Nuestros investigadores

Ignacio Aldana Moraza

Facultad de Farmacia y Nutrición. Universidad de Navarra
Líneas de investigación
Síntesis de compuestos biológicamente activos. Cáncer. Malaria. Obesidad y metabolismo. Tuberculosis. Leishmania. Chagas

Publicaciones científicas más recientes (desde 2010)

Autores: Quiliano, M.; Pabon, A.; Moles, E. ; et al.
ISSN 0223-5234  Vol. 152  2018  págs. 489 - 514
Design, synthesis, structure-activity relationship, cytotoxicity studies, in silico drug-likeness, genotoxicity screening, and in vivo studies of new 1-aryl-3-substituted propanol derivatives led to the identification of nine compounds with promising in vitro (55, 56, 61, 64, 66, and 70-73) and in vivo (66 and 72) antimalarial profiles against Plasmodium falciparum and Plasmodium berghei. Compounds 55, 56, 61, 64, 66 and 70-73 exhibited potent antiplasmodial activity against chloroquine-resistant strain FCR-3 (IC(50)s <0.28 mu M), and compounds 55, 56, 64, 70, 71, and 72 showed potent biological activity in chloroquine-sensitive and multidrug-resistant strains (IC(50)s < 0.7 mu M for 3D7, D6, FCR-3 and C235). All of these compounds share appropriate drug-likeness profiles and adequate selectivity indexes (77 < SI < 184) as well as lack genotoxicity. In vivo efficacy tests in a mouse model showed compounds 66 and 72 to be promising candidates as they exhibited significant parasitemia reductions of 96.4% and 80.4%, respectively. Additional studies such as liver stage and sporogony inhibition, target exploration of heat shock protein 90 of P. falciparum, targeted delivery by immunoliposomes, and enantiomer characterization were performed and strongly reinforce the hypothesis of 1-aryl-3-substituted propanol derivatives as promising antimalarial compounds. (C) 2018 Elsevier Masson SAS. All rights reserved.
Autores: Bonilla-Ramirez, L.; Rios, A.; Quiliano, M.; et al.
ISSN 0223-5234  Vol. 158  2018  págs. 68 - 81
Emergence of drug resistance and targeting all stages of the parasite life cycle are currently the major challenges in antimalarial chemotherapy. Molecular hybridization combining two scaffolds in a single molecule is an innovative strategy for achieving these goals. In this work, a series of novel quinoxaline 1,4-di-N-oxide hybrids containing either chloroquine or primaquine pharmacophores was designed, synthesized and tested against both chloroquine sensitive and multidrug resistant strains of Plasmodium falciparum. Only chloroquine-based compounds exhibited potent blood stage activity with compounds 4b and 4e being the most active and selective hybrids at this parasite stage. Based on their intraerythrocytic activity and selectivity or their chemical nature, seven hybrids were then evaluated against the liver stage of Plasmodium yoelii, Plasmodium berghei and Plasmodium falciparum infections. Compound 4b was the only chloroquine-quinoxaline 1,4-di-N-oxide hybrid with a moderate liver activity, whereas compound 6a and 6b were identified as the most active primaquine-based hybrids against exoerythrocytic stages, displaying enhanced liver activity against P. yoelii and P. berghei, respectively, and better SI values than primaquine. Although both primaquine-quinoxaline 1,4-di-N-oxide hybrids slightly reduced the infection of mosquitoes, they inhibited sporogony of P. berghei and compound 6a showed 92% blocking of transmission. In vivo liver efficacy assays revealed that compound 6a showed causal prophylactic activity affording parasitaemia reduction of up to 95% on day 4. Absence of genotoxicity and in vivo acute toxicity were also determined. These results suggest the approach of primaquine-quinoxaline 1,4-di-N-oxide hybrids as new potential dual-acting antimalarials for further investigation.
Autores: Moles, E.; Galiano, Silvia; Gomes, A.; et al.
ISSN 0142-9612  Vol. 145  2017  págs. 178 - 191
Most drugs currently entering the clinical pipeline for severe malaria therapeutics are of lipophilic nature, with a relatively poor solubility in plasma and large biodistribution volumes. Low amounts of these compounds do consequently accumulate in circulating Plasmodium-infected red blood cells, exhibiting limited antiparasitic activity. These drawbacks can in principle be satisfactorily dealt with by stably encapsulating drugs in targeted nanocarriers. Here this approach has been adapted for its use in immunocompetent mice infected by the Plasmodium yoelii 17XL lethal strain, selected as a model for human blood infections by Plasmodium falciparum. Using immunoliposomes targeted against a surface protein characteristic of the murine erythroid lineage, the protocol has been applied to two novel antimalarial lipophilic drug candidates, an aminoquinoline and an aminoalcohol. Large encapsulation yields of >90% were obtained using a citrate-buffered pH gradient method and the resulting immunoliposomes reached in vivo erythrocyte targeting and retention efficacies of >80%. In P. yoelii-infected mice, the immunoliposomized aminoquinoline succeeded in decreasing blood parasitemia from severe to uncomplicated malaria parasite densities (i.e. from >= 25% to ca. 5%), whereas the same amount of drug encapsulated in non-targeted liposomes had no significant effect on parasite growth. Pharmacokinetic analysis indicated that this good performance was obtained with a rapid clearance of immunoliposomes from the circulation (blood half-life of ca. 2 h), suggesting a potential for improvement of the proposed model.
Autores: Quiliano, M.; Pabon, A.; Ramirez Calderon, G.; et al.
ISSN 0960-894X  Vol. 27  Nº 8  2017  págs. 1820 - 1825
We report the design (in silico ADMET criteria), synthesis, cytotoxicity studies (HepG-2 cells), and biological evaluation of 15 hydrazine/hydrazide quinoxaline 1,4-di-N-oxide derivatives against the 3D7 chloroquine sensitive strain and FCR-3 multidrug resistant strain of Plasmodium falciparum and Leishmania infantum (axenic amastigotes). Fourteen of derivatives are novel quinoxaline 1,4-di-N-oxide derivatives. Compounds 18 (3D7 IC50 = 1.40 mu M, FCR-3 IC50 = 2.56 mu M) and 19 (3D7 IC50 = 0.24 mu M, FCR-3 IC50 = 2.8 mu M) were identified as the most active against P. falciparum, and they were the least cytotoxic (CC50-values > 241 mu M) and most selective (SI > 86). None of the compounds tested against L. infantum were considered to be active. Additionally, the functional role of the hydrazine and hydrazide structures were studied in the quinoxaline 1,4-di-N-oxide system.
Autores: Quiliano, M.; Fong, K. Y.; et al.
ISSN 2211-3207  Vol. 6  Nº 3  2016  págs. 184 - 198
Synthesis of new 1-aryl-3-substituted propanol derivatives followed by structure-activity relationship, in silico drug-likeness, cytotoxicity, genotoxicity, in silico metabolism, in silico pharmacophore modeling, and in vivo studies led to the identification of compounds 22 and 23 with significant in vitro anti-plasmodial activity against drug sensitive (D6 IC50 <= 0.19 mu M) and multidrug resistant (FCR-3 IC50 <= 0.40 mu M and C235 IC50 <= 0.28 mu M) strains of Plasmodium falciparum. Adequate selectivity index and absence of genotoxicity was also observed. Notably, compound 22 displays excellent parasitemia reduction (98 +/- 1%), and complete cure with all treated mice surviving through the entire period with no signs of toxicity. One important factor is the agreement between in vitro potency and in vivo studies. Target exploration was performed; this chemotype series exhibits an alternative antimalarial mechanism. (C) 2016 The Authors. Published by Elsevier Ltd on behalf of Australian Society for Parasitology.
Autores: Gil, Ana Gloria; Pabón, A.; Galiano, Silvia; et al.
ISSN 1420-3049  Vol. 19  Nº 2  2014  págs. 2166 - 2180
We report the synthesis and antimalarial activities of eighteen quinoxaline and quinoxaline 1,4-di-N-oxide derivatives, eight of which are completely novel. Compounds 1a and 2a were the most active against Plasmodium falciparum strains. Structure-activity relationships demonstrated the importance of an enone moiety linked to the quinoxaline ring.
Autores: Adriana Pabón; Pérez-Silanes, S; et al.
ISSN 1420-3049  Vol. 18  Nº 4  2013  págs. 4718 - 4727
Malaria and leishmaniasis are two of the World's most important tropical parasitic diseases. Continuing with our efforts to identify new compounds active against malaria and leishmaniasis, twelve new 1,4-di-N-oxide quinoxaline derivatives were synthesized and evaluated for their in vitro antimalarial and antileishmanial activity against Plasmodium falciparum FCR-3 strain, Leishmania infantum and Leishmania amazonensis. Their toxicity against VERO cells (normal monkey kidney cells) was also assessed. The results obtained indicate that a cyclopentyl derivative had the best antiplasmodial activity (2.9 mu M), while a cyclohexyl derivative (2.5 mu M) showed the best activity against L. amazonensis, and a 3-chloropropyl derivative (0.7 mu M) showed the best results against L. infantum. All these compounds also have a Cl substituent in the R-7 position.
Autores: Pérez-Silanes, S; Goutham Devarapally; Torres, Enrique; et al.
ISSN 0018-019X  Vol. 96  Nº 2  2013  págs. 217 - 227
Autores: Torres, Enrique; Moreno-Viguri, Elsa; Galiano, Silvia; et al.
ISSN 0223-5234  Vol. 66  2013  págs. 324 - 334
As a continuation of our research and with the aim of obtaining new agents against Chagas disease, an extremely neglected disease which threatens 100 million people, eighteen new quinoxaline 1,4-di-N-oxide derivatives have been synthesized following the Beirut reaction. The synthesis of the new derivatives was optimized through the use of a new and more efficient microwave-assisted organic synthetic method. The new derivatives showed excellent in vitro biological activity against Trypanosoma cruzi. Compound 17, which was substituted with fluoro groups at the 6- and 7-positions of the quinoxaline ring, was the most active and selective in the cytotoxicity assay. The electrochemical study showed that the most active compounds, which were substituted by electron-withdrawing groups, possessed a greater ease of reduction of the N-oxide groups.
Autores: Pérez-Silanes, S; et al.
ISSN 1420-3049  Vol. 17  Nº 7  2012  págs. 7737 - 7757
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.
Autores: Adriana Pabón; Galiano, Silvia; et al.
ISSN 1420-3049  Vol. 17  Nº 8  2012  págs. 9451 - 9461
Autores: Pérez-Silanes, S; et al.
ISSN 0223-5234  Vol. 52  2012  págs. 1 - 13
The combination of antagonism at histamine H-3 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 H-3 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 H-3 antagonism affinity. However, since all these derivatives failed to block K-ATP channels, the link of these two related moieties should not be considered a good pharmacophore for obtaining new dual H-3 antagonists with insulinotropic activity, suggesting the necessity to propose a new chemical hybrid prototype. (C)2012 Elsevier Masson SAS. All rights reserved.
Autores: Estevez, Yannick; Quiliano, Miguel; et al.
Revista: Experimental Parasitology
ISSN 0014-4894  Vol. 127  Nº 4  2011  págs. 745 - 751
Autores: Benítez, Diego; Cabrera, Mauricio; Hernández, Paola; et al.
ISSN 0022-2623  Vol. 54  Nº 10  2011  págs. 3624 - 3636
Autores: Pérez-Silanes, S; et al.
ISSN 1871-5265  Vol. 11  Nº 2  2011  págs. 196 - 204
Autores: Pérez-Silanes, S; Quiliano, Miguel; et al.
Revista: Experimental Parasitology
ISSN 0014-4894  Vol. 128  Nº 2  2011  págs. 97 - 103
Autores: Moreno-Viguri, Elsa; Pérez-Silanes, S; Gouravaram, Shrabani; et al.
Revista: Electrochimica Acta
ISSN 0013-4686  Vol. 56  Nº 9  2011  págs. 3270 - 3275
Autores: Torres, Enrique; Moreno-Viguri, Elsa; et al.
Revista: Bioorganic & Medicinal Chemistry Letters
ISSN 0960-894X  Vol. 21  Nº 12  2011  págs. 3699 - 3703
Autores: Pabón, Adriana; Castillo, Denis; et al.
Revista: Bioorganic & Medicinal Chemistry Letters
ISSN 0960-894X  Vol. 21  Nº 15  2011  págs. 4498 - 4502
Autores: Pontiki, Eleni; Hadjipavlou-Litina, Dimitra; et al.
ISSN 1747-0277  Vol. 77  Nº 4  2011  págs. 255 - 267
Autores: Moreno-Viguri, Elsa; Gabano, Elisabetta; Torres, Enrique; et al.
Revista: Molecules
ISSN 1420-3049  Vol. 16  Nº 9  2011  págs. 7893 - 7908
Autores: Aisa, Bárbara; Ramírez, M.J.; et al.
Revista: J Med Chem
ISSN 0022-2623  Vol. 54  Nº 8  2011  págs. 3086 - 3090
Autores: Moreno-Viguri, Elsa; Pérez-Silanes, S; et al.
ISSN 0223-5234  Vol. 45  Nº 10  2010  págs. 4418 - 4426
Autores: Moreno-Viguri, Elsa; et al.
Revista: Bioorganic & Medicinal Chemistry
ISSN 0968-0896  Vol. 18  Nº 7  2010  págs. 2713 - 2719
Autores: Schrey, Anna K.; Galiano, Silvia; et al.
Revista: Bioorganic & Medicinal Chemistry
ISSN 0968-0896  Vol. 18  Nº 21  2010  págs. 7365 - 7379
Autores: Aldana, Ignacio; Moreno-Viguri, Elsa; Cerecetto, H.; et al.
Revista: Drugs of the future
ISSN 0377-8282  Vol. 35  Nº Suppl. A  2010  págs. 220