Screening of Trypanosoma cruzi glycosomal glyceraldehyde-3-phosphate dehydrogenase enzyme inhibitors

Abstract

RESUMO: "Busca de inibidores da enzima glicossomal gliceraldeído 3-fosfato desidrogenase de Trypanosoma cruzi". Nesse trabalho foi avaliada a atividade inibitória sobre a enzima glicossomal gliceraldeído-3-fosfato desidrogenase de T. cruzi (gGAPDH) de extratos vegetais oriundos de plantas das famílias Meliaceae e Rutaceae, na concentração de 100 mg/mL. Foram testados 46 extratos, dos quais 15 apresentaram atividade inibitória significativa (% AI ≥ 50). A maioria dos extratos de plantas da família Meliaceae (Cedrela fissilis, Cipadessa fruticosa e Trichilia ramalhoi) apresentou grande potencial em inibir a atividade enzimática. O fracionamento do extrato hexânico dos galhos de C. fruticosa permitiu o isolamento de três flavonóides: flavona, 7-metoxiflavona e 3',4',5',5,7-pentametoxiflavona. Os dois últimos foram ativos na inibição da atividade de gGAPDH. Desta forma, as três espécies de Meliaceae testadas podem ser consideradas promissoras na busca de compostos protótipos para o controle da doença de Chagas.Unitermo: Rutaceae, Meliaceae, flavonóides, gGAPDH, Trypanosoma cruzi, inibidores. ABSTRACT:The inhibitory activity of crude extracts of Meliaceae and Rutaceae plants on glycosomal glyceraldehyde-3-phosphate dehydrogenase (gGAPDH) enzyme from Trypanosoma cruzi was evaluated at 100 mg/mL. Forty-six extracts were tested and fifteen of them showed significant inhibitory activity (IA % ≥ 50). The majority of the assayed extracts of Meliaceae plants (Cedrela fissilis, Cipadessa fruticosa and Trichilia ramalhoi) showed high ability to inhibit the enzymatic activity. The fractionation of the hexane extract from branches of C. fruticosa led to the isolation of three flavonoids: flavone, 7-methoxyflavone and 3',4',5',5,7-pentamethoxyflavone. The two last compounds showed high ability to inhibit the gGAPDH activity. Therefore, the assayed Meliaceae species could be considered as a promising source of lead compounds against Chagas' disease.

Trypanocidal activity of flavonoids and limonoids isolated from Myrsinaceae and Meliaceae active plant extracts

“…Recently, we reported the inhibitory activity of crude extracts of Meliaceae and Rutaceae plants on glycosomal glyceraldehyde-3-phosphate dehydrogenase (gGAPDH) enzyme from T. cruzi. The results showed that crude extracts from C. fruticosa showed high ability to inhibit the enzyme activity (Leite et al, 2009). Thus, this specie could be considered as a promising source of lead compounds against Chagas' disease.…”

Flavonoids as efficient scaffolds: Recent trends for malaria, leishmaniasis, Chagas disease, and dengue

“…From the database searches, 830 (“malaria and flavonoids”: 540; “Chagas disease and flavonoids”: 60; “leishmaniasis and flavonoids”: 124; “dengue and flavonoids”: 106) potentially relevant records were identified, from which 737 were excluded after screening the titles or abstracts. The full reports of 93 articles were acquired: 83 studies related to natural flavonoids (Adinehbeigi, Razi Jalali, Shahriari, & Bahrami, ; Allard et al, ; Anusuya & Gromiha, ; Anusuya & Gromiha, ; Assis et al, ; Azebaze et al, ; Beer et al, ; Cabanillas et al, ; Castro, Barrios, Chinchilla, & Guerrero, ; Cheema et al, ; Cornelio et al, ; Coulerie et al, ; Cunha‐Rodrigues et al, ; Da Rocha et al, ; Da Silva, Maquiaveli, & Magalhães, ; De Monbrison et al, ; De Sousa et al, ; De Sousa et al, ; Dos Reis, Manjolin, Maquiaveli, Santos‐Filho, & da Silva, ; Ezenyi et al, ; Fonseca‐Silva, Inacio, Canto‐Cavalheiro, & Almeida‐Amaral, ; Fonseca‐Silva, Inacio, Canto‐Cavalheiro, Menna‐Barreto, & Almeida‐Amaral, ; Frabasile et al, ; Freitas et al, ; Ganesh et al, ; Gontijo et al, ; Grael, Albuquerque, & Lopes, ; Grecco et al, ; Güida et al, ; Heh et al, ; Houël et al, ; Ichino et al, ; Ijaz, Ahmad, Ahmad, ul Haq, & Wang, ; Inacio, Gervazoni, Canto‐Cavalheiro, & Almeida‐Amaral, ; Ismail & Jusoh, ; Jasmeen et al, ; Jin et al, ; Kapingu et al, ; Kiat et al, ; Kimmel et al, ; Konziase, ; Kraft et al, ; Kraft et al, ; Lage et al, ; Lage et al, ; Lehane & Saliba, ; Leite et al, ; Lu et al, ; Manjolin, dos Reis, Maquiaveli, Santos‐Filho, & da Silva, ; Marín et al, ; Marín et al, ; Mittra et al, ; Moghaddam et al, ; Montenegro, Gonzalez, Ortega‐Barria, & Luis Cubi...…”

“…cruzi GAPDH inhibitory activity (IC 50 : 22 μM), although its cytotoxicity to mammalian cells was not indicated (Cornelio et al, ; Freitas et al, ). Another study summarizes the T. cruzi GAPDH inhibitory activity of 3′,4′,5′,5,7‐pentamethoxyflavone ( 151 ) and 7‐methoxy flavone ( 152 ) with percentages of inhibition of 100% and 78.3%, respectively (Leite et al, ). Also, Tasdemir et al () reported the anti‐ T. cruzi activity of chrysin dimethylether ( 153 ; IC 50 : 3.5 μg/ml; SI: 5.51, L6 cells) and 3′‐hydroxydaidzein ( 154 ; IC 50 : 4.7 μg/ml; SI: 4.53, L6 cells; Table ).…”

Phytotoxicity of alkaloids, coumarins and flavonoids isolated from 11 species belonging to the Rutaceae and Meliaceae families

“…2 and 9 from roots and aerial parts of Ruta graveolens (Paulini et al, 1989;Masuda et al, 1998); 4 from roots of Citrus sinensis grafted on Citrus limonia (Cazal et al, 2009); 5 from stems and leaves of Raunia resinosa (Velozo et al, 1997); 7 from the fruit of Swinglea glutinosa (Santos, 2005); 15, 16 and 17 from stem and taproots of Hortia oreadica (Braga et al, 2012); 18, 23 and 24 from the fruit, branches and leaves of C. fruticosa Bl. (Leite et al, 2009); 21 from the fruit of Neoraputia magnifica (Tomazela et al, 2000;Passador et al, 1997); 22 from leaves of Neoraputia alba (Arruda et al, 1993); 25 and 29 from stems and leaves of Neoraputia paraensis (Moraes et al, 2003); 26 and 27 from peel; and 31 from the fruit of Murraya paniculata (Ferracin et al, 1998). Metabolites 13, 14, 19, 20, 28 and 30 were obtained from commercial sources in order to carry out bioassays.…”