Publications by authors named "José Luis Lavandera"

11 Publications

  • Page 1 of 1

Evaluation of the Antioxidant and Neuroprotectant Activities of New Asymmetrical 1,3-Diketones.

Molecules 2018 Jul 24;23(8). Epub 2018 Jul 24.

Instituto de Medicina Molecular Aplicada (IMMA), Facultad de Medicina, Universidad CEU San Pablo, Campus de Montepríncipe, Boadilla, E-28668 Madrid, Spain.

A series of fourteen new asymmetrical 1,3-diketone derivatives have been synthesized and evaluated in the ABTS, FRAP and DPPH assays as a new chemotype with antioxidant and drug-like properties. All the compounds displayed low cytotoxicity in comparison to curcumin against the human neuroblastoma SH-SY5Y cell line. Among them, (3,5)-6-(2,5-difluoro-4-hydroxy-phenyl)-1,1,1-trifluoro-4-hydroxyhexa-3,5-dien-2-one () and (3,5)-6-(2,3-difluoro-4-hydroxy-phenyl)-1,1,1-trifluoro-4-hydroxyhexa-3,5-dien-2-one () with excellent solubility and chemical stability in biorelevant media, have also shown a similar Fe chelation behavior to that of curcumin. Additionally, both derivatives and have afforded good neuroprotection activity against H₂O₂ induced oxidative stress in the same neuronal cell line, with a significant reduction of intracellular ROS levels, in parallel with a good recovery of the Mitochondrial Membrane Potential (ΔΨ). Compounds and with a promising antioxidant and drug-like profile, with low cytotoxic and good neuroprotectant activity, constitute a new interesting chemical class with high potential as new therapeutic agents against neurodegenerative diseases.
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http://dx.doi.org/10.3390/molecules23081837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222706PMC
July 2018

Functional screening of selective mitochondrial inhibitors of Plasmodium.

Int J Parasitol Drugs Drug Resist 2018 08 9;8(2):295-303. Epub 2018 May 9.

Diseases of the Developing World (DDW), Tres Cantos Medicine Development Campus, GlaxoSmithKline, Severo Ochoa 2, 28760, Tres Cantos, Madrid, Spain. Electronic address:

Phenotypic screening has produced most of the new chemical entities currently in clinical development for malaria, plus many lead compounds active against Plasmodium falciparum asexual stages. However, lack of knowledge about the mode of action of these compounds delays and may even hamper their future development. Identifying the mode of action of the inhibitors greatly helps to prioritise compounds for further development as novel antimalarials. Here we describe a whole-cell method to detect inhibitors of the mitochondrial electron transport chain, using oxygen consumption as high throughput readout in 384-well plate format. The usefulness of the method has been confirmed with the Tres Cantos Antimalarial Compound Set (TCAMS). The assay identified 124 respiratory inhibitors in TCAMS, seven of which were novel anti-plasmodial chemical structures never before described as mitochondrial inhibitors.
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http://dx.doi.org/10.1016/j.ijpddr.2018.04.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6039321PMC
August 2018

Antitubercular drugs for an old target: GSK693 as a promising InhA direct inhibitor.

EBioMedicine 2016 Jun 8;8:291-301. Epub 2016 May 8.

Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain. Electronic address:

Despite being one of the first antitubercular agents identified, isoniazid (INH) is still the most prescribed drug for prophylaxis and tuberculosis (TB) treatment and, together with rifampicin, the pillars of current chemotherapy. A high percentage of isoniazid resistance is linked to mutations in the pro-drug activating enzyme KatG, so the discovery of direct inhibitors (DI) of the enoyl-ACP reductase (InhA) has been pursued by many groups leading to the identification of different enzyme inhibitors, active against Mycobacterium tuberculosis (Mtb), but with poor physicochemical properties to be considered as preclinical candidates. Here, we present a series of InhA DI active against multidrug (MDR) and extensively (XDR) drug-resistant clinical isolates as well as in TB murine models when orally dosed that can be a promising foundation for a future treatment.
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http://dx.doi.org/10.1016/j.ebiom.2016.05.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4919555PMC
June 2016

Mycobacterium tuberculosis gyrase inhibitors as a new class of antitubercular drugs.

Antimicrob Agents Chemother 2015 Apr 12;59(4):1868-75. Epub 2015 Jan 12.

Diseases of the Developing World, GSK, Severo Ochoa 2, Tres Cantos, Madrid, Spain.

One way to speed up the TB drug discovery process is to search for antitubercular activity among compound series that already possess some of the key properties needed in anti-infective drug discovery, such as whole-cell activity and oral absorption. Here, we present MGIs, a new series of Mycobacterium tuberculosis gyrase inhibitors, which stem from the long-term efforts GSK has dedicated to the discovery and development of novel bacterial topoisomerase inhibitors (NBTIs). The compounds identified were found to be devoid of fluoroquinolone (FQ) cross-resistance and seem to operate through a mechanism similar to that of the previously described NBTI GSK antibacterial drug candidate. The remarkable in vitro and in vivo antitubercular profiles showed by the hits has prompted us to further advance the MGI project to full lead optimization.
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http://dx.doi.org/10.1128/AAC.03913-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4356839PMC
April 2015

Fueling open-source drug discovery: 177 small-molecule leads against tuberculosis.

ChemMedChem 2013 Feb 10;8(2):313-21. Epub 2013 Jan 10.

Tres Cantos Medicines Development Campus (TCMDC), GlaxoSmithKline (GSK), Severo Ochoa 2, Tres Cantos, Madrid, Spain.

With the aim of fuelling open-source, translational, early-stage drug discovery activities, the results of the recently completed antimycobacterial phenotypic screening campaign against Mycobacterium bovis BCG with hit confirmation in M. tuberculosis H37Rv were made publicly accessible. A set of 177 potent non-cytotoxic H37Rv hits was identified and will be made available to maximize the potential impact of the compounds toward a chemical genetics/proteomics exercise, while at the same time providing a plethora of potential starting points for new synthetic lead-generation activities. Two additional drug-discovery-relevant datasets are included: a) a drug-like property analysis reflecting the latest lead-like guidelines and b) an early lead-generation package of the most promising hits within the clusters identified.
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http://dx.doi.org/10.1002/cmdc.201200428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3743164PMC
February 2013

Structure-guided discovery of phenyl-diketo acids as potent inhibitors of M. tuberculosis malate synthase.

Chem Biol 2012 Dec;19(12):1556-67

Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA.

The glyoxylate shunt plays an important role in fatty acid metabolism and has been shown to be critical to survival of several pathogens involved in chronic infections. For Mycobacterium tuberculosis (Mtb), a strain with a defective glyoxylate shunt was previously shown to be unable to establish infection in a mouse model. We report the development of phenyl-diketo acid (PDKA) inhibitors of malate synthase (GlcB), one of two glyoxylate shunt enzymes, using structure-based methods. PDKA inhibitors were active against Mtb grown on acetate, and overexpression of GlcB ameliorated this inhibition. Crystal structures of complexes of GlcB with PDKA inhibitors guided optimization of potency. A selected PDKA compound demonstrated efficacy in a mouse model of tuberculosis. The discovery of these PDKA derivatives provides chemical validation of GlcB as an attractive target for tuberculosis therapeutics.
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http://dx.doi.org/10.1016/j.chembiol.2012.09.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3530165PMC
December 2012

An Invitation to Open Innovation in Malaria Drug Discovery: 47 Quality Starting Points from the TCAMS.

ACS Med Chem Lett 2011 Oct 3;2(10):741-6. Epub 2011 Aug 3.

Tres Cantos Medicines Development Campus, DDW, GlaxoSmithKline , Severo Ochoa 2, 28760 Tres Cantos, Spain.

In 2010, GlaxoSmithKline published the structures of 13533 chemical starting points for antimalarial lead identification. By using an agglomerative structural clustering technique followed by computational filters such as antimalarial activity, physicochemical properties, and dissimilarity to known antimalarial structures, we have identified 47 starting points for lead optimization. Their structures are provided. We invite potential collaborators to work with us to discover new clinical candidates.
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http://dx.doi.org/10.1021/ml200135pDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4018116PMC
October 2011

Cyclodextrin/poly(anhydride) nanoparticles as drug carriers for the oral delivery of atovaquone.

Biomed Microdevices 2011 Dec;13(6):1015-25

Diseases of the Developing World-DDW, Tres Cantos Medicines Development Campus, GlaxoSmithKline R&D, 28760 Tres Cantos, Spain.

The aim was to study the ability of bioadhesive cyclodextrin-poly(anhydride) nanoparticles as carriers for the oral delivery of atovaquone (ATO). In order to increase the loading capacity of ATO by poly(anhydride) nanoparticles, the following oligosaccharides were assayed: 2-hydroxypropyl-β-cyclodextrin (HPCD), 2,6-di-O-methyl-β-cyclodextrin (DCMD), randomly methylated-β-cyclodextrin (RMCD) and sulfobuthyl ether-β-cyclodextrin (SBECD). Nanoparticles were obtained by desolvation after the incubation between the poly(anhydride) with the ATO-cyclodextrin complexes. For the pharmacokinetic studies, ATO formulations were administered orally in rats. Overall, ATO displayed a higher affinity for methylated cyclodextrins than for the other derivatives. However, for in vivo studies, both ATO-DMCD-NP and ATO-HPCD-NP were chosen. These nanoparticle formulations showed more adequate physicochemical properties in terms of size (<260 nm), drug loading (17.8 and 16.9 μg/mg, respectively) and yield (>75%). In vivo, nanoparticle formulations induced higher and more prolonged plasmatic levels of atovaquone than control suspensions of the drug in methylcellulose. Relative bioavailability of ATO when loaded in nanoparticles ranged from 52% (for ATO-HPCD NP) to 71% (for ATO-DMCD NP), whereas for the suspension control formulation the bioavailability was only about 30%. The encapsulation of atovaquone in cyclodextrins-poly(anhydride) nanoparticles seems to be an interesting strategy to improve the oral bioavailability of this lipophilic drug.
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http://dx.doi.org/10.1007/s10544-011-9571-1DOI Listing
December 2011

Thousands of chemical starting points for antimalarial lead identification.

Nature 2010 May;465(7296):305-10

Tres Cantos Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain.

Malaria is a devastating infection caused by protozoa of the genus Plasmodium. Drug resistance is widespread, no new chemical class of antimalarials has been introduced into clinical practice since 1996 and there is a recent rise of parasite strains with reduced sensitivity to the newest drugs. We screened nearly 2 million compounds in GlaxoSmithKline's chemical library for inhibitors of P. falciparum, of which 13,533 were confirmed to inhibit parasite growth by at least 80% at 2 microM concentration. More than 8,000 also showed potent activity against the multidrug resistant strain Dd2. Most (82%) compounds originate from internal company projects and are new to the malaria community. Analyses using historic assay data suggest several novel mechanisms of antimalarial action, such as inhibition of protein kinases and host-pathogen interaction related targets. Chemical structures and associated data are hereby made public to encourage additional drug lead identification efforts and further research into this disease.
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http://dx.doi.org/10.1038/nature09107DOI Listing
May 2010

Plasmodium falciparum: stage specific effects of a selective inhibitor of lactate dehydrogenase.

Exp Parasitol 2005 Oct;111(2):105-14

Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, WC1E 7HT, UK.

Plasmodium falciparum lactate dehydrogenase (PfLDH) is essential for ATP generation. Based on structural differences within the active site between P. falciparum and human LDH, we have identified a series of heterocyclic azole-based inhibitors that selectively bind within the PfLDH but not the human LDH (hLDH) active site and showed anti-malarial activity in vitro and in vivo. Here we expand on an azole, OXD1, from this series and found that the anti-P. falciparum activity was retained against a panel of strains independently of their anti-malarial drug sensitivity profile. Trophozoites had relatively higher PfLDH enzyme activity and PfLDH-RNA expression levels than rings and were the most susceptible stages to OXD1 exposure. This is probably linked to their increased energy requirements and consistent with glycolysis being an essential metabolic pathway for parasite survival within the erythrocyte. Further structural elaboration of these azoles could lead to the identification of compounds that target P. falciparum through such a novel mechanism and with more potent anti-malarial activity.
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http://dx.doi.org/10.1016/j.exppara.2005.06.007DOI Listing
October 2005

Identification and activity of a series of azole-based compounds with lactate dehydrogenase-directed anti-malarial activity.

J Biol Chem 2004 Jul 26;279(30):31429-39. Epub 2004 Apr 26.

Department of Biochemistry and Molecular Recognition Centre, University of Bristol, Bristol BS8 1TD, United Kingdom.

Plasmodium falciparum, the causative agent of malaria, relies extensively on glycolysis coupled with homolactic fermentation during its blood-borne stages for energy production. Selective inhibitors of the parasite lactate dehydrogenase (LDH), central to NAD(+) regeneration, therefore potentially provide a route to new antimalarial drugs directed against a novel molecular target. A series of heterocyclic, azole-based compounds are described that preferentially inhibit P. falciparum LDH at sub-micromolar concentrations, typically at concentrations about 100-fold lower than required for human lactate dehydrogenase inhibition. Crystal structures show these competitive inhibitors form a network of interactions with amino acids within the active site of the enzyme, stacking alongside the nicotinamide ring of the NAD(+) cofactor. These compounds display modest activity against parasitized erythrocytes, including parasite strains with known resistance to existing anti-malarials and against Plasmodium berghei in BALB/c mice. Initial toxicity data suggest the azole derivatives have generally low cytotoxicity, and preliminary pharmoco-kinetic data show favorable bioavailability and circulation times. These encouraging results suggest that further enhancement of these structures may yield candidates suitable for consideration as new therapeutics for the treatment of malaria. In combination these studies also provide strong support for the validity of targeting the Plasmodium glycolytic pathway and, in particular, LDH in the search for novel anti-malarials.
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http://dx.doi.org/10.1074/jbc.M402433200DOI Listing
July 2004