DSpace Angular :: Browsing by Author "Salas, Cristian O."

Browsing by Author "Salas, Cristian O."

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2,3-Diketopiperazine as potential scaffold to develop new anti-Chagasic agents
(2023) Osorio-Nieto, Urbano; Salas, Cristian O.; Mendez-Alvarez, Domingo; Rivera, Gildardo; Moreno-Rodriguez, Adriana; Perez-Cervera, Yobana; Castillo-Real, Lizet Monserrat; Espinosa-Bustos, Christian
Continuing our program to develop compounds with potential activity against Trypanosoma cruzi, in this work we have designed and synthesized and evaluated in vitro on the trypomastigote form a new series of 2,3-diketopiperazines derivatives. By means of a two-step sequence, where one of them was a catalytic and selective C(sp(3))-H-bond reaction, nine final compounds (5a-i) were obtained. Most of these 2,3-diketopiperazines were highly active against the trypomastigote strain NINOA (LC50 < 100 mu M) compared to the reference drugs benznidazole (Bzn) and nifurtimox (Nfx). Likewise, compounds 5c and 5h showed high potency against the trypomastigote strain A1 (LC50 = 25.2 and 40.49 mu M, respectively), with 5c being four to five times more active than the reference drugs. In addition, the cytotoxicity of these compounds was determined in the murine macrophage J774 cell line, presenting in most cases, higher selectivity rates compared to Bzn and Nfx. In silico studies suggested that these 2,3-diketopiperazine derivatives could be inhibitors of the Fe-SOD enzyme at the cytosolic and mitochondrial level. Finally, these compounds would also have good oral bioavailability according to theoretical predictions.
A convenient and simple synthesis of N-arylpirrolopyrimidines using boronic acids and promoted by copper (II) acetate
(2017) Espinosa-Bustos, Christian; Villegas, Alondra; Salas, Cristian O.
A convenient and simple synthesis of novel N-arylated 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine using several aryl boronic acids and copper (II) acetate is described. The yields obtained for all derivatives are in the range of 45-70 % and this synthetic approach is extensible to other heterocycles such as 1H-indazoles.
Combined molecular modelling and 3D-QSAR study for understanding the inhibition of NQO1 by heterocyclic quinone derivatives
(2018) Lopez-Lira, Claudia; Alzate-Morales, Jans H.; Paulino, Margot; Mella-Raipan, Jaime; Salas, Cristian O.; Tapia Apati, Ricardo; Soto-Delgado, Jorge
Crystal structure of 4-chloro-2-methyl-6-(4-(trifluoromethoxy)phenyl)pyrimidine, c12h8clf3n2o
(2018) Bertrand, Jean-Luc; Salas, Cristian O.; Brito, Ivan
Expanding the chemical space of aryloxy-naphthoquinones as potential anti-Chagasic agents: synthesis and trypanosomicidal activity
(SPRINGER BIRKHAUSER, 2021) Becerra, Nohemi A.; Espinosa Bustos, Christian; Vazquez, Karina; Rivera, Gildardo; Paulino, Margot; Cantero, Jorge; Nogueda, Benjamin; Chacon Vargas, Fabiola; Castillo Velazquez, Uziel; Elizondo Rodriguez, Ana F.; Toledo, Sofia; Moreno Rodriguez, Adriana; Aranda, Mario; Salas, Cristian O.
In continuation our effort to research the chemical space of aryloxy-naphthoquinones as potential anti-Chagas agents, we synthesized nine derivatives and these compounds were evaluated in vitro against the epimastigote and trypomastigote forms of Mexican strains of Trypanosoma cruzi (T. cruzi). Most of these derivatives are highly active against epimastigote forms (IC50 < 1.0 mu M) compared to the reference drug benznidazole (Bzn). Then these were evaluated on trypomastigotes, which is showing better potency results than Bzn for compounds 3b and 3g. In addition, the cytotoxicity of these compounds was determined on the murine macrophage cell line J774. 3b and 3i were the most selective compounds against NINOA trypomastigote and INC-5 epimastigote forms, respectively. Further these compounds also have good oral bioavailability according to theoretical predictions. Finally, we were able to determine optimal substitution patterns using pharmacophoric models. All these results are provided very useful structural information to continue our designing of naphthoquinone derivatives against T. cruzi.
Experimental and theoretical physicochemical study of a new dispirocompound: 4′-(4-fluorophenyl)-2′,7-dimethyl-1,4-dihydro-3H-dispiro[cyclopent[b]indol-2,5′-[1,2]oxazinan-6′3"-indolin]-2",3-dione
(2021) Satheeshkumar, Rajendran; Montecinos, Rodrigo; Vera, Ariesny; Prasad, Karnam Jayarampillai Rajendra; Kaminsky, Werner; Salas, Cristian O.
We present Et3N mediated synthesis of a novel dispirocompound from 5-methyl-2-(4'-fluorophenylidine)-1-oxo-1,2,3,8-tetrahydrocyclopent[b]indole, isatin, and sarcosine through 1,3-dipolar cycloaddition reaction. The crystal structure of synthesised compound, 4'-(4-fluorophenyl)-2',7-dimethyl-1,4-dihydro-3H-dispiro[cyclopent[b]indol-2,5'-[1,2]oxazinan-6',3 ''-indolinl-2 '',3-dione is reported. FT-IR, H-1 and C-13 NMR chemical shifts as measured and calculated using B3LYP method with the 6-311G(d,p) basis set in gas phase were found in good agreement. The optimized geometry of the dispirocompound was compared with experimental XRD values. DFT calculations of the molecular electrostatic potential (MEP), Non-covalent interactions and Hirshfeld Surface analysis, Non-linear optical (NLO) properties and frontier molecular orbitals (FMO) identified chemically active sites of the dispirocompound responsible for its chemical reactivity. (C) 2020 Elsevier B.V. All rights reserved.
Exploring the Effect of Halogenation in a Series of Potent and Selective A2B Adenosine Receptor Antagonists
(2023) Prieto-Diaz, Ruben; Gonzalez-Gomez, Manuel; Fojo-Carballo, Hugo; Azuaje, Jhonny; El Maatougui, Abdelaziz; Majellaro, Maria; Loza, Maria, I; Brea, Jose; Fernandez-Duenas, Victor; Paleo, M. Rita; Diaz-Holguin, Alejandro; Garcia-Pinel, Beatriz; Mallo-Abreu, Ana; Estevez, Juan C.; Andujar-Arias, Antonio; Garcia-Mera, Xerardo; Gomez-Tourino, Iria; Ciruela, Francisco; Salas, Cristian O.; Gutierrez-de-Teran, Hugo; Sotelo, Eddy
The modulation of the A2B adenosine receptor is a promising strategy in cancer (immuno) therapy, with A2BAR antagonists emerging as immune checkpoint inhibitors. Herein, we report a systematic assessment of the impact of (di-and mono-)halogenation at positions 7 and/or 8 on both A2BAR affinity and pharmacokinetic properties of a collection of A2BAR antagonists and its study with structure-based free energy perturbation simulations. Monohalogenation at position 8 produced potent A2BAR ligands irrespective of the nature of the halogen. In contrast, halogenation at position 7 and dihalogenation produced a halogen-size-dependent decay in affinity. Eight novel A2BAR ligands exhibited remarkable affinity (Ki < 10 nM), exquisite subtype selectivity, and enantioselective recognition, with some eutomers eliciting sub-nanomolar affinity. The pharmacokinetic profile of representative derivatives showed enhanced solubility and microsomal stability. Finally, two compounds showed the capacity of reversing the antiproliferative effect of adenosine in activated primary human peripheral blood mononuclear cells.
In vitro and In vivo Biological Activity of Two Aryloxy-naphthoquinones in Mice Infected with Trypanosoma cruzi Strains
(2024) Vazquez, Karina; Moreno-Rodriguez, Adriana; Dominguez-Diaz, Luis R.; Bertrand, Jeanluc; Salas, Cristian O.; Rivera, Gildardo; Cervera, Yobana Perez; Bocanegra-Garcia, Virgilio
Background: Chagas disease, a condition caused by Trypanosoma cruzi, is an endemic disease in Latin American countries that affects approximately eight million people worldwide. It is a continuing public health problem. As nifurtimox and benznidazole are the two pharmacological treatments currently used to treat it, the present research proposes new therapeutic alternatives. Previous studies conducted on naphthoquinone derivatives have found interesting trypanocidal effects on epimastigotes, with the molecules 2-phenoxy-1,4-naphthoquinone (IC50= 50 nM and SI < 250) and 2-(3-nitrophenoxy)-naphthalene-1,4-dione (IC50= 20 nM y SI=625) presenting the best biological activity. Method: The present study evaluated the efficacy of in vitro, ex vivo and in vivo models of two aryloxyquinones, 2-phenoxy-1,4-naphthoquinone (1) and 2-(3-nitrophenoxy)-naphthalene-1,4- dione (2), against two Mexican T. cruzi strains in both their epimastigote and blood Trypomastigote stage. Both compounds were evaluated against T. cruzi using a mouse model (CD1) infected with Mexican isolates of T. cruzi, nifurtimox and benznidazole used as control drugs. Finally, the cytotoxicity of the two compounds against the J774.2 mouse macrophage cell line was also determined. Result: The in vitro and in vivo results obtained indicated that both quinones were more active than the reference drugs. Compound 1 presents in vivo activity, showing up to 40% parasite reduction after 8 h of administration, a finding which is 1.25 times more effective than the results obtained using nifurtimox. Conclusion: These are encouraging results for proposing new naphthoquinone derivatives with potential anti-T. cruzi activity
In Vivo and in vitro antitumor activity of tomatine in hepatocellular carcinoma
(2022) Echeverria, Cesar; Martin, Aldo; Simon, Felipe; Salas, Cristian O.; Nazal, Mariajesus; Varela, Diego; Perez-Castro, Ramon A.; Santibanez, Juan F.; Valdes-Valdes, Ricardo O.; Forero-Doria, Oscar; Echeverria, Javier
Background: There is abundant ethnopharmacological evidence the uses of regarding Solanum species as antitumor and anticancer agents. Glycoalkaloids are among the molecules with antiproliferative activity reported in these species. Purpose: To evaluate the anticancer effect of the Solanum glycoalkaloid tomatine in hepatocellular carcinoma (HCC) in vitro (HepG2 cells) and in vivo models. Methods: The resazurin reduction assay was performed to detect the effect of tomatine on cell viability in human HepG2 cell lines. Programmed cell death was investigated by means of cellular apoptosis assays using Annexin V. The expression of cancer related proteins was detected by Western blotting (WB). Reactive oxygen species (ROS) and calcium were determined by 2,7-dichlorodihydrofluorescein diacetate and Fluo-4, respectively. Intrahepatic HepG2 xenograft mouse model was used to elucidate the effect of tomatine on tumor growth in vivo. Results and Discussion: Tomatine reduced HepG2 cell viability and induced the early apoptosis phase of cell death, consistently with caspase-3, -7, Bcl-2 family, and P53 proteins activation. Furthermore, tomatine increased intracellular ROS and cytosolic Ca+2 levels. Moreover, the NSG mouse xenograft model showed that treating mice with tomatine inhibited HepG2 tumor growth. Conclusion: Tomatine inhibits in vitro and in vivo HCC tumorigenesis in part via modulation of p53, Ca+2, and ROS signalling. Thus, the results suggest the potential cancer therapeutic use of tomatine in HCC patients.
Mode of action of p-quinone derivatives with trypanocidal activity studied by experimental and in silico models
(2023) Ballesteros-Casallas, Andres; Quiroga, Cristina; Ortiz, Cecilia; Benitez, Diego; Denis, Pablo A.; Figueroa, David; Salas, Cristian O.; Bertrand, Jeanluc; Tapia, Ricardo A.; Sanchez, Patricio; Miscione, Gian Pietro; Comini, Marcelo A.; Paulino, Margot
Quinones are attractive pharmacological scaffolds for developing new agents for the treatment of different transmissible and non-transmissible human diseases due to their capacity to alter the cell redox homeostasis.The bioactivity and potential mode of action of 19 p-quinone derivatives fused to different aromatic rings (carbo or heterocycles) and harboring distinct substituents were investigated in infective Trypanosoma brucei brucei. All the compounds, except for a furanequinone (EC50=38 mu M), proved to be similarly or even more potent (EC50 = 0.5-5.5 mu M) than the clinical drug nifurtimox (EC50 = 5.3 mu M). Three furanequinones and one thia-zolequinone displayed a higher selectivity than nifurtimox. Two of these selective hits resulted potent inhibitors of T. cruzi proliferation (EC50=0.8-1.1 mu M) but proved inactive against Leishmania infantum amastigotes.Most of the p-quinones induced a rapid and marked intracellular oxidation in T. b. brucei. DFT calculations on the oxidized quinone (Q), semiquinone (Q center dot-) and hydroquinone (QH2) suggest that all quinones have negative Delta G for the formation of Q center dot-. Qualitative and quantitative structure-activity relationship analyses in two or three dimensions of different electronic and biophysical descriptors of quinones and their corresponding bioactivities (killing potency and oxidative capacity) were performed.Charge distribution over the quinone ring carbons of Q and Q.-and the frontier orbitals energies of SUMO (Q.-) and LUMO (Q) correlate with their oxidative and trypanocidal activity. QSAR analysis also highlighted that both bromine substitution in the p-quinone ring and a bulky phenyl group attached to the furane and thiazole rings (which generates a negative charge due to the 7C electron system polarized by the nearby heteroatoms) are favorable for activity.By combining experimental and in silico procedures, this study disclosed important information about p-qui-nones that may help to rationally tune their electronic properties and biological activities.
New Smoothened ligands based on the purine scaffold as potential agents for treating pancreatic cancer
(2024) Espinosa-Bustos, Christian; Bertrand, Jeanluc; Villegas-Menares, Alondra; Guerrero, Simon; Di Marcotullio, Lucia; Navacci, Shirin; Schulte, Gunnar; Kozielewicz, Pawel; Bloch, Nicolas; Villela, Valentina; Paulino, Margot; Kogan, Marcelo J.; Cantero, Jorge; Salas, Cristian O.
Aberrant activation of the Hedgehog (Hh) signalling pathway has been associated with the development and progression of pancreatic cancer. For this reason, blockade of Hh pathway by inhibitors targeting the G proteincoupled receptor Smoothened (SMO) has been considered as a therapeutic target for the treatment of this cancer. In our previous work, we obtained a new SMO ligand based on a purine scaffold (compound I), which showed interesting antitumor activity in several cancer cell lines. In this work, we report the design and synthesis of 17 new purine derivatives, some of which showed high cytotoxic effect on Mia-PaCa-2 (Hh-dependent pancreatic cancer cell lines) and low toxicity on non-neoplastic HEK-293 cells compared with gemcitabine, such as 8f, 8g and 8h (IC50 = 4.56, 4.11 and 3.08 mu M, respectively). Two of these purines also showed their ability to bind to SMO through NanoBRET assays (pKi = 5.17 for 8f and 5.01 for 8h), with higher affinities to compound I (pKi = 1.51). In addition, docking studies provided insight the purine substitution pattern is related to the affinity on SMO. Finally, studies of Hh inhibition for selected purines, using a transcriptional functional assay based on luciferase activity in NIH3T3 Shh-Light II cells, demonstrated that 8g reduced GLI activity with a IC50 = 6.4 mu M as well as diminished the expression of Hh target genes in two specific Hh-dependent cell models, Med1 cells and Ptch1- /- mouse embryonic fibroblasts. Therefore, our results provide a platform for the design of SMO ligands that could be potential selective cytotoxic agents for the treatment of pancreatic cancer.
Pharmacological insights emerging from the characterization of a large collection of synthetic cannabinoid receptor agonists designer drugs
(2023) Gioe-Gallo, Claudia; Ortigueira, Sandra; Brea, Jose; Raich, Iu; Azuaje, Jhonny; Paleo, M. Rita; Majellaro, Maria; Loza, Maria Isabel; Salas, Cristian O.; Garcia-Mera, Xerardo; Navarro, Gemma; Sotelo, Eddy
Synthetic cannabinoid receptor agonists (SCRAs) constitute the largest and most defiant group of abuse designer drugs. These new psychoactive substances (NPS), developed as unregulated alternatives to cannabis, have potent cannabimimetic effects and their use is usually associated with episodes of psychosis, seizures, dependence, organ toxicity and death. Due to their ever-changing structure, very limited or nil structural, pharmacological, and toxicological information is available to the scientific community and the law enforcement offices. Here we report the synthesis and pharmacological evaluation (binding and functional) of the largest and most diverse collection of enantiopure SCRAs published to date. Our results revealed novel SCRAs that could be (or may currently be) used as illegal psychoactive substances. We also report, for the first time, the cannabimimetic data of 32 novel SCRAs containing an (R) configuration at the stereogenic center. The systematic pharmacological profiling of the library enabled the identification of emerging Structure-Activity Relationship (SAR) and Structure-Selectivity Relationship (SSR) trends, the detection of ligands exhibiting incipient cannabinoid re-ceptor type 2 (CB2R) subtype selectivity and highlights the significant neurotoxicity of representative SCRAs on mouse primary neuronal cells. Several of the new emerging SCRAs are currently expected to have a rather limited potential for harm, as the evaluation of their pharmacological profiles revealed lower potencies and/or efficacies. Conceived as a resource to foster collaborative investigation of the physiological effects of SCRAs, the library obtained can contribute to addressing the challenge posed by recreational designer drugs.
Phenoxy- and Phenylamino-Heterocyclic Quinones: Synthesis and Preliminary Anti-Pancreatic Cancer Activity
(WILEY-V C H VERLAG GMBH, 2022) Sanchez, Patricio; Salas, Cristian O.; Gallardo-Fuentes, Sebastian; Villegas, Alondra; Veloso, Nicolas; Honores, Jessica; Inman, Martyn; Isaacs, Mauricio; Contreras, Renato; Moody, Christopher J.; Cisterna, Jonathan; Brito, Ivan; Tapia, Ricardo A.
The successful application of fragment-based drug discovery strategy for the efficient synthesis of phenoxy- or phenylamino-2-phenyl-benzofuran, -benzoxazole and -benzothiazole quinones is described. Interestingly, in the final step of the synthesis of the target compounds, unusual results were observed on the regiochemistry of the reaction of bromoquinones with phenol and aniline. A theoretical study was carried out for better understanding the factors that control the regiochemistry of these reactions. The substituted heterocyclic quinones were evaluated in vitro to determine their cytotoxicity by the MTT method in three pancreatic cancer cell lines (MIA-PaCa-2, BxPC-3, and AsPC-1). Phenoxy benzothiazole quinone 26a showed potent cytotoxic activity against BxPC-3 cell lines, while phenylamino benzoxazole quinone 20 was the most potent on MIA-PaCa-2 cells. Finally, electrochemical properties of these quinones were determined to correlate with a potential mechanism of action. All these results, indicate that the phenoxy quinone fragment led to compounds with increased activity against pancreatic cancer cells.
(-)-Shikimic Acid as a Chiral Building Block for the Synthesis of New Cytotoxic 6-Aza-Analogues of Angucyclinones
(2018) Quinones, Natalia; Hernandez, Santiago; Espinoza Catalan, Luis; Villena, Joan; Brito, Ivan; Cabrera Caballero, Alan Raúl; Salas, Cristian O.; Cuellar Fritis, Mauricio Alcides
Solvent-Free Synthesis of New Quinoline Derivatives via Eaton's Reagent Catalysed Friedlander Synthesis
(2022) Satheeshkumar, Rajendran; Prasad, Karnam Jayarampillai Rajendra; Wang Wen-Long; Espinosa-Bustos, Christian; Salas, Cristian O.
An interest for the development of new 2-acetyl/propanoyl quinolines via Friedlander synthesis is one of the most studied synthetic approaches. Herein we report the use of a freshly prepared Eaton's reagent (phosphorus pentoxide in methanesulfonic acid) as catalyst without solvents to obtain quinoline derivatives. Eleven 2-acetylquinolines were synthesized in high yields (85-96%) from symmetrical 1,2-diketone, butan-2,3-dione with o-aminoarylketones in the presence of Eaton's reagent. Subsequently, a novel regioselective solvent free reaction is reported for synthesis of o-aminoarylketones with unsymmetrical 1,2-diketone, pentan-2,3-dione, to yield different 2-propanoylquinolines. Eaton's reagent performs a unique way of this reaction as a powerful desiccant, condensing, cyclizing and dehydrating agent. Among these advantages of Eaton's reagent was found as an inexpensive and easily accessible catalyst for the Friedlander synthesis.
Studies on the Michael addition of naphthoquinones to sugar nitro olefins: first synthesis of polyhydroxylated hexahydro-11H-benzo[a]carbazole-5,6-diones and hexahydro-11bH-benzo[b]carbazole-6,11-diones
(PERGAMON-ELSEVIER SCIENCE LTD, 2012) Otero, Jose M.; Barcia, Jose C.; Salas, Cristian O.; Thomas, Pablo; Estevez, Juan C.; Estevez, Ramon J.
A strategy for the synthesis of the novel (6bR,7R,8S,9S,10S,10aR)-8-(benzyloxy)-7,9,10-trihydroxy-6b,7,8,9,10,10a-hexahydro-11H-benzo[a]carbazole-5,6-dione is reported. The key steps were the Michael addition of 2-hydroxy-1,4-naphthoquinone to 1-nitrocyclohexene or 3-O-benzyl-5,6-dideoxy-1,2-O-isopropylidene-6-nitro-alpha-D-xylo-hex-5-enefuranose and the diastereoselective intramolecular Henry reaction of 3-O-benzyl-5,6-dideoxy-S-C-(3'-hydroxy-1',4'-naphthoquinon-2'-yl)-1,2-O-isopropylidene-6-nitro-alpha-D-glucofuranose to give the key (1S,25,35,4R,5R,6R)-3-(benzyloxy)-1,2,4-trihydroxy-5-(3'-hydroxy-1',4'-naphthoquinon-2'-yl)-6-nitrocyclohexane. When 2-hydroxy-1,4-naphthoquinone was replaced by (1,4-dimethoxynaphthalen-2-yl)lithium, the novel (1R,2S,35,4R,4aS,11bS)-2-(benzyloxy)-1,3,4-trihydroxy-1,2,3,4,4a,5-hexahydro-11bH-benzo[b]carbazole-6,11-dione was obtained. (C) 2011 Elsevier Ltd. All rights reserved.
Synthesis and antiprotozoal activity of naphthofuranquinones and naphthothiophenequinones containing a fused thiazole ring
(2003) Tapia Apati, Ricardo; Alegría Aguirre, Luz Katiushka; Pessoa Mahana, Carlos David; Salas, Cristian O.; Cortés, Manuel J.; Valderrama Guerrero, Jaime Adolfo; Sarciron, M. E.; Pautet, F.; Walchshofer, N.; Fillion, H.

Browsing by Author "Salas, Cristian O."

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