Dias-Filho BP, Ximenes VF, et al. Trypanocidal action of eupomatenoid-5 is related to mitochondrion dysfunction and oxidative damage in Trypanosoma cruzi. Microbes Infect. 2011; 13: 1018-24.
Piper regnellii	eupomatenoid-5	-	-	-	9.0^b+	5.0^b$	³⁸38. Vendrametto MC, Santos AOD, Nakamura CV, Dias-Filho BP, Cortez DAG, Ueda-Nakamura T. Evaluation of antileishmanial activity of eupomatenoid-5, a compound isolated from leaves of Piper regnellii var. pallescens. Parasitol Res. 2010; 59(2): 154-8.
Tanacetum parthenium	aqueous extract ethanolic extract ethyl-acetate extract hexane fraction dichloromethane fraction ethyl-acetate fraction methanol fraction parthenolide	280.0^b* 3.0^b* 50.0^b* 2.1^b* 2.1^b* 79.0^b* 40.0^b* 0.5^b*	- - - - - - - -	- - - - - - - 51.0^d*	- - - - - - - -	- - - - - - - -	⁴⁰40. Izumi E, Morello LG, Ueda-Nakamura T, Yamada-Ogatta SF, Dias-Filho BP, Cortez DAG, et al. Trypanosoma cruzi: antiprotozoal activity of parthenolide obtained from Tanacetum parthenium (L.) Schultz Bip. (Asteraceae, Compositae) against epimastigote and amastigote forms. Exp Parasitol. 2008; 118(3): 324-30.
Tanacetum parthenium	guaianolide	18.1^c*	5.7^c$	66.6^c*	-	-	⁴²42. Cogo J, Caleare AO, Ueda-Nakamura T, Dias-Filho BP, Ferreira ICP, Nakamura CV. Trypanocidal activity of guaianolide obtained from Tanacetum parthenium (L.) Schultz-Bip. and its combinational effect with benznidazole. Phytomedicine. 2012; 20(1): 59-66.
Tanacetum parthenium	aqueous extract ethanolic extract hexane extract ethyl-acetate extract dichloromethane fraction hexane fraction ethyl-acetate fraction methanol fraction	- - - - - - - -	- - - - - - - -	- - - - - - - -	490.0^b& 434.0^b& 409.0^b& 29.0^b& 3.6^b& 7.0^b& 43.1^b& 43.8^b&	74.8^b& 36.7^b& 42.4^b& <10^b& 2.7^b& 2.9^b& 28.3^b& 48.4^b&	⁴³43. Tiuman TS, Ueda-Nakamura T, Dias-Filho BP, Cortez DAG, Nakamura CV. Studies on the effectiveness of Tanacetum parthenium against Leishmania amazonensis. Acta Protozool. 2005; 44: 245-51.
Tanacetum parthenium	parthenolide	-	-	-	0.37^b&	0.81^b&	⁴⁴44. Tiuman TS, Ueda-Nakamura T, Cortez DA, Dias-Filho BP, Morgado-Díaz JA, Souza W, et al. Antileishmanial activity of parthenolide, a sesquiterpene lactone isolated from Tanacetum parthenium. Antimicrob Agents Chemother. 2005; 49: 176-82.
Porophyllum ruderale	dichloromethane extract dichloromethane fraction compound A compound B	- - - -	- - - -	- - - -	60.3^b+ 57.5^b+ 7.7^b+ 21.3^b+	77.7^b+ 72.5^b+ 19.0^b+ 28.7^b+	⁴⁵45. Takahashi HT, Novello CR, Ueda-Nakamura T, Dias-Filho BP, Mello JCP, Nakamura CV. Thiophene derivatives with antileishmanial activity isolated from aerial parts of Porophyllum ruderale (Jacq.) Cass. Molecules. 2011; 16: 3469-78.
Arrabidaea chica	hydroethanolic extract petroleum ether fraction hexane fraction chloroform fraction dichloromethane fraction ethyl-acetate fraction pheophorbide A	213.8^b* 689.0^b* 213.3^b* 204.7^b* 184.7^b* 556.7^b* >100^b*	24.8^b$ >100^b$ 24.0^b$ 19.8^b$ 16.2^b$ 66.7^b$ 2.3^b$	>100^b* - - 13.7^b* - - 2.3^b*	- - - - - - -	- - - - - - -	⁴⁷47. Miranda N, Gerola AP, Novello CR, Ueda-Nakamura T, Silva SO, Dias-Filho BP, et al. Pheophorbide A, a compound isolated from the leaves of Arrabidaea chica, induces photodynamic inactivation of Trypanosoma cruzi. Photodiagnosis Photodyn Ther. 2017; 19: 256-65.
Copaifera reticulata	copaiba oil	-	-	-	5.0^b+	20.0^b+	⁵¹51. Santos AO, Ueda-Nakamura T, Dias-Filho BP, Veiga-Junior VF, Pinto AC, Nakamura CV. Effect of Brazilian copaiba oils on Leishmania amazonensis. J Ethnopharmacol. 2008; 120(2): 204-8.
Copaifera martii	copaíba oil	-	-	-	-	100.0^e	⁵³53. Santos AO, Costa MA, Ueda-Nakamura T, Dias-Filho BP, Veiga-Junior VF, Lima MMS, et al. Leishmania amazonensis: effects of oral treatment with copaiba oil in mice. Exp Parasitol. 2011; 129(2): 145-51.
Copaifera officinalis	agathic acid hydroxycopalic acid kaurenoic acid methyl copalate pinifolic acid polyaltic acid	- - - - - -	- - - - - -	- - - - - -	28.0^b+ 2.5^b+ 28.0^b+ 6.0^b+ 70.0^b+ 35.0^b+	17.0^b+ 18.0^b+ 3.5^b+ 14.0^b+ 4.0^b+ 15.0^b+	⁵⁴54. dos Santos AO, Izumi E, Ueda-Nakamura T, Dias-Filho BP, Veiga-Júnior VF, Nakamura CV. Antileishmanial activity of diterpene acids in copaiba oil. Mem Inst Oswaldo Cruz. 2013; 108(1): 59-64.
Copaifera spp.	methyl copalate acid copalic acid 3β-hydroxycopalic acid agathic acid pinifolic acid polyaltic acid kaurenoic acid β-caryophylene	83.3^c* 42.7^c* 41.2^c* 86.8^c* 85.4^c* 167.7^c* 167.2^c* 78.4^c*	377.3^c$ 444.0^c$ 453.1^c$ 823.3^c$ 163.0^c$ 965.1^c$ 596.0^c$ 1,593.0^c$	2.5^c* 1.3^c* 1.8^c* 14.9^c* 18.6^c* 28.4^c* 16.5^c* 63.7^c*	- - - - - - - -	- - - - - - - -	⁵⁵55. Izumi E, Ueda-Nakamura T, Veiga-Júnior VF, Pinto AC, Nakamura CV. Terpenes from Copaifera demonstrated in vitro antiparasitic and synergic activity. J Med Chem. 2012; 55(7): 2994-3001.
Copaifera reticulata Copaifera martii Copaifera cearenses Copaifera paupera Copaifera langsdorfii Copaifera multijuga Copaifera officinalis Copaifera lucens	copaiba oil	17.0^b* 19.0^b* 35.0^b* 18.5^b* 30.5^b* 19.0^b* 21.5^b* 51.0^b*	285.0^b$ 97.5^b$ 210.0^b$ 182.5^b$ 175.0^b$ 242.5^b$ 110.0^b$ 215.0^b$	<5.0^b* <5.0^b* 7.3^b* <5.0^b* 7.7^b* <5.0^b* <5.0^b* 10.0^b*	- - - - - - - -	- - - - - - - -	⁵⁶56. Izumi E, Ueda-Nakamura T, Veiga-Júnior VF, Nakamura CV. Toxicity of oleoresins from the genus Copaifera in Trypanosoma cruzi: a comparative study. Planta Med. 2013; 79: 952-8.

Species	Protozoa	Alterations	References
Eupomatenoid-5 from Piper regnellii	Trypanosoma cruzi epimastigotes	SEM: rounded and deformed cells TEM: mitochondrial swelling, kinetoplast alteration, myelin-like figures, multinucleation	³⁶36. Luize PS, Ueda-Nakamura T, Dias-Filho BP, Cortez DAG, Morgado-Diaz JA, De Souza W, et al. Ultrastructural alterations induced by the neolignan dihydrobenzofuranic eupomatenoid-5 on epimastigote and amastigote forms of Trypanosoma cruzi. Parasitol Res. 2006; 100: 31-7.
Eupomatenoid-5 from Piper regnellii	T. cruzi amastigotes	TEM: cytoplasmic vacuolisation, autophagic vacuoles
Eupomatenoid-5 from Piper regnellii	T. cruzi epimastigotes	FC: depolarisation of the mitochondrial membrane SA: lipid peroxidation, increased glucose-6-phosphate dehydrogenase, increase in H₂O₂ consumption	³⁷37. Pelizzaro-Rocha KJ, Veiga-Santos P, Lazarin-Bidoia D, Ueda-Nakamura T, Dias-Filho BP, Ximenes VF, et al. Trypanocidal action of eupomatenoid-5 is related to mitochondrion dysfunction and oxidative damage in Trypanosoma cruzi. Microbes Infect. 2011; 13: 1018-24.
Eupomatenoid-5 from Piper regnellii	T. cruzi trypomastigotes	SEM: plasma membrane damage with leakage of cytoplasmic contents TEM: plasma membrane detachment, cytoplasmic vacuolisation FC: depolarisation of the mitochondrial membrane SA: lipid peroxidation
Eupomatenoid-5 from Piper regnellii	T. cruzi epimastigotes, trypomastigotes and amastigotes	FM: DNA fragmentation, autophagic vacuoles FC: depolarisation of the mitochondrial membrane, cell membrane disruption, increase in ROS/RNS production, phosphatidylserine exposure, decrease in cell volume SA: increase in mitochondrial O₂•− production, decrease in total reduced thiol levels, lipid peroxidation	³²32. Lazarin-Bidoia D, Desoti VC, Ueda-Nakamura T, Dias-Filho BP, Nakamura CV, Silva SO. Further evidence of the trypanocidal action of eupomatenoid-5: confirmation of involvement of reactive oxygen species and mitochondria owing to a reduction in trypanothione reductase activity. Free Radic Biol Med. 2013; 60: 17-28.
Eupomatenoid-5 from Piper regnellii	Leishmania amazonensis promastigotes	TEM: mitochondrial swelling, autophagic vacuoles, vesicles located in the flagellar pocket, myelin-like figures	³⁸38. Vendrametto MC, Santos AOD, Nakamura CV, Dias-Filho BP, Cortez DAG, Ueda-Nakamura T. Evaluation of antileishmanial activity of eupomatenoid-5, a compound isolated from leaves of Piper regnellii var. pallescens. Parasitol Res. 2010; 59(2): 154-8.
Eupomatenoid-5 from Piper regnellii	L. amazonensis promastigotes	SEM: reduction and rounding of the cellular body FC: depolarisation of the mitochondrial membrane, phosphatidylserine exposure, decrease in cell volume, plasma membrane disruption, G0/G1 phase cell cycle arrest SA: increase in mitochondrial O₂•− production, increased total ROS production, decrease in total reduced thiol levels	³⁹39. Garcia FP, Lazarin-Bidoia D, Ueda-Nakamura T, Silva SO, Nakamura CV. Eupomatenoid-5 isolated from leaves of Piper regnellii induces apoptosis in Leishmania amazonensis. Evid Based Complement Alternat Med. 2013; 2013: 940531.
Parthenolide from Tanacetum parthenium	T. cruzi epimastigotes	SEM: distortion and decrease of the cell body and flagellum length TEM: mitochondrial swelling, multinuclear cells, increase of reservosomes, autophagic vacuoles, concentric structures, myelin-like figures, rearrangement of internal membranes	⁴⁰40. Izumi E, Morello LG, Ueda-Nakamura T, Yamada-Ogatta SF, Dias-Filho BP, Cortez DAG, et al. Trypanosoma cruzi: antiprotozoal activity of parthenolide obtained from Tanacetum parthenium (L.) Schultz Bip. (Asteraceae, Compositae) against epimastigote and amastigote forms. Exp Parasitol. 2008; 118(3): 324-30.
Parthenolide from Tanacetum vulgare	T. cruzi trypomastigotes	SEM: rounding and shortening of the parasite, loss of integrity of the plasma membrane	⁴¹41. Pelizzaro-Rocha KJ, Tiuman TS, Izumi E, Ueda-Nakamura T, Dias-Filho BP, Nakamura CV. Synergistic effects of parthenolide and benznidazole on Trypanosoma cruzi. Phytomedicine. 2010; 18(1): 36-9.
Guaianolide from Tanacetum parthenium	T. cruzi epimastigotes	SEM: thinning and stretching of the cell body and flagellum TEM: presence of membranes that involved organelles, myelin-like figures FC: cell volume reduction, decrease in mitochondrial membrane potential	⁴²42. Cogo J, Caleare AO, Ueda-Nakamura T, Dias-Filho BP, Ferreira ICP, Nakamura CV. Trypanocidal activity of guaianolide obtained from Tanacetum parthenium (L.) Schultz-Bip. and its combinational effect with benznidazole. Phytomedicine. 2012; 20(1): 59-66.
Guaianolide from Tanacetum parthenium	T. cruzi trypomastigotes	SEM: rounding and shortening of the parasite with leakage of cytoplasmic contents
Parthenolide from Tanacetum parthenium	L. amazonensis promastigotes	TEM: vesicles located in the flagellar pocket, structures similar to large lysosomes	⁴⁴44. Tiuman TS, Ueda-Nakamura T, Cortez DA, Dias-Filho BP, Morgado-Díaz JA, Souza W, et al. Antileishmanial activity of parthenolide, a sesquiterpene lactone isolated from Tanacetum parthenium. Antimicrob Agents Chemother. 2005; 49: 176-82.
Compound A and B from Porophyllum ruderale	L. amazonensis promastigotes and amastigotes	SEM: rounded and swollen cells TEM: mitochondrial swelling FC: decrease in mitochondrial membrane potential	⁴⁶46. Takahashi HT, Britta EA, Longhini R, Ueda-Nakamura T, Mello JCP, Nakamura CV. Antileishmanial activity of 5-methyl-2,2':5',2 »,» ®,® §,§ , ¹,¹ ²,² ³,³ ß,ß Þ,Þ þ,þ ×,× Ú,Ú ú,ú Û,Û û,û Ù,Ù ù,ù ¨,¨ Ü,Ü ü,ü Ý,Ý ý,ý ¥,¥ ÿ,ÿ ¶,¶ -terthiophene isolated from Porophyllum ruderale is related to mitochondrial dysfunction in Leishmania amazonensis. Planta Med. 2013; 79(5): 330-3.
Pheophorbide A from Arrabidaea chica	T. cruzi trypomastigotes	SEM: rounding and shortening of the parasite body TEM: mitochondrial swelling, autophagic vacuoles, concentric membrane structures, abnormal chromatin distribution nuclear	⁴⁷47. Miranda N, Gerola AP, Novello CR, Ueda-Nakamura T, Silva SO, Dias-Filho BP, et al. Pheophorbide A, a compound isolated from the leaves of Arrabidaea chica, induces photodynamic inactivation of Trypanosoma cruzi. Photodiagnosis Photodyn Ther. 2017; 19: 256-65.
Pheophorbide A from Arrabidaea chica	T. cruzi amastigotes	SEM: rounding of the parasite, plasma membrane damage
Copaiba oil from Copaifera reticulata	L. amazonensis promastigotes	SEM: rounded shape with two flagella, protein denaturation of the cell surface TEM: mitochondrial swelling, vesicles located in the flagellar pocket, cytoplasmic vacuolisation	⁵²52. Santos AO, Ueda-Nakamura T, Dias-Filho BP, Veiga-Junior VF, Nakamura CV. Copaiba oil: an alternative to development of new drugs against leishmaniasis. Evid Based Complement Alternat Med. 2012; 2012: 898419.
Copaiba oil from Copaifera reticulata	L. amazonensis amastigotes	SEM: rupture of the plasma membrane with loss of their contents, protein denaturation of the cell surface TEM: mitochondrial swelling, vesicles located in the flagellar pocket, cytoplasmic vacuolisation FC: decrease in mitochondrial membrane potential, increase in permeability of the plasma membrane
Hydroxycopalic acid from Copaifera officinalis	L. amazonensis promastigotes	SEM: rounded cells, rupture of the plasma membrane with loss of the cell contents, alterations of the flagellar membrane TEM: mitochondrial damage, vesicles located in the flagellar pocket, abnormal chromatin condensation nuclear	⁵⁴54. dos Santos AO, Izumi E, Ueda-Nakamura T, Dias-Filho BP, Veiga-Júnior VF, Nakamura CV. Antileishmanial activity of diterpene acids in copaiba oil. Mem Inst Oswaldo Cruz. 2013; 108(1): 59-64.
Agathic, kaurenoic and pinifolic acids from Copaifera officinalis	L. amazonensis amastigotes	FC: depolarisation of the mitochondrial membrane potential, increase in plasma membrane permeability	⁵⁴54. dos Santos AO, Izumi E, Ueda-Nakamura T, Dias-Filho BP, Veiga-Júnior VF, Nakamura CV. Antileishmanial activity of diterpene acids in copaiba oil. Mem Inst Oswaldo Cruz. 2013; 108(1): 59-64.
Terpenes from Copaifera spp.	T. cruzi epimastigotes	TEM: mitochondrial swelling, organelle disorganisation, membranous vacuole formation, concentric membrane structures FC: depolarisation of the mitochondrial potential, increase in plasma membrane permeability AS: lipid peroxidation	⁵⁵55. Izumi E, Ueda-Nakamura T, Veiga-Júnior VF, Pinto AC, Nakamura CV. Terpenes from Copaifera demonstrated in vitro antiparasitic and synergic activity. J Med Chem. 2012; 55(7): 2994-3001.
Copaiba oil from Copaifera spp.	T. cruzi epimastigotes	FC: depolarisation of the mitochondrial potential AS: lipid peroxidation	⁵⁶56. Izumi E, Ueda-Nakamura T, Veiga-Júnior VF, Nakamura CV. Toxicity of oleoresins from the genus Copaifera in Trypanosoma cruzi: a comparative study. Planta Med. 2013; 79: 952-8.
Copaiba oil from Copaifera spp.	T. cruzi amastigotes	TEM: swelling of the kinetoplast and chromatin condensation in both the nucleus and mitochondrion, disorganisation of the membranes