TY - JOUR
T1 - A fluorinated phenylbenzothiazole arrests the trypanosoma cruzi cell cycle and diminishes the infection of mammalian host cells
AU - Cuevas-Hernández, Roberto I.
AU - Girard, Richard M.B.M.
AU - Martínez-Cerón, Sarai
AU - Da Silva, Marcelo Santos
AU - Elias, Maria Carolina
AU - Crispim, Marcell
AU - Trujillo-Ferrara, José G.
AU - Silber, Ariel Mariano
N1 - Publisher Copyright:
© 2020 American Society for Microbiology. All rights reserved.
PY - 2020/1/27
Y1 - 2020/1/27
N2 - Chagas disease (CD) is a human infection caused by Trypanosoma cruzi. CD was traditionally endemic to the Americas; however, due to migration it has spread to countries where it is not endemic. The current chemotherapy to treat CD induces several side effects, and its effectiveness in the chronic phase of the disease is controversial. In this contribution, substituted phenylbenzothiazole derivatives were synthesized and biologically evaluated as trypanocidal agents against Trypanosoma cruzi. The trypanocidal activities of the most promising compounds were determined through systematic in vitro screening, and their modes of action were determined as well. The physicochemical-structural characteristics responsible for the trypanocidal effects were identified, and their possible therapeutic application in Chagas disease is discussed. Our results show that the fluorinated compound 2-methoxy-4-[5-(trifluoromethyl)-1,3-benzothiazol-2-yl] phenol (BT10) has the ability to inhibit the proliferation of epimastigotes [IC50(Epi) 23.11.75] and intracellular forms of trypomastigotes [IC50(Tryp) 8.52.9M] and diminishes the infection index by more than 80%. In addition, BT10 has the ability to selectively fragment 68% of the kinetoplastid DNA compared with 5% of nucleus DNA. The mode of action for BT10 on T. cruzi suggests that the development of fluorinated phenylbenzothiazole with electron-withdrawing substituent is a promising strategy for the design of trypanocidal drugs.
AB - Chagas disease (CD) is a human infection caused by Trypanosoma cruzi. CD was traditionally endemic to the Americas; however, due to migration it has spread to countries where it is not endemic. The current chemotherapy to treat CD induces several side effects, and its effectiveness in the chronic phase of the disease is controversial. In this contribution, substituted phenylbenzothiazole derivatives were synthesized and biologically evaluated as trypanocidal agents against Trypanosoma cruzi. The trypanocidal activities of the most promising compounds were determined through systematic in vitro screening, and their modes of action were determined as well. The physicochemical-structural characteristics responsible for the trypanocidal effects were identified, and their possible therapeutic application in Chagas disease is discussed. Our results show that the fluorinated compound 2-methoxy-4-[5-(trifluoromethyl)-1,3-benzothiazol-2-yl] phenol (BT10) has the ability to inhibit the proliferation of epimastigotes [IC50(Epi) 23.11.75] and intracellular forms of trypomastigotes [IC50(Tryp) 8.52.9M] and diminishes the infection index by more than 80%. In addition, BT10 has the ability to selectively fragment 68% of the kinetoplastid DNA compared with 5% of nucleus DNA. The mode of action for BT10 on T. cruzi suggests that the development of fluorinated phenylbenzothiazole with electron-withdrawing substituent is a promising strategy for the design of trypanocidal drugs.
KW - Antiparasitic agents
KW - Chemotherapy
KW - Phenylbenzothiazole
KW - Trypanosoma cruzi
KW - kDNA
UR - http://www.scopus.com/inward/record.url?scp=85078563318&partnerID=8YFLogxK
U2 - 10.1128/AAC.01742-19
DO - 10.1128/AAC.01742-19
M3 - Artículo
C2 - 31712204
AN - SCOPUS:85078563318
SN - 0066-4804
VL - 64
JO - Antimicrobial Agents and Chemotherapy
JF - Antimicrobial Agents and Chemotherapy
IS - 2
M1 - e01742
ER -