34 research outputs found
New heterobimetallic ferrocenyl derivatives are promising antitrypanosomal agents
In the search for a more effective chemotherapy for the treatment of Chagas´ disease and human African trypanosomiasis, caused by Trypanosoma cruzi and Trypanosoma brucei parasites, respectively, the use of organometallic compounds may be a promising strategy. In this work, eight new heterobimetallic compounds are described including four 5-nitrofuryl containing thiosemicarbazones as bioactive ligands (HL1-HL4) and dppf = 1,1′-bis(diphenylphosphino) ferrocene as an organometallic co-ligand. Complexes of the formula [MII(L)(dppf)](PF6) with M = Pd or Pt were synthesized and fully characterized in the solid state and in solution, including the determination of the molecular structure of four of them by single crystal X-ray diffraction methods. Most compounds showed activity in the low micromolar or submicromolar range against both parasites, with the platinum compounds being more active than the palladium analogues. Activity was significantly increased by generation of the M-dppf compounds (3-24 fold increase with respect to free ligands HL for T. cruzi and up to 99 fold increase with respect to HL for T. brucei). The inclusion of the organometallic co-ligand also led to lower toxicity in mammalian cells and higher selectivity towards both parasites when compared to the free HL compounds. The complexes interact with DNA and affect the redox metabolism of the parasites. Furthermore, the most active and selective compound of the new series showed no in vivo toxicity in zebrafish embryos.Fil: RodrĂguez Arce, Esteban. Universidad de la RepĂşblica; UruguayFil: Putzu, Eugenia. Universidad de la RepĂşblica; UruguayFil: Lapier, Michel. Universidad de Chile; ChileFil: Maya, Juan Diego. Universidad de Chile; ChileFil: Olea Azar, Claudio. Universidad de Chile; ChileFil: EcheverrĂa, Gustavo Alberto. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - La Plata. Instituto de FĂsica La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de FĂsica La Plata; ArgentinaFil: Piro, Oscar Enrique. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - La Plata. Instituto de FĂsica La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de FĂsica La Plata; ArgentinaFil: Medeiros, Andrea. Instituto Pasteur de Montevideo; Uruguay. Universidad de la RepĂşblica; UruguayFil: Sardi, Florencia. Instituto Pasteur de Montevideo; UruguayFil: Comini, Marcelo. Instituto Pasteur de Montevideo; UruguayFil: Risi, GastĂłn. Instituto Pasteur de Montevideo; UruguayFil: Salinas, Gustavo. Instituto Pasteur de Montevideo; UruguayFil: Abad Villamor, Ana Isabel. Instituto Superior TĂ©cnico; PortugalFil: Pessoa, JoĂŁo Costa. Instituto Superior TĂ©cnico; PortugalFil: Otero, LucĂa. Universidad de la RepĂşblica; UruguayFil: Gambino, Dinorah. Universidad de la RepĂşblica; Urugua
New heterobimetallic ferrocenyl derivatives are promising antitrypanosomal agents
In the search for a more effective chemotherapy for the treatment of Chagas’ disease and human African trypanosomiasis, caused by Trypanosoma cruzi and Trypanosoma brucei parasites, respectively, the use of organometallic compounds may be a promising strategy. In this work, eight new heterobimetallic compounds are described including four 5-nitrofuryl containing thiosemicarbazones as bioactive ligands (HL1–HL4) and dppf = 1,1′-bis(diphenylphosphino) ferrocene as an organometallic co-ligand. Complexes of the formula [MII(L)(dppf)](PF6) with M = Pd or Pt were synthesized and fully characterized in the solid state and in solution, including the determination of the molecular structure of four of them by single crystal X-ray diffraction methods. Most compounds showed activity in the low micromolar or submicromolar range against both parasites, with the platinum compounds being more active than the palladium analogues. Activity was significantly increased by generation of the M-dppf compounds (3–24 fold increase with respect to free ligands HL for T. cruzi and up to 99 fold increase with respect to HL for T. brucei). The inclusion of the organometallic co-ligand also led to lower toxicity in mammalian cells and higher selectivity towards both parasites when compared to the free HL compounds. The complexes interact with DNA and affect the redox metabolism of the parasites. Furthermore, the most active and selective compound of the new series showed no in vivo toxicity in zebrafish embryos.Instituto de FĂsica La Plat
June 25: COVID Impacts Special Session
Day Three of the CoLang 2020 Web Series occurred on June 25, 2020 from 2:00-4:00 p.m. Mountain Daylight Time and included the following presentations and presenters:
Day 3: COVID Impacts Special Session
2:30 Directors\u27 Introduction
3:27 Opening Prayer by Aspen Decker
5:12 Agenda for the COVID-19 Impacts Special Session
Native American Language Support Center
7:45 Moderator’s Introduction
8:55 Presentation: Rosalyn LaPier
Maya Health Alliance
28:53 Moderator’s Introduction
31:14 Presentation: Brent Henderson, Michel Juarez and Karyn Choy
COVID-19 Myth Busters
52:48 Moderator’s Introduction
54:08 Presentation: Seunghun Lee
1:22:30 Moderated Q&A/discussion: Jean-Luc Pierite
Houma Language Project
1:39:40 Moderator’s Introduction
1:41:37 Presentation: Hali Dardar, Ben Wood, Brittany Jimez & Colleen Billiot
2:10:25 Closing Prayer by Aspen Decker
2:11:22 Closing comments & thanks
2:15:13 CoLang 2022 Promotional Vide
Pentamidine antagonizes the benznidazole's effect in vitro, and lacks of synergy in vivo: Implications about the polyamine transport as an anti-Trypanosoma cruzi target
Benznidazole is the first-line drug used in treating Chagas disease, which is caused by the parasite Trypanosoma cruzi (T. cruzi). However, benznidazole has limited efficacy and several adverse reactions. Pentamidine is an antiprotozoal drug used in the treatment of leishmaniasis and African trypanosomiasis. In T. cruzi, pentamidine blocks the transport of putrescine, a precursor of trypanothione, which constitutes an essential molecule in the resistance of T. cruzi to benznidazole. In the present study, we describe the effect of the combination of benznidazole and pentamidine on isolated parasites, mammalian cells and in mice infected with T. cruzi. In isolated trypomastigotes, we performed a dose matrix scheme of combinations, where pentamidine antagonized the effect of benznidazole, mainly at concentrations below the EC50 of pentamidine. In T. cruzi-infected mammalian cells, pentamidine reversed the effect of benznidazole (measured by qPCR). In comparison, in infected BALB/c mice, pentamidine failed to get synergy with benznidazole, measured on mice survival, parasitemia and amastigote nest quantification. To further explain the in vitro antagonism, we explored whether pentamidine affects intracellular trypanothione levels, however, pentamidine produced no change in trypanothione concentrations. Finally, the T cruzi polyamine permease (TcPAT12) was overexpressed in epimastigotes, showing that pentamidine has the same trypanocidal effect, independently of transporter expression levels. These results suggest that, in spite of the high potency in the putrescine transport blockade, TcPAT12 permease is not the main target of pentamidine, and could explain the lack of synergism between pentamidine and benznidazole. (C) 2016 Elsevier Inc. All rights reserved
Rhenium(I) tricarbonyl compounds of bioactive thiosemicarbazones: Synthesis, characterization and activity against Trypanosoma cruzi
© 2017 Elsevier Inc. American Trypanosomiasis is a chronic infection discovered and described in 1909 by the Brazilian scientist Carlos Chagas. It is caused by the protozoan parasite Trypanosoma cruzi. Although it affects about 10 million people in Latin America, the current chemotherapy is still inadequate. The discovery of new drugs is urgently needed. Our group is focused on the development of prospective metal-based drugs mainly based on bioactive ligands and pharmacologically interesting metal ions. In this work three new rhenium(I) tricarbonyl compounds fac-[ReI(CO)3Br(HL)] where HL = 5-nitrofuryl containing thiosemicarbazones were synthesized and fully characterized in solution and in the solid state. The in vitro evaluation of the compounds on T. cruzi trypomastigotes (Dm28c strain) showed that the Re(I) compounds are 8 to 15 times more active than the reference drug Nifurtimox and show a 4 to 17 fold increase in activity in respect to the free (HL) ligands. Obtained compound
Endogenous overexpression of an active phosphorylated form of DNA polymerase β under oxidative stress in Trypanosoma cruzi
© 2018 Rojas et al. Trypanosoma cruzi is exposed during its life to exogenous and endogenous oxidative stress, leading to damage of several macromolecules such as DNA. There are many DNA repair pathways in the nucleus and mitochondria (kinetoplast), where specific protein complexes detect and eliminate damage to DNA. One group of these proteins is the DNA polymerases. In particular, Tc DNA polymerase β participates in kinetoplast DNA replication and repair. However, the mechanisms which control its expression under oxidative stress are still unknown. Here we describe the effect of oxidative stress on the expression and function of Tc DNA polymerase β To this end parasite cells (epimastigotes and trypomastigotes) were exposed to peroxide during short periods of time. Tc DNA polymerase β which was associated physically with kinetoplast DNA, showed increased protein levels in response to peroxide damage in both parasite forms analyzed. Two forms of DNA polymerase β were identified and ov
Synthesis, characterization and in vitro anti-Trypanosoma cruzi and anti-Mycobacterium tuberculosis evaluations of cyrhetrenyl and ferrocenyl thiosemicarbazones
Articulo de publicaciĂłn SCOPUSTo study the electronic influence of the organometallic moieties in thiosemicarbazones, two short libraries
of cyrhetrenyl thiosemicarbazone and ferrocenyl thiosemicarbazone hybrids were synthesized
and tested for their antichagasic and antitubercular activities. The unreported cyrhetrenyl thiosemicarbazone
derivatives of the form [(h5-C5H4)eC(R1) ÂĽ NNHC(S)NHR2]Re(CO)3 (R1 ÂĽ H, CH3; R2 ÂĽ H,
CH3, CH2CH3, C6H5) were prepared from cyrhetrenylcarbaldehyde (1a) or acetylcyrhetrene (1b) and the
corresponding thiosemicarbazide. The 1H and 13C NMR spectra indicate that these compounds have the
anti-(E) conformation in solution, and the X-ray crystal structure of formylcyrhetrene 4-methyl-thiosemicarbazone
(2b) confirms that this complex also adopts the anti-(E) form in the solid state. The new
cyrhetrenyl thiosemicarbazones and their ferrocene analogues were screened in vitro against Trypanosoma
cruzi and Mycobacterium tuberculosis. The anti-T. cruzi evaluation showed that the ferrocenyl derivatives
were more efficient trypanocidal agents compared to their cyrhetrenyl counterparts. The
incorporation of any organometallic fragment into thiosemicarbazone scaffold showed moderate antituberculosis
activity against mc27000 strain.MECESUP and CONICYT
FONDECYT-Chil
Evaluation of the novel antichagasic activity of [1,2,3]triazolo[1,5-a]triazolo[1,5-apyridine derivatives
© 2017 Bentham Science Publishers. Trypanosoma cruzi is the causative agent of Chagas disease. This parasite is vulnerable to the effects of ROS as its main defense mechanism against exogenous agents trypanothione is also another weakness of the parasite that investigated related to the inhibition of enzymes belonging P450 system, mainly CYP51. In our group we have synthesized a series of triazoles known as [1,2,3]triazolo[1,5-a]pyridyl ketones, and pyridyl ketones. These families have shown interesting structural features due to the presence of electron withdrawing moieties attached to the main heterocycle (triazoles and/or pyridines) and are proposed as potential target in the parasite, by the presence of the carbonyl group being able to be reduced and form a free radical that could interact with molecular oxygen generating ROS in the parasite. Furthermore, the triazole ring and pyridines have been considered as potent inhibitors of sterol biosynthesis, the lock being part CYP51. Ou
Biological and chemical study of fused tri- and tetracyclic indazoles and analogues with important antiparasitic activity
A series of fused tri- and tetracyclic indazoles and analogues compounds (NID) with potential antiparasitic effects were studied using voltamperometric and spectroscopic techniques. Nitroanion radicals generated by cyclic voltammetry were characterized by electron spin resonance spectroscopy (ESR) and their spectral lines were explained and analyzed using simulated spectra. In addition, we examined the interaction between radical species generated from nitroindazole derivatives and glutathione (GSH). Biological assays such as activity against Trypanosoma cruzi and cytotoxicity against macrophages were carried out. Finally, spin trapping and molecular modeling studies were also done in order to elucidate the potentials action mechanisms involved in the trypanocidal activity. © 2012 Elsevier B.V. All rights reserved
ESR, electrochemical, molecular modeling and biological evaluation of 4-substituted and 1,4-disubstituted 7-nitroquinoxalin-2-ones as potential anti-Trypanosoma cruzi agents
Electrochemical and ESR studies were carried out in this work with the aim of characterizing the reduction
mechanisms of 4-substituted and 1,4-disubstituted 7-nitroquinoxalin-2-ones by means of cyclic voltammetry
in DMSO as aprotic solvent. Two reduction mechanisms were found for these compounds: the first,
for compounds bearing a labile hydrogen by following a self-protonation mechanism (ECE steps), and the
second, for compounds without labile hydrogen, based on a purely electrochemical reduction mechanism
(typical of nitroheterocycles). The electrochemical results were corroborated using ESR spectroscopy
allowing us to propose the hyperfine splitting pattern of the nitro-radical, which was later corroborated
by the ESR simulation spectra. All these compounds were assayed as growth inhibitors against Trypanosoma
cruzi: first, on the non-proliferative (and infective) form of the parasite (trypomastigote stage),
and then, the ones that displayed activity, were assayed on the non-infective form (epimastigote stage).
Thus, we found four new compounds highly active against T. cruzi. Finally, molecular modeling studies
suggest the inhibition of the trypanothione reductase like one of the possible mechanisms involved in
the trypanocidal action.This research was supported by FONDECYT (Chile) through the
project 1071068 in collaboration with the project CSIC 16/07-08
and by the “ComisiĂłn Interministerial de Ciencia y TecnologĂa” (CICYT,
Spain) Project SAF2006-04698. B. Aguilera grateful to CONICYT
(Chile) - Doctoral fellowship - 21080766