Guillermo Roberto Labadie
@iquir-conicet.gov.ar
IQUIR-CONICET
RESEARCH, TEACHING, or OTHER INTERESTS
Drug Discovery, Organic Chemistry, Spectroscopy, Multidisciplinary
Scopus Publications
Scholar Citations
Scholar h-index
Scholar i10-index
Scopus Publications
Renzo Carlucci, Juan A. Arancibia, and Guillermo R. Labadie
Elsevier BV
Alejandro I. Recio‐Balsells, Renzo Carlucci, Simone Giovannuzzi, Fabrizio Carta, Claudiu T. Supuran, Babu L. Tekwani, Héctor R. Morbidoni, and Guillermo R. Labadie
Wiley
AbstractIn previous studies, we demonstrated the potent activity of a library of 25 N,N′‐disubstituted diamines (NNDDA) toward Trypanosomatid and Apicomplexa parasites. Considering the structure similarity between this collection and SQ109, an antituberculosis compound, and its compelling antiparasitic properties, we aimed to repurpose this library for tuberculosis treatment. We assayed this collection against Mycobacterium tuberculosis H37Rv and M. avium, obtaining several compounds with MIC values below 10 µM. The most active analogs were also evaluated against M. smegmatis, a non‐pathogenic species, and the non‐tuberculosis mycobacteria M. abscessus, M. kansasii, and M. fortuitum. 3c stands out as the lead mycobacterial compound of the collection, with potent activity against M. tuberculosis (minimal inhibitory concentration [MIC] = 3.4 µM) and moderate activity against M. smegmatis, M. kansasii, and M. fortuitum (all with MIC values of 26.8 µM). To unravel the mechanism of action, we employed the web‐based platform Polypharmacology Browser 2 (PPB2), obtaining carbonic anhydrases as potential drug targets. Nevertheless, none of the compounds displayed experimental inhibition. In summary, our study confirms the validity of the repurposing approach and underscores the antimycobacterial potential of NNDDA compounds, especially the analog 3c, setting a stepping stone for further studies.
Santanu Sasidharan and Guillermo R. Labadie
Frontiers Media SA
Topic to highlight the latest advances in the fi ght against tropical diseases. The Research Topic includes three articles on the prevention of viral diseases: dengue and hepatitis B. The review by Norshidah et al., focuses on the development of antivirals targeting the NS2B/NS3 protease of the dengue virus by examining 105 studies from 2015-2022 in depth. The review discusses the need to integrate in silico and in vitro screening for better antivirals against dengue virus. The second dengue article by Qin et al., shows the antiviral activity of Brucea javanica extracts and demonstrates that the oil emulsion is able to suppress hepatitis B virus replication by effectively upregulating IL-6 production. Interestingly, bruceine B, a major component of B. javanica seeds, was identi fi ed as the active agent responsible for IL-6 induction and hepatitis B virus inhibition. Bourgeois et al. in their study on dengue virus, evaluated kinase regulation using a machine learning approach that uses drug target information and a small drug screening to predict
Chantal Reigada, Fabio Digirolamo, Facundo Galceran, Melisa Sayé, Carolina Carrillo, Pablo Torres, Agostina Cammarata, Romina Julieta Glisoni, Guillermo Labadie, Mariana Reneé Miranda,et al.
Elsevier BV
Renzo Carlucci, María-Natalia Lisa, and Guillermo R. Labadie
American Chemical Society (ACS)
The 1,2,3-triazole scaffold has become very attractive to identify new chemical entities in drug discovery projects. Despite the widespread use of click chemistry to synthesize numerous 123Ts, there are few drugs on the market that incorporate this scaffold as a substructure. To investigate the true potential of 123Ts in protein-ligand interactions, we examined the noncovalent interactions between the 1,2,3-triazole ring and amino acids in protein-ligand cocrystals using a geometrical approach. For this purpose, we constructed a nonredundant database of 220 PDB IDs from available 123T-protein cocrystal structures. Subsequently, using the Protein Ligand Interaction Profiler web platform (PLIP), we determined whether 1,2,3-triazoles primarily act as linkers or if they can be considered interactive scaffolds. We then manually analyzed the geometrical descriptors from 333 interactions between 1,4-disubstituted 123T rings and amino acid residues in proteins. This study demonstrates that 1,2,3-triazoles exhibit diverse preferred interactions with amino acids, which contribute to protein-ligand binding.
María Sol Ballari, Exequiel O. J. Porta, Evelyn Arel Zalazar, Carla M. Borini Etichetti, José M. Padrón, Javier E. Girardini, and Guillermo R. Labadie
Elsevier BV
Miguel Villarreal-Parra, Gabriel E. Di Gresia, Guillermo R. Labadie, and Margarita M. Vallejos
American Chemical Society (ACS)
The Banert cascade is an efficient synthetic strategy for obtaining 4,5-disubstituted 1,2,3-triazoles. The reaction can proceed via a sigmatropic or prototropic mechanism depending on the substrate and the conditions. In this work, the mechanisms of both pathways from propargylic azides with different electronic features were investigated using density functional theory, quantum theory of atoms in molecules, and natural bond orbital approaches. The calculated energy barriers were consistent with the experimental data. Three patterns of electron density distribution on the transition structures were observed, which reflected the behaviors of the reactants in the Banert cascade. The stronger conjugative effects were associated with lower/higher free activation energies of sigmatropic/prototropic reactions, respectively. A clear relationship between the accumulation of the charge at the C3 atom of propargylic azides with the energy barriers for prototropic reactions was found. Thus, the obtained results would allow the prediction of the reaction's course by evaluating reactants.
Exequiel O.J. Porta, María Sol Ballari, Renzo Carlucci, Shane Wilkinson, Guoyi Ma, Babu L. Tekwani, and Guillermo R. Labadie
Elsevier BV
Santiago M. Ruatta, Denis N. Prada Gori, Martín Fló Díaz, Franca Lorenzelli, Karen Perelmuter, Lucas N. Alberca, Carolina L. Bellera, Andrea Medeiros, Gloria V. López, Mariana Ingold,et al.
Frontiers Media SA
Introduction: The identification of chemical compounds that interfere with SARS-CoV-2 replication continues to be a priority in several academic and pharmaceutical laboratories. Computational tools and approaches have the power to integrate, process and analyze multiple data in a short time. However, these initiatives may yield unrealistic results if the applied models are not inferred from reliable data and the resulting predictions are not confirmed by experimental evidence.Methods: We undertook a drug discovery campaign against the essential major protease (MPro) from SARS-CoV-2, which relied on an in silico search strategy –performed in a large and diverse chemolibrary– complemented by experimental validation. The computational method comprises a recently reported ligand-based approach developed upon refinement/learning cycles, and structure-based approximations. Search models were applied to both retrospective (in silico) and prospective (experimentally confirmed) screening.Results: The first generation of ligand-based models were fed by data, which to a great extent, had not been published in peer-reviewed articles. The first screening campaign performed with 188 compounds (46 in silico hits and 100 analogues, and 40 unrelated compounds: flavonols and pyrazoles) yielded three hits against MPro (IC50 ≤ 25 μM): two analogues of in silico hits (one glycoside and one benzo-thiazol) and one flavonol. A second generation of ligand-based models was developed based on this negative information and newly published peer-reviewed data for MPro inhibitors. This led to 43 new hit candidates belonging to different chemical families. From 45 compounds (28 in silico hits and 17 related analogues) tested in the second screening campaign, eight inhibited MPro with IC50 = 0.12–20 μM and five of them also impaired the proliferation of SARS-CoV-2 in Vero cells (EC50 7–45 μM).Discussion: Our study provides an example of a virtuous loop between computational and experimental approaches applied to target-focused drug discovery against a major and global pathogen, reaffirming the well-known “garbage in, garbage out” machine learning principle.
Renzo Carlucci, Sebastián N. Jäger, and Guillermo R. Labadie
Elsevier BV
Renzo Carlucci, Gabriel Di Gresia, María Gabriela Mediavilla, Julia A. Cricco, Babu L. Tekwani, Shabana I. Khan, and Guillermo R. Labadie
Royal Society of Chemistry (RSC)
We have previously shown that prenyl and aliphatic 1,2,3-triazoles displayed antiparasitic and antimycobacterial activity. Herein, new series of analogues were prepared looking for antimalarial drug candidates.
Luz Díaz-Storani, Anaelle A. Clary, Diego M. Moreno, María Sol Ballari, Exequiel O.J. Porta, Andrea B.J. Bracca, Jonathan B. Johnston, and Guillermo R. Labadie
Elsevier BV
C.M. Jiménez, H.L. Álvarez, M.S. Ballari, G.R. Labadié, C.A.N. Catalán, R.E. Toso, and D.A. Sampietro
Oxford University Press (OUP)
This work aimed to identify secondary metabolites from aerial parts of Euphorbia species functional for control of toxigenic Fusarium species responsible of cereal grain rots.
Julia Fernández de Luco, Alejandro I. Recio-Balsells, Diego G. Ghiano, Ana Bortolotti, Juán Manuel Belardinelli, Nina Liu, Pascal Hoffmann, Christian Lherbet, Peter J. Tonge, Babu Tekwani,et al.
Royal Society of Chemistry (RSC)
A collection of 37 triazolyl-triclosan derivatives were prepared as possible antileishmanial drugs. The InhA ortholog in Leishmania donovani was proposed as a putative druggable target.
Diego G. Ghiano, Alejandro Recio-Balsells, Ana Bortolotti, Lucas A. Defelipe, Adrián Turjanski, Héctor R. Morbidoni, and Guillermo R. Labadie
Elsevier BV
Noelia S. Medrán, Melisa Sayé, Claudio A. Pereira, Babu L. Tekwani, Agustina La-Venia, and Guillermo R. Labadie
Elsevier BV
José R. Soberón, Melina A. Sgariglia, José A. Carabajal Torrez, Franco A. Aguilar, Edgardo J.I. Pero, Diego A. Sampietro, Julia Fernández de Luco, and Guillermo R. Labadie
Elsevier BV
Lucía Fargnoli, Esteban A. Panozzo-Zénere, Lucas Pagura, María Julia Barisón, Julia A. Cricco, Ariel M. Silber, and Guillermo R. Labadie
Frontiers in Chemistry Frontiers Media SA
Claudio A. Pereira, Melisa Sayé, Chantal Reigada, Ariel M. Silber, Guillermo R. Labadie, Mariana R. Miranda, and Edward Valera-Vera
Cambridge University Press (CUP)
AbstractDuring three decades, only about 20 new drugs have been developed for malaria, tuberculosis and all neglected tropical diseases (NTDs). This critical situation was reached because NTDs represent only 10% of health research investments; however, they comprise about 90% of the global disease burden. Computational simulations applied in virtual screening (VS) strategies are very efficient tools to identify pharmacologically active compounds or new indications for drugs already administered for other diseases. One of the advantages of this approach is the low time-consuming and low-budget first stage, which filters for testing experimentally a group of candidate compounds with high chances of binding to the target and present trypanocidal activity. In this work, we review the most common VS strategies that have been used for the identification of new drugs with special emphasis on those applied to trypanosomiasis and leishmaniasis. Computational simulations based on the selected protein targets or their ligands are explained, including the method selection criteria, examples of successful VS campaigns applied to NTDs, a list of validated molecular targets for drug development and repositioned drugs for trypanosomatid-caused diseases. Thereby, here we present the state-of-the-art of VS and drug repurposing to conclude pointing out the future perspectives in the field.
Pamela S. Forastieri, Liliana E. Luna, Raquel M. Cravero, and Guillermo R. Labadie
Wiley
AbstractThe 9H‐xanthene derivatives, like PW2, displayed a wide spectrum of bioactivities. Herein, we reported a rapid and simple synthetic route for compounds containing the xanthenic moiety in their structure and amides. The efficient preparation of novel 1,8‐dioxo‐2,3,4,5,6,7,8,9‐octahydro‐1‐xanthen‐9‐yl‐ acetic acid alkyl esters by multicomponent tandem Michael‐cyclization reactions starting from cyclohexanediones and alkynes is described. Iodine and cerium (IV) ammonium nitrate were used for the oxidative aromatization step proving a series of 1,8‐mono and dialkoxy‐alkyl‐xanthenyl‐9‐yl acetic acid esters in good yields. The proposed mechanism for the oxidative aromatization involves several organic transformations. The final step was the incorporation of an amide to mimic the PW2 structure that was prepared by hydrolysis of the esters, followed by the amide formation using N,N‐dimethyl‐1,3‐ propandiamine, and benzylamine.
Margarita M. Vallejos and Guillermo R. Labadie
Royal Society of Chemistry (RSC)
The factors controlling the allyl azides equilibrium has been studied by different theoretical approaches setting the basis to predict the regioisomers predominance in the equilibrium mixture.
Julia Fernández de Luco, Gastón Prez, Bruno Hernández Cravero, Diego de Mendoza, and Guillermo R. Labadie
MyJove Corporation
This work presents a method to prepare an analytical standard to analyze 2-arachidonoyl glycerol (2-AG) qualitatively and quantitatively by liquid chromatography-electrospray Ionization-tandem mass spectrometry (LC-ESI-MS/MS). Endocannabinoids are conserved lipid mediators that regulate multiple biological processes in a variety of organisms. In C. elegans, 2-AG has been found to possess different roles, including modulation of dauer formation and cholesterol metabolism. This report describes a method to overcome the difficulties associated with the costs and stability of deuterated standards required for 2-AG quantification. The procedure for the synthesis of the standard is simple and can be performed in any laboratory, without the need for organic synthesis expertise or special equipment. In addition, a modification of Folch's method to extract the deuterated standard from C. elegans culture is described. Finally, a quantitative and analytic method to detect 2-AG using the stable isotopically labeled analog 1-AG-d5 is described, which provides reliable results in a fast-chromatographic run. The procedure is useful for studying the multiple roles of 2-AG in C. elegans while also being applicable to other studies of metabolites in different organisms.
Exequiel O. J. Porta, Ignasi Bofill Verdaguer, Consuelo Perez, Claudia Banchio, Mauro Ferreira de Azevedo, Alejandro M. Katzin, and Guillermo R. Labadie
Royal Society of Chemistry (RSC)
Repurposing strategies present an enormous advantage for drug discovery, especially in malaria, where resources are scarce.
Sebastián N. Jäger, Exequiel O.J. Porta, and Guillermo R. Labadie
Elsevier BV
Martin Sabatini, Santiago Comba, Silvia Altabe, Alejandro I. Recio‐Balsells, Guillermo R. Labadie, Eriko Takano, Hugo Gramajo, and Ana Arabolaza
Wiley
Iterative type I polyketide synthases (PKS) are megaenzymes essential to the biosynthesis of an enormously diverse array of bioactive natural products. Each PKS contains minimally three functional domains, β‐ketosynthase (KS), acyltransferase (AT), and acyl carrier protein (ACP), and a subset of reducing domains such as ketoreductase (KR), dehydratase (DH), and enoylreductase (ER). The substrate selection, condensation reactions, and β‐keto processing of the polyketide growing chain are highly controlled in a programmed manner. However, the structural features and mechanistic rules that orchestrate the iterative cycles, processing domains functionality, and chain termination in this kind of megaenzymes are often poorly understood. Here, we present a biochemical and functional characterization of the KS and the AT domains of a PKS from the mallard duck Anas platyrhynchos (ApPKS). ApPKS belongs to an animal PKS family phylogenetically more related to bacterial PKS than to metazoan fatty acid synthases. Through the dissection of the ApPKS enzyme into mono‐ to didomain fragments and its reconstitution in vitro, we determined its substrate specificity toward different starters and extender units. ApPKS AT domain can effectively transfer acetyl‐CoA and malonyl‐CoA to the ApPKS ACP stand‐alone domain. Furthermore, the KS and KR domains, in the presence of Escherichia coli ACP, acetyl‐CoA, and malonyl‐CoA, showed the ability to catalyze the chain elongation and the β‐keto reduction steps necessary to yield a 3‐hydroxybutyryl‐ACP derivate. These results provide new insights into the catalytic efficiency and specificity of this uncharacterized family of PKSs.