http://hdl.handle.net/10171/18550 2013-05-21T00:52:34Z http://hdl.handle.net/10171/27915 Title: Synthesis of quinoxaline 1,4-di-N-oxide derivatives on solid support using room temperature and microwave-assisted solvent-free procedures Author(s) : Gomez-Caro, L.C. (Lilia C.); Sanchez-Sanchez, M. (Mario); Bocanegra-Garcia, V. (Virgilio); Rivera, G. (Gildardo); Monge, A. (Antonio) Abstract: We describe the synthesis of 12 new ethyl and methyl quinoxaline-7-carboxylate 1,4-di-N-oxide derivatives on solid supports with room temperature and microwave-assisted solvent-free procedures. Results show that solid supports have good catalytic activity in the formation of quinoxaline 1,4-di-N-oxide derivatives. We found that florisil and montmorillonite KSF and K10 could be used as new, easily available, inexpensive alternatives of catalysts. Additionally, room temperature and microwave-irradiation solvent-free synthesis was more efficient than a conventional procedure (Beirut reaction), reducing reaction time and increasing yield. 2010-12-31T23:00:00Z http://hdl.handle.net/10171/27871 Title: Novel phenazine 5,10-dioxides release OH in simulated hypoxia and induce reduction of tumour volume in vivo Author(s) : Lavaggi, M.L. (María L.); Cabrera, M. (Mauricio); Pintos, C. (Cristina); Arredondo, C. (Carolina); Pachon, G. (Gisela); Rodriguez, J. (Jorge); Raymondo, S. (Stella); Pacheco, J.P. (José Pedro); Cascante, M. (Marta); Olea-Azar, C. (Claudio); Lopez-de-Cerain, A. (Adela); Monge, A. (Antonio); Cerecetto, H. (Hugo); Gonzalez, M. (Mercedes) Abstract: Phenazine 5,10-dioxides (PDOs) are a new class of bioreductive cytotoxins, which could act towards tumours containing hypoxic regions. The PDOs selective-hypoxic bioreduction was probed in vitro; however, the mechanism of action has not been completely explained. Besides, PDOs in vivo antitumour activities have not been demonstrated hitherto. We study the mechanism of hypoxic/normoxic cytotoxicity of PDO representative members. Electron spin resonance is used to confirm (•)OH production, alkaline comet assay to determine genotoxicity, and gel electrophoresis and flow cytometry to analyze DNA fragmentation and cell cycle distribution. Chemically induced rat breast tumours are employed to evaluate in vivo activities. For the most selective cytotoxin, 7(8)-bromo-2-hydroxyphenazine 5,10-dioxide (PDO1), exclusive hypoxic (•)OH production is evidenced, while for the unselective ones, (•)OH is produced in both conditions (normoxia and simulated hypoxia). In normoxia (Caco-2 cells), PDO1 induces cell-cycle arrest and DNA fragmentation but does not significantly induce apoptosis neither at IC(50) nor IC(80). No difference in the comet-assay scores are observed in normoxia and simulated hypoxia being the unselective 2-amino-7(8)-bromophenazine 5,10-dioxide (PDO2) the most genotoxic. The in vivo efficacy with the absence of systemic toxicity of PDO1 and PDO2 is checked out. Results from this study highlight the potential of PDOs as new therapeutics for cancer. 2010-12-31T23:00:00Z http://hdl.handle.net/10171/23742 Title: New salicylamide and sulfonamide derivatives of quinoxaline 1,4-di-N-oxide with antileishmanial and antimalarial activities Author(s) : Barea, C. (Carlos); Pabon, A. (Adriana); Castillo, D. (Denis); Zimic, M. (Mirko); Quiliano, M. (Miguel); Galiano, S. (Silvia); Perez-Silanes, S. (Silvia); Monge, A. (Antonio); Deharo, E. (Eric); Aldana, I. (Ignacio) Abstract: Continuing with our efforts to identify new active compounds against malaria and leishmaniasis, fourteen new 3-amino-1,4-di-N-oxide quinoxaline-2-carbonitrile derivatives were synthesized and evaluated for their in vitro antimalarial and antileishmanial activity against Plasmodium falciparum Colombian FCR-3 strain and Leishmania amazonensis strain MHOM/BR/76/LTB-012A. Further computational studies were carried out in order to analyze graphic SAR and ADME properties. The results obtained indicate that compounds with one halogenous group substituted in position 6 and 7 provide an efficient approach for further development of antimalarial and antileishmanial agents. In addition, interesting ADME properties were found 2010-12-31T23:00:00Z http://hdl.handle.net/10171/23603 Title: New quinoxaline derivatives as potential MT₁ and MT₂ receptor ligands. Author(s) : Ancizu, S. (Saioa); Castrillo, N. (Nerea); Perez-Silanes, S. (Silvia); Aldana, I. (Ignacio); Monge, A. (Antonio); Delagrange, P. (Philippe); Caignard, D.H. (Daniel-Henry); Galiano, S. (Silvia) Abstract: Ever since the idea arose that melatonin might promote sleep and resynchronize circadian rhythms, many research groups have centered their efforts on obtaining new melatonin receptor ligands whose pharmacophores include an aliphatic chain of variable length united to an N-alkylamide and a methoxy group (or a bioisostere), linked to a central ring. Substitution of the indole ring found in melatonin with a naphthalene or quinoline ring leads to compounds of similar affinity. The next step in this structural approximation is to introduce a quinoxaline ring (a bioisostere of the quinoline and naphthalene rings) as the central nucleus of future melatoninergic ligands 2011-12-31T23:00:00Z http://hdl.handle.net/10171/23602 Title: Studies on log Po/w of quinoxaline di-N-oxides: a comparison of RP-HPLC experimental and predictive approaches. Author(s) : Moreno, E. (Elsa); Gabano, E. (Elisabetta); Torres, E. (Enrique); Platts, J.A. (James A.); Ravera, M. (Mauro); Aldana, I. (Ignacio); Monge, A. (Antonio); Perez-Silanes, S. (Silvia) Abstract: As reported in our previous papers, a series of quinoxaline-2-carboxamide 1,4-di-N-oxide derivatives were synthesized and studied as anti-tuberculosis agents. Here, the capability of the shake-flask method was studied and the retention time (expressed as log K) of 20 compounds were determined by RP-HPLC analysis. We found that the prediction of log P by the RP-HPLC analysis can result in a high accuracy and can replace the shake-flask method avoiding the experimental problems presented by quinoxaline di-N-oxides. The studied compounds were subjected to the ALOGPS module with the aim of comparing experimental log Po/w values and predicted data. Moreover, a preliminary in silico screening of the QSAR relationship was made confirming the influence of reduction peak potential, lipophilicity, H-bond donor capacity and molecular dimension descriptors on anti-tuberculosis activity. 2010-12-31T23:00:00Z http://hdl.handle.net/10171/23601 Title: Antiplasmodial and leishmanicidal activities of 2-cyano-3-(4-phenylpiperazine-1-carboxamido) quinoxaline 1,4-dioxide derivatives. Author(s) : Barea, C. (Carlos); Pabon, A. (Adriana); Galiano, S. (Silvia); Perez-Silanes, S. (Silvia); González, G. (German); Deyssard, C. (Chloe); Monge, A. (Antonio); Deharo, E. (Eric); Aldana, I. (Ignacio) Abstract: Malaria and leishmaniasis are two of the World’s most important tropical parasitic diseases. Thirteen new 2-cyano-3-(4-phenylpiperazine-1-carboxamido) quinoxaline 1,4-dioxide derivatives (CPCQs) were synthesized and evaluated for their in vitro antimalarial and antileishmanial activity against erythrocytic forms of Plasmodium falciparum and axenic forms of Leishmania infantum. Their toxicity against VERO cells (normal monkey kidney cells) was also assessed. None of the tested compounds was efficient against Plasmodium, but two of them showed good activity against Leishmania. Toxicity on VERO was correlated with leishmanicidal properties. 2011-12-31T23:00:00Z http://hdl.handle.net/10171/23600 Title: New 1-aryl-3-substituted propanol derivatives as antimalarial agents Author(s) : Perez-Silanes, S. (Silvia); Berrade, L. (Luis); Garcia–Sanchez, R.N. (Rory N.); Mendoza, A. (Adela); Galiano, S. (Silvia); Martin-Perez-Solorzano, B. (Berta); Nogal-Ruiz, J.J. (Juan J.); Martinez-Fernandez, A.R. (Antonio R.); Aldana, I. (Ignacio); Monge, A. (Antonio) Abstract: This paper describes the synthesis and in vitro antimalarial activity against a P. falciparum 3D7 strain of some new 1-aryl-3-substituted propanol derivatives. Twelve of the tested compounds showed an IC50 lower than 1 μM. These compounds were also tested for cytotoxicity in murine J774 macrophages. The most active compounds were evaluated for in vivo activity against P. berghei in a 4-day suppressive test. Compound 12 inhibited more than 50% of parasite growth at a dose of 50 mg/kg/day. In addition, an FBIT test was performed to measure the ability to inhibit ferriprotoporphyrin biocrystallization. This data indicates that 1-aryl-3-substituted propanol derivatives hold promise as a new therapeutic option for the treatment of malaria. 2008-12-31T23:00:00Z http://hdl.handle.net/10171/23599 Title: Heterocyclic-2-carboxylic acid (3-cyano-1,4-di-N-oxidequinoxalin-2-yl)amide derivatives as hits for the development of neglected disease drugs. Author(s) : Ancizu, S. (Saioa); Moreno, E. (Elsa); Torres, E. (Enrique); Burguete, A. (Asunción); Perez-Silanes, S. (Silvia); Benitez, D. (Diego); Villar, R. (Raquel); Solano, B. (Beatriz); Marin, A. (Adoración); Aldana, I. (Ignacio); Cerecetto, H. (Hugo); Gonzalez, M. (Mercedes); Monge, A. (Antonio) Abstract: Neglected diseases represent a major health problem. It is estimated that one third of the world population is infected with tuberculosis (TB). Besides TB, Chagas disease, affects approximately 20 million people. Quinoxalines display great activities against TB and Chagas. Forty new quinoxaline 1,4-di-N-oxide derivatives have been prepared and tested against M. tuberculosis and T. cruzi. Carboxylic acid quinoxaline 1,4-di-N-oxides (CAQDOs) 5 and 17 showed MIC values on the same order as the reference antituberculosis drug, rifampicin. Meanwhile, CAQDOs 12 and 22 presented IC50 values in the same order as the anti-chagasic drug, nifurtimox. 2008-12-31T23:00:00Z http://hdl.handle.net/10171/23598 Title: Unexpected reduction of ethyl 3-phenylquinoxaline-2- carboxylate 1,4-di-N-oxide derivatives by amines. Author(s) : Lima, L.M. (Lidia M.); Vicente, E. (Esther); Solano, B. (Beatriz); Perez-Silanes, S. (Silvia); Aldana, I. (Ignacio); Monge, A. (Antonio) Abstract: The unexpected tendency of amines and functionalized hydrazines to reduce ethyl 3-phenylquinoxaline-2-carboxylate 1,4-di-N-oxide (1) to afford a quinoxaline 1c and mono-oxide quinoxalines 1a and 1b is described. The experimental conditions were standardized to the use of two equivalents of amine in ethanol under reflux for two hours, with the aim of studying the distinct reductive profiles of the amines and the chemoselectivity of the process. With the exception of hydrazine hydrate, which reduced compound 1 to a 3-phenyl-2-quinoxalinecarbohydrazide derivative, the amines only acted as reducing agents. 2007-12-31T23:00:00Z http://hdl.handle.net/10171/23597 Title: Synthesis and antiplasmodial activity of 3-furyl and 3-thienylquinoxaline-2-carbonitrile 1,4-di-N-oxide derivatives Author(s) : Vicente, E. (Esther); Charnaud, S. (Sarah); Bongard, E. (Emily); Villar, R. (Raquel); Burguete, A. (Asunción); Solano, B. (Beatriz); Ancizu, S. (Saioa); Perez-Silanes, S. (Silvia); Aldana, I. (Ignacio); Vivas, L. (Livia); Monge, A. (Antonio) Abstract: The aim of this study was to identify new compounds active against Plasmodium falciparum based on our previous research carried out on 3-phenylquinoxaline- 2-carbonitrile 1,4-di-N-oxide derivatives. Twelve compounds were synthesized and evaluated for antimalarial activity. Eight of them showed an IC50 < 1 μM against the 3D7 strain. Derivative 1 demonstrated high potency (IC50= 0.63 μM) and good selectivity (SI=10.35), thereby becoming a new lead-compound. 2007-12-31T23:00:00Z http://hdl.handle.net/10171/23596 Title: Substitutions of fluorine atoms and phenoxy groups in the synthesis of quinoxaline 1,4-di-N-oxide derivatives. Author(s) : Vicente, E. (Esther); Villar, R. (Raquel); Burguete, A. (Asunción); Solano, B. (Beatriz); Ancizu, S. (Saioa); Perez-Silanes, S. (Silvia); Aldana, I. (Ignacio); Monge, A. (Antonio) Abstract: The unexpected substitution of fluorine atoms and phenoxy groups attached to quinoxaline or benzofuroxan rings is described. The synthesis of 2-benzyl- and 2-phenoxy- 3-methylquinoxaline 1,4-di-N-oxide derivatives was based on the classical Beirut reaction. The tendency of fluorine atoms linked to quinoxaline or benzofuroxan rings to be replaced by a methoxy group when dissolved in an ammonia saturated solution of methanol was clearly demonstrated. In addition, 2-phenoxyquinoxaline 1,4-di-N-oxide derivatives became 2-aminoquinoxaline 1,4-di-N-oxide derivatives in the presence of gaseous ammonia. 2007-12-31T23:00:00Z http://hdl.handle.net/10171/23595 Title: Novel sulfonylurea derivatives as H3 receptor antagonists. Preliminary SAR studies Author(s) : Ceras, J. (Javier); Cirauqui, N. (Nuria); Perez-Silanes, S. (Silvia); Aldana, I. (Ignacio); Monge, A. (Antonio); Galiano, S. (Silvia) Abstract: The combination of antagonism at histamine H3 receptor and the stimulation of insulin secretion have been proposed as an approach to new dual therapeutic agents for the treatment of type 2 diabetes mellitus associated with obesity. We have designed and synthesized a new series of non-imidazole derivatives, based on a basic amine ring connected through an alkyl spacer of variable length to a phenoxysulfonylurea moiety. These compounds were initially evaluated for histamine H3 receptor binding affinities, suggesting that a propoxy chain linker between the amine and the core ring could be essential for optimal binding affinity. Compound 56, 1-(naphthalen-1-yl)-3-[(p-(3-pyrrolidin-1-ylpropoxy)benzene)]sulfonylurea exhibited the best H3 antagonism affinity. However, since all these derivatives failed to block KATP channels, the link of these two related moieties should not be considered a good pharmacophore for obtaining new dual H3 antagonists with insulinotropic activity, suggesting the necessity to propose a new chemical hybrid prototype. 2011-12-31T23:00:00Z http://hdl.handle.net/10171/21042 Title: Studies on LogP o/w of Quinoxaline di-N-osides: a comparison of RP-HPLC experimental and predictive approaches Author(s) : Moreno, E. (Elsa); Gabano, E. (Elisabetta); Platts, J.A. (James A.); Ravera, M. (Mauro); Aldana, I. (Ignacio); Monge, A. (Antonio); Perez-Silanes, S. (Silvia) Abstract: As reported in our previous papers, a series of quinoxaline-2-carboxamide 1,4-di-N-oxide derivatives were synthesized and studied as anti-tuberculosis agents. Here, the capability of the shake-flask method was studied and the retention time (expressed as log K) of 20 compounds were determined by RP-HPLC analysis. We found that the prediction of log P by the RP-HPLC analysis can result in a high accuracy and can replace the shake-flask method avoiding the experimental problems presented by quinoxaline di-N-oxides. The studied compounds were subjected to the ALOGPS module with the aim of comparing experimental log Po/w values and predicted data. Moreover, a preliminary in silico screening of the QSAR relationship was made confirming the influence of reduction peak potential, lipophilicity, H-bond donor capacity and molecular dimension descriptors on anti-tuberculosis activity. 2011-09-12T22:00:00Z http://hdl.handle.net/10171/18732 Title: New 1,4-di-N-oxide-quinoxaline-2-ylmethylene isonicotinic acid hydrazide derivatives as anti-Mycobacterieum tuberculosis agents Author(s) : Torres, E. (Enrique); Moreno, E. (Elsa); Ancizu, S. (Saioa); Barea, C. (C.); Galiano, S. (S.); Aldana, I. (Ignacio); Monge, A. (Antonio); Perez-Silanes, S. (Silvia) Abstract: The increase in the prevalence of drug-resistant tuberculosis cases demonstrates the need of discovering new and promising compounds with antimycobacterial activity. As a continuation of our research and with the aim of identifying new antitubercular drugs candidates, a new series of quinoxaline 1,4-di-N-oxide derivatives containing isoniazid was synthesized and evaluated for in vitro anti-tuberculosis activity against Mycobacterium tuberculosis H37Rv strain. Moreover, various drug-like properties of new compounds were predicted. Taking into account the biological results and the promising drug-likeness profile of these compounds, make them valid leads for further experimental research. 2010-12-31T23:00:00Z http://hdl.handle.net/10171/18731 Title: 1,4-Di-N-oxide quinoxaline-2-carboxamide: Cyclic voltammetry and relationship between electrochemical behavior, structure and anti-tuberculosis activity Author(s) : Moreno, E. (Elsa); Perez-Silanes, S. (Silvia); Gouravaram, S. (S.); Macharam, A. (Abinav); Ancizu, S. (Saioa); Torres, E. (Enrique); Aldana, I. (Ignacio); Monge, A. (Antonio); Crawford, P.W. (Philip W.) Abstract: To gain insight into the mechanism of action, the redox properties of 37 quinoxaline-2-carboxamide 1,4-di-N-oxides with varying degrees of anti-tuberculosis activity were studied in dimethylformamide (DMF) using cyclic voltammetry and first derivative cyclic voltammetry. For all compounds studied, electrochemical reduction in DMF is consistent with the reduction of the N-oxide functionality to form a radical anion. The influence of molecular structure on reduction potential is addressed and it can be said that a general relationship exists between reduction potential and reported antimicrobial activity. For those compounds which have demonstrated promising biological activity, the more active the compound the less negative the reduction potential typically is. The results suggest the possible participation of charge transfer processes in the mechanism of action of quinoxaline di-N-oxides against tuberculosis and offer new insights into the design of future antitubercular drugs. 2010-12-31T23:00:00Z