Water soluble organometallic small molecules as promising antibacterial agents: synthesis, physical–chemical properties and biological evaluation to tackle bacterial infections

This work was supported by the Spanish Ministerio de Economia y Competitividad (PID2019-106832RB-100, and SAF2017-82261-P grant cofounded by the European Regional Development Fund) and the Generalitat de Catalunya (2017SGR1720). J. A. M. Xavier acknowledges DOC-FAM program under the Marie Sklodowska-Curie grant agreement N degrees 754397. A. B. Buades, M. Nuez and J. A. M. Xavier are enrolled in the PhD program of the UAB.The Na[3,3’-Fe(8-I-1,2-C2B9H10)2] and Na[2,2’-M(1,7-C2B9H11)] (M = Co3+, Fe3+) small molecules are synthesized and the X-ray structures of [(H3O)(H2O)5][2,2’-Co(1,7-C2B9H11)2] and [Cs(MeCN)][8,8’-I2-Fe(1,2 C2B9H10)2], both displaying a transoid conformation of the [M(C2B9)2]− framework, are reported. Importantly, the supramolecular structure of [(H3O)(H2O)5][2,2’-Co(1,7-C2B9H11)2] presents 2D layers leading to a lamellar arrangement of the anions while the cation layers form polymeric water rings made of six- and fourmembered rings of water molecules connected via OH⋯H hydrogen bonds; B–H⋯O contacts connect the cationic and anionic layers. Herein, we highlight the influence of the ligand isomers (ortho-/meta-), the metal effect (Co3+/Fe3+) on the same isomer, as well as the influence of the presence of the iodine atoms on the physical–chemical and biological properties of these molecules as antimicrobial agents to tackle antibioticresistant bacteria, which were tested with four Gram-positive bacteria, five Gram-negative bacteria, and three Candida albicans strains that have been responsible for human infections. We have demonstrated an antimicrobial effect against Candida species (MIC of 2 and 3 nM for Na[3,3’-Co(8-I-1,2-C2B9H10)2] and Na[2,2’-Co (1,7-C2B9H11)2], respectively), and against Gram-positive and Gram-negative bacteria, including multiresistant MRSA strains (MIC of 6 nM for Na[3,3’-Co(8-I-1,2-C2B9H10)2]). The selectivity index for antimicrobial activity of Na[3,3’-Co(1,2-C2B9H11)2] and Na[3,3’-Co(8-I-1,2-C2B9H10)2] compounds is very high (165 and 1180, respectively), which reveals that these small anionic metallacarborane molecules may be useful to tackle antibioticresistant bacteria. Moreover, we have demonstrated that the outer membrane of Gram-negative bacteria constitutes an impermeable barrier for the majority of these compounds. Nonetheless, the addition of two iodine groups in the structure of the parent Na[3,3’-Co(1,2-C2B9H11)2] had an improved effect (3–7 times) against Gram-negative bacteria. Possibly the changes in their physical–chemical properties make the meta-isomers and the ortho-di-iodinated small molecules more permeable for crossing this barrier. It should be emphasized that the most active metallabis(dicarbollide) small molecules are both transoid conformers in contrast to the ortho- [3,3’-Co(1,2-C2B9H11)2]− that is cisoid. The fact that these small molecules cross the mammalian membrane and have antimicrobial properties but low toxicity for mammalian cells (high selectivity index, SI) represents a promising tool to treat infectious intracellular bacteria. Since there is an urgent need for antibiotic discovery and development, this study represents a relevant advance in the field.Spanish Government PID2019-106832RB-100 SAF2017-82261-PGeneralitat de CatalunyaGeneral Electric 2017SGR1720DOC-FAM program under the Marie Sklodowska-Curie grant 75439

m-Carborane as a Novel Core for Periphery-Decorated Macromolecules

© 2020 by the authors.Closo m-C2B10H12 can perform as a novel core of globular periphery-decorated macromolecules. To do this, a new class of di and tetrabranched m-carborane derivatives has been synthesized by a judicious choice of the synthetic procedure, starting with 9,10-I2-1,7-closo-C2B10H10. The 2a-NPA (sum of the natural charges of the two bonded atoms) value for a bond, which is defined as the sum of the NPA charges of the two bonded atoms, matches the order of electrophilic reaction at the different cluster bonds of the icosahedral o-and m- carboranes that lead to the formation of B-I bonds. As for m-carborane, most of the 2a-NPA values of B-H vertexes are positive, and their functionalization is more challenging. The synthesis and full characterization of dibranched 9,10-R2-1,7-closo-carborane (R = CH2CHCH2, HO(CH2)3, Cl(CH2)3, TsO(CH2)3, C6H5COO(CH2)3, C6H5COO(CH2)3, N3(CH2)3, CH3CHCH, and C6H5C2N3(CH2)3) compounds as well as the tetrabranched 9,10-R2-1,7-R2-closo-C2B10H8 (R = CH2CHCH2, HO(CH2)3) are presented. The X-ray diffraction of 9,10-(HO(CH2)3)2-1,7-closo-C2B10H10 and 9,10-(CH3CHCH)2-1,7-closo-C2B10H10, as well as their Hirshfeld surface analysis and decomposed fingerprint plots, are described. These new reported tetrabranched m-carborane derivatives provide a sort of novel core for the synthesis of 3D radially grown periphery-decorated macromolecules that are different to the 2D radially grown core of the tetrabranched o-carborane framework.This research was funded by the Spanish MINECO, grant number CTQ2016-75150-R, and Generalitat de Catalunya, grant number 2017 SGR 1720. C.V. and Z.K. thanks European Union’s Horizon 2020 Marie Skłodowska-Curie grant agreement MSCA-IF-2016-751587.Peer reviewe

3,2,1 and stop! An innovative, straightforward and clean route for the flash synthesis of metallacarboranes

[Co(C2B9H11)2]−, analogs to metallocene, can be readily synthesised in high yield by a fast and clean solvent-free reaction of [HNMe3][C2B9H12] with CoCl2·xH2O. This innovative approach, applied to both ortho and meta isomers, yields the desired structures by simply heating the solid compounds to high temperature for a very short time.This work has been supported by MINECO (CTQ2016-75150-R), Generalitat de Catalunya (2017 SGR 1720).We acknowledge support of the publication fee by the CSIC Open Access Support Initiative through its Unit of Information Resources for Research (URICI)Peer reviewe

Periphery Decorated and Core Initiated Neutral and Polyanionic Borane Large Molecules: Forthcoming and Promising Properties for Medicinal Applications

A mini-review based on radial growing macromolecules and core initiated Borane periphery decorated with o-carboranes and metallacarboranes that has been developed in the authors laboratories is reported. The review is divided into four sections; three of them are related to the design and synthesis of these large boron-containing molecules and the fourth deals with the unique properties of anionic metallacarborane molecules that provide a glimpse of their potential for their promising use in medicinal applications. Their unique stability along with their geometrical and electronic properties, as well as the precise steric structure of 1,2-closo-C2B10H12 (o-carborane) that has the potential for the incorporation of many substituents: at the carbon (Cc), at the boron and at both carbon and boron vertices, suggests this cluster as an innovative building block or platform for novel applications that cannot be achieved with organic hydrocarbon compounds. Poly(aryl-ether) dendrimers grown from fluorescent cores, such as 1,3,5-triarylbenzene or meso-porphyrins, have been decorated with boron clusters to attain rich boron containing dendrimers. Octasilsesquioxane cubes have been used as a core for its radial growth to get boron-rich large molecules. The unique properties of cobaltabisdicarbollide cluster, which include: i) self-assembly in water to produce monolayer nano-vesicles, ii) crossing lipid bilayer membranes, iii) interacting with membrane cells, iv) facilitating its visualization within cells by Raman and fluorescence techniques and v) their use as molecular platform for “in vivo” imaging are discussed in detail.This work has been supported by the Spanish Ministerio de Economía y Competitividad (MINECO, project CTQ2016-75150-R) and Generalitat de Catalunya (2017 SGR 1720).Peer reviewe

Crystal structure and Hirshfeld surface analysis of [N(CH3)4][2,2′-Fe(1,7-closo-C2B9H11)2]

This work investigates the meta-ferrabis(dicarbollide) anion that was isolated as salt of tetramethylammonium. The structure of the obtained crystal consisted of discrete [2,2′-Fe(1,7-closo-C2B9H11)2]− anions and disordered [N(CH3)4]+ cations. The anion had a considerable chemical stability ensured by ionic and Van der Waals interactions. Thus, Hirshfeld surfaces and fingerprint plot were used to visualize, explore, and quantify intermolecular interactions in the crystal lattice of the title compound. This investigation proved that close contacts were dominated by H⋯H interactions.peerReviewe

Too Persistent to Give Up: Aromaticity in Boron Clusters Survives Radical Structural Changes

o-C2B10H12 isomerizes to m-C2B10H12 upon heating at 400 °C. Deboronation in o-C2B10H12 is a relatively easy process, whereas it is more difficult in m-C2B10H12. These two experimental facts indicate that m-C2B10H12 is thermodynamically more stable than o-C2B10H12. On the other hand, it is widely accepted that closo-boranes and -carboranes are aromatic compounds. In this work, we relate the difficulty in the deboronation of the carboranes with their stability and aromaticity. We do this by combining lab work and DFT calculations. Computationally, our results show that the higher thermodynamic stability of m-C2B10H12 is not related to aromaticity differences but to the location of the C atoms in the carborane structure. It is also demonstrated that the aromaticity observed in closo-boranes and -carboranes is also present in their nido counterparts, and consequently, we conclude that aromaticity in boron clusters survives radical structural changes. Further, sandwich metallocenes (e.g., ferrocene) and sandwich metallabis(dicarbollides) (e.g., [Co(C2B9H11)2]−) have traditionally been considered to be similar. Here it is shown that they are not. Metallabis(dicarbollides) display global aromaticity, whereas metallocenes present local aromaticity in the ligands. Remarkable and unique is the double probe given by 1H and 11B NMR tracing the reciprocally antipodal endocyclic open face Hec and B1. These magnetic studies have permitted one to correlate both nuclei and relate them to a diatropic current in the plane at the middle of the nido-[C2B9H12]−. This observation is the first unique evidence that proves experimentally the existence of diatropic currents, and thence aromaticity, in clusters and is comparable to the existence of diatropic currents in planar aromatic compounds. Additionally, heteroboranes with two carbon atoms have been compared to heterocycles with two nitrogen or boron atoms, e.g., C2B10H12 carboranes versus planar N2C4H4 diazines or [B2C4H4]2– diboratabenzenes, thereby proving the higher persistence of the aromaticity of the tridimensional compounds in heteroatom-substituted species. This research accounts very well for the “paradigm for the electron requirements of clusters”, in which a closo-cluster that is aromatic upon addition of 2e– becomes also an aromatic nido-species, and explains the informative schemes by Rudolph and Williams.This work has been supported by the Ministerio de Economía y Competitividad (MINECO) of Spain (Projects CTQ2017-85341-P, CTQ2016-75150-R, CTQ2016-77558-R, and MDM-2017-0767) and the Generalitat de Catalunya (projects 2017SGR39, 2017SGR1720, and 2017SGR348). Excellent service by the Supercomputer center of the Consorci de Serveis Universitaris de Catalunya (CSUC) is gratefully acknowledged. Dedicated to Prof. Alan Welch.Peer reviewe

Nous resultats de les sals de bor per lluitar contra la resistència antimicrobiana

Els antibiòtics són medicaments que s'utilitzen enfront de les infeccions produïdes per bacteris, tant en animals com en persones. Usar-los de manera inadequada pot generar resistència, cosa que significa que deixen de ser efectius. La resistència antimicrobiana és avui dia una de les majors amenaces per a la salut mundial. En aquest article, el grup de recerca de Clara Viñas de l'Institut de Materials de Barcelona (ICMAB-CSIC) en col·laboració amb altres universitats (UdG, Córdoba, Durham), presenta el seu treball en el qual s'ha avaluat les propietats antimicrobianes de les sals de bor. Els resultats semblen ser prometedors per a quatre soques de bacteris i tres de fongs.Los antibióticos son medicamentos que se utilizan frente a las infecciones producidas por bacterias, tanto en animales como en personas. Usarlos de manera inadecuada puede generar resistencia, lo que significa que dejan de ser efectivos. La resistencia antimicrobiana es hoy en día una de las mayores amenazas para la salud mundial. En este artículo, el grupo de investigación de Clara Viñas del Instituto de Materiales de Barcelona (ICMAB-CSIC) en colaboración con otras universidades (UdG, Córdoba, Durham), presenta su trabajo en el que se ha evaluado las propiedades antimicrobianas de las sales de boro. Los resultados parecen ser prometedores para cuatro cepas de bacterias y tres de hongos

Metallacarborane Assemblies as Effective Antimicrobial Agents, Including a Highly Potent Anti-MRSA Agent

The salts Na[ROC(O)Ph], Na[1-ROC(O)-1,12-C2B10H11], K2[1,4-(ROC(O))2-C6H4], and K2[1,12-(ROC(O))2-1,12-C2B10H10], where R is the cobaltabis(dicarbollide)-diethylene glycol group [3,3′-Co(8-(OCH2CH2OCH2CH2)-1,2-C2B9H10)(1′,2′-C2B9H11)]−, were synthesized from the corresponding carboxylate salt and the zwitterion [3,3′-Co(8-(CH2CH2O)2-1,2-C2B9H10)(1′,2′-C2B9H11)]. The dianion in K2[1,12-(ROC(O))2-1,12-C2B10H10] showed at least one K+ cation to be tightly bound to the dianion via K···O and K···H–B interactions with both p-carborane and cobaltabis(dicarbollide) clusters on the basis of NMR and MS data and support of hybrid-DFT computations. An evaluation of the antimicrobial properties of these compounds revealed all of the salts to be highly effective antibacterial agents for four Gram-positive bacteria strains (standard minimum inhibitory concentration, MIC, of 1 mg/L for Na[ROC(O)Ph]; Na[3]) and antifungal agents for three Candida albicans strains (MIC 4 mg/L for the salts K2[4] and K2[6]). One of the four Gram-positive bacteria strains tested was a life-threatening superbug methicillin-resistant Staphylococcus aureus (MRSA) isolate, which is resistant to many commercial antimicrobial drugs. The cobaltabis(dicarbollide) derivative Na[3] has a remarkable inhibitory effect on the MRSA strain with an MIC of only 1 mg/L and a minimum bactericidal concentration (MBC) of 2 mg/L, thus suggesting its potential as an antibacterial agent against MRSA

Water soluble organometallic small molecules as promising antibacterial agents : synthesis, physical–chemical properties and biological evaluation to tackle bacterial infections

The Na[3,3′-Fe(8-I-1,2-C2B9H10)2] and Na[2,2′-M(1,7-C2B9H11)] (M = Co3+, Fe3+) small molecules are synthesized and the X-ray structures of [(H3O)(H2O)5][2,2′-Co(1,7-C2B9H11)2] and [Cs(MeCN)][8,8′-I2-Fe(1,2 C2B9H10)2], both displaying a transoid conformation of the [M(C2B9)2]− framework, are reported. Importantly, the supramolecular structure of [(H3O)(H2O)5][2,2′-Co(1,7-C2B9H11)2] presents 2D layers leading to a lamellar arrangement of the anions while the cation layers form polymeric water rings made of six- and four-membered rings of water molecules connected via OH⋯H hydrogen bonds; B–H⋯O contacts connect the cationic and anionic layers. Herein, we highlight the influence of the ligand isomers (ortho-/meta-), the metal effect (Co3+/Fe3+) on the same isomer, as well as the influence of the presence of the iodine atoms on the physical–chemical and biological properties of these molecules as antimicrobial agents to tackle antibiotic-resistant bacteria, which were tested with four Gram-positive bacteria, five Gram-negative bacteria, and three Candida albicans strains that have been responsible for human infections. We have demonstrated an antimicrobial effect against Candida species (MIC of 2 and 3 nM for Na[3,3′-Co(8-I-1,2-C2B9H10)2] and Na[2,2′-Co(1,7-C2B9H11)2], respectively), and against Gram-positive and Gram-negative bacteria, including multiresistant MRSA strains (MIC of 6 nM for Na[3,3′-Co(8-I-1,2-C2B9H10)2]). The selectivity index for antimicrobial activity of Na[3,3′-Co(1,2-C2B9H11)2] and Na[3,3′-Co(8-I-1,2-C2B9H10)2] compounds is very high (165 and 1180, respectively), which reveals that these small anionic metallacarborane molecules may be useful to tackle antibiotic-resistant bacteria. Moreover, we have demonstrated that the outer membrane of Gram-negative bacteria constitutes an impermeable barrier for the majority of these compounds. Nonetheless, the addition of two iodine groups in the structure of the parent Na[3,3′-Co(1,2-C2B9H11)2] had an improved effect (3–7 times) against Gram-negative bacteria. Possibly the changes in their physical–chemical properties make the meta-isomers and the ortho-di-iodinated small molecules more permeable for crossing this barrier. It should be emphasized that the most active metallabis(dicarbollide) small molecules are both transoid conformers in contrast to the ortho- [3,3′-Co(1,2-C2B9H11)2]− that is cisoid. The fact that these small molecules cross the mammalian membrane and have antimicrobial properties but low toxicity for mammalian cells (high selectivity index, SI) represents a promising tool to treat infectious intracellular bacteria. Since there is an urgent need for antibiotic discovery and development, this study represents a relevant advance in the field.peerReviewe