Mechanochemical Synthesis of New Praziquantel Cocrystals: Solid-State Characterization and Solubility.

New cocrystals of praziquantel with suberic, 3-hydroxybenzoic, benzene-1,2,4,5-tetracarboxylic, trimesic, and 5-hydroxyisophthalic acids were obtained through ball milling experiments. The optimal conditions for the milling process were chosen by changing the solvent volume and the mechanical action time. Supramolecular interactions in the new cocrystals are detailed based on single-crystal X-ray diffraction analysis, confirming the expected formation of hydrogen bonds between the praziquantel carbonyl group and the carboxyl (or hydroxyl) moieties of the coformers. Different structural characterization techniques were performed for all samples, but the praziquantel:suberic acid cocrystal includes a wider range of investigations such as thermal analysis, infrared and X-ray photoelectron spectroscopies, and SEM microscopy. The stability for up to five months was established by keeping it under extreme conditions of temperature and humidity. Solubility studies were carried out for all the new forms disclosed herein and compared with the promising cocrystals previously reported with salicylic, 4-aminosalicylic, vanillic, and oxalic acids. HPLC analyses revealed a higher solubility for most of the new cocrystal forms, as compared to pure praziquantel.

Antibiotic Coordination Frameworks against Antibiotic Resistance: How to Involve Students through Experimental Practices in the Search for Solutions to Public Health Problems.

For decades, multiple varieties of antibiotics have been successfully used for therapeutic purposes. Nevertheless, antibiotic resistance is currently one of the major threats to global health. This work presents an innovative laboratory practice carried out in an inorganic medicinal chemistry course within the Degrees of Pharmacy and Biochemistry for undergraduate students. This experiment includes three classes of 2 h each. The first class consisted of the mechanochemical synthesis of an antibiotic coordination framework (ACF) using a known antibiotic (nalidixic acid) and zinc as the ligand. The prepared Zn-nalidixic acid ACF (Zn-ACF) was obtained in up to 82% yield with high purity. On the second day, the synthesized Zn-ACF was characterized by Fourier-transform infrared spectroscopy (FTIR) and powder X-ray diffraction (PXRD). Finally, during the last class, the antimicrobial activity was tested against Escherichia coli by the well diffusion method. The students verified the higher antimicrobial activity of Zn-ACF compared to nalidixic acid, proving that small changes in the chemical structure can result in great biological differences. In the end, the students presented their results in a poster format, encouraging the development of their soft skills and scientific results communication and dissemination. In the future, it is expected that such a laboratory experiment at the interface between medicinal chemistry, microbiology, analytical techniques, public health, and pharmacology will lead to the development and implementation of some service-learning practices and will serve as a model to look at for other courses and institutions.

Enhanced selectivity towards melanoma cells with zinc(II)-Schiff bases containing imidazole derivatives.

Zinc(II)-complexes with the general formula [Zn(L)2] containing 8-hydroxyquinoline Schiff bases functionalized with 1-(3-aminopropyl)imidazole or 1-(3-aminopropyl)-2-methyl-1H-imidazole on 2-position and their respective ligands (HL1 or HL2) were synthesized and characterized by NMR, UV-Vis, FTIR and CD spectroscopies as well as ESI-MS spectrometry. Single crystals of HL2 and [Zn(L1)2]n were analysed by SC-XRD. [Zn(L1)2]n shows a 1D polymeric chain structure of alternating Zn(II) cations and bridging Schiff base ligands, in contrast to previously reported monomeric structures of analogous complexes. DFT calculations were performed to rationalize the polymeric X-ray structure of Zn(L1)2. Results showed that the ligands can bind as bi- or tridentate to Zn(II) and there is the possibility of a dynamic behavior for the complexes in solution. Both ligands and complexes present limited stability in aqueous media, however, in the presence of bovine serum albumin the complexes are stable. Molecular docking simulations and circular dichroism spectroscopic studies suggest binding to this protein in close proximity to the Trp213 residue. Biological studies on a panel of cancer cells revealed that the Zn(II)-complexes have a lower impact on cell viability than cisplatin, except for triple-negative breast cancer cells in which they were comparable. Notwithstanding, they display much higher selectivity towards cancer cells vs. normal cells, than cisplatin. They induce the generation of ROS and DNA double-strand breaks, primarily through apoptosis as the mode of cell death. Overall, the novel Zn(II)-complexes demonstrate improved induction of apoptosis and higher selectivity, particularly for melanoma cells, compared to previously reported analogues, making them promising candidates for clinical application.

Alkoxy-Bridged Dicopper(II) Cores Meet Tetracyanonickelate Linkers: Structural, Magnetic, and Theoretical Investigation of Cu/Ni Coordination Polymers.

Two heterometallic Cu(II)/Ni(II) coordination polymers, [Cu2(Hbdea)2Ni(CN)4]n (1) and [Cu2(dmea)2Ni(CN)4]n·nH2O (2), were successfully self-assembled in water by reacting Cu(II) nitrate with H2bdea (N-butyldiethanolamine) and Hdmea (N,N-dimethylethanolamine) in the presence of sodium hydroxide and [Ni(CN)4]2-. These new coordination polymers were investigated by single-crystal and powder X-ray diffraction and fully characterized by FT-IR spectroscopy, thermogravimetry, elemental analysis, variable-temperature magnetic susceptibility measurements, and theoretical DFT and CASSCF calculations. Despite differences in crystal systems, in both compounds, each dinuclear building block [Cu2(µ-aminopolyalcoholate)2]2+ is bridged by diamagnetic [Ni(CN)4]2- linkers, resulting in 1D (1) or 2D (2) metal-organic architectures. Experimental magnetic studies show that both compounds display strong antiferromagnetic coupling (J = -602.1 cm-1 for 1 and -151 cm-1 for 2) between Cu(II) ions within the dimers mediated by the µ-O-alkoxo bridges. These results are corroborated by the broken symmetry DFT studies, which also provide further insight into the electronic structures of copper dimeric units. By reporting a facile self-assembly synthetic protocol, this study can be a model to widen a still limited family of heterometallic Cu/Ni coordination polymer materials with different functional properties.

Halimane Derivatives from Plectranthus ornatus Codd. as Novel Anti-cancer Agents.

The Plectranthus genus is often cited for its medicinal properties. Plectranthus ornatus Codd. is traditionally used in Africa for the treatment of gastric and liver diseases and their leaves are used for their antibiotic action. The main constituent of P. ornatus is the halimane compound, 11 R∗-acetoxyhalima-5,13E-dien-15-oic acid (Hal), described for its antimicrobial and anticancer properties. The objective of this work was to improve the activity of the halimane lead molecule. Further physiochemical characterisation was performed on Hal. To the best of our knowledge, this work constitutes the first published data of the absolute configurations by SCXRD and thermal stability of Hal. Using Hal, reactions with different amines were carried out to afford novel semi-synthetic derivatives and their structural elucidation was completed. The cytotoxicity of the derivatives was assessed against three leukaemia cancer cell lines (CCRF-CEM, K562 and HL-60). The antioxidant activity was investigated using H2O2-induced HGF-1 cells and their anti-inflammatory activity was studied using RT-PCR and ELISA. Our data showed that amide derivatives of Hal presented moderate cytotoxicity and more potent activity when compared to the parent molecule, giving insight into the SAR of Hal. The derivatives also displayed protection against oxidative damage to DNA. Finally, the derivatives possessed anti-inflammatory properties at the level of gene and protein expression for the cytokines IL-1ß, TNF-α and IL-6, induced by LPS in normal HGF-1 cells. Overall, our study provides useful insight into the enhanced biological activities of semi-synthetic Hal derivatives, as a starting point for novel drug formulations in cancer therapy.

Shock-Induced Degradation of Guanosine and Uridine Promoted by Nickel and Carbonate: Potential Applications.

Experimental studies of the degradation of two ribonucleosides (guanosine and uridine) were carried out by making use of mechanochemistry. Mechanochemical experiments reveal the decomposition of guanosine and uridine, promoted by nickel(II) and carbonate ions, into guanine and uracil, respectively. These nucleobases were identified by HPLC and 1H NMR spectroscopy (this applied only to uracil). Additionally, density-functional theory (DFT) methodologies were used to probe the energetic viability of several degradation pathways, including in the presence of the abovementioned ions. Three mechanisms were analysed via ribose ring-opening: dry, single-molecule water-assisted, and metal-assisted, wherein the last two mechanisms confirmed the mechanochemical degradation of both ribonucleosides into respective nucleobase moieties. These results can contribute to an astrobiological interpretation of the extraterrestrial sample's contents.

Structural Optimization of Antimycobacterial Azaaurones Towards Improved Solubility and Metabolic Stability.

While N-acetyl azaaurones have already been disclosed for their potential against tuberculosis (TB), their low metabolic stability remains an unaddressed liability. We now report a study designed to improve the metabolic stability and solubility of the azaaurone scaffold and to identify the structural requirements for antimycobacterial activity. Replacing the N-acetyl moiety for a N-carbamoyl group led to analogues with sub- and nanomolar potencies against M. tuberculosis H37Rv, as well as equipotent against drug-susceptible and drug-resistant M. tuberculosis isolates. The new N-carbamoyl azaaurones exhibited improved microsomal stability, compared to their N-acetylated counterparts, with several compounds displaying moderate to high kinetic solubility. The frequency of spontaneous resistance to azaaurones was observed to be in the range of 10-8 , a value that is comparable to current TB drugs in the market. Overall, these results reveal that azaaurones are amenable to structural modifications to improve metabolic and solubility liabilities, and highlight their potential as antimycobacterial agents.

Promising anticancer agents based on 8-hydroxyquinoline hydrazone copper(II) complexes.

We report the synthesis and characterization of a group of benzoylhydrazones (Ln) derived from 2-carbaldehyde-8-hydroxyquinoline and benzylhydrazides containing distinct para substituents (R = H, Cl, F, CH3, OCH3, OH and NH2, for L1-7, respectively; in L8 isonicotinohydrazide was used instead of benzylhydrazide). Cu(II) complexes were prepared by reaction of each benzoylhydrazone with Cu(II) acetate. All compounds were characterized by elemental analysis and mass spectrometry as well as by FTIR, UV-visible absorption, NMR or electron paramagnetic resonance spectroscopies. Complexes isolated in the solid state (1-8) are either formulated as [Cu(HL)acetate] (with L1 and L4) or as [Cu(Ln)]3 (n = 2, 3, 5, 6, 7 and 8). Single crystal X-ray diffraction studies were done for L5 and [Cu(L5)]3, confirming the trinuclear formulation of several complexes. Proton dissociation constants, lipophilicity and solubility were determined for all free ligands by UV-Vis spectrophotometry in 30% (v/v) DMSO/H2O. Formation constants were determined for [Cu(LH)], [Cu(L)] and [Cu(LH-1)] for L = L1, L5 and L6, and also [Cu(LH-2)] for L = L6, and binding modes are proposed, [Cu(L)] predominating at physiological pH. The redox properties of complexes formed with L1, L5 and L6 are investigated by cyclic voltammetry; the formal redox potentials fall in the range of +377 to +395 mV vs. NHE. The binding of the Cu(II)-complexes to bovine serum albumin was evaluated by fluorescence spectroscopy, showing moderate-to-strong interaction and suggesting formation of a ground state complex. The interaction of L1, L3, L5 and L7, and of the corresponding complexes with calf thymus DNA was evaluated by thermal denaturation. The antiproliferative activity of all compounds was evaluated in malignant melanoma (A-375) and lung (A-549) cancer cells. The complexes show higher activity than the corresponding free ligand, and most complexes are more active than cisplatin. Compounds 1, 3, 5, and 8 were selected for additional studies: while these complexes induce reactive oxygen species and double-strand breaks in both cancer cells, their ability to induce cell-death by apoptosis varies. Within the set of compounds tested, 8 emerges as the most promising one, presenting low IC50 values, and high induction of oxidative stress and DNA damage, which eventually lead to high rates of apoptosis.

Eco-friendly fabricated multibioactive Ca(II)-antibiotic coordination framework coating on zinc towards improved bone tissue regeneration.

Zinc is a biodegradable candidate material for bone regeneration; however, concomitant implant-related infection and rejection require new solutions to raise the biomedical potential of zinc. Functionalization towards localized drug administration with bioactive frameworks can be a solution. It is herein reported for the first time an eco-friendly approach for coating zinc with multibioactive antibiotic coordination frameworks (ACF). ACF1, a new 1D framework with deprotonated nalidixic and salicylic acids, obtained by mechanochemistry, results from the coordination of Ca(II) centers to the organic acids anions. To maximize ACF1 loading and cells' adhesion, the surface area was increased by creating a porous 3D Zn layer. A coverage of ∼70% of the surface with ACF1, achieved by electrophoretic deposition in an aqueous solution, preserved the desired Zn degradation as |Z| in the order of 103 Ω.cm2 is attained for both bare and coated samples in physiological conditions. The bioactivities of the ACF1 powder are a strong antibacterial activity against Escherichia coli (MIC of 1.95 µg/mL) and weaker against Staphylococcus aureus (MIC of 250 µg/mL), while osteoblasts' cytocompatibility is achieved for concentration ranging between 10 and 100 µg/mL. In its coating form, the degradation of Zn coated with ACF1 results in nalidixic acid release, which may convey antibacterial activity to the implant. The osteoinduction observe over this new biomaterial relates to the precipitation of an apatite layer built from the Ca(II) of ACF1. The work described herein, where unexplored eco-friendly approaches were used, presents a new trend for the design of multibioactive coatings on bioresorbable metallic materials.

Hybrid Silver(I)-Doped Soybean Oil and Potato Starch Biopolymer Films to Combat Bacterial Biofilms.

This study describes the preparation, characterization, and antimicrobial properties of novel hybrid biopolymer materials doped with bioactive silver(I) coordination polymers (bioCPs). Two new bioCPs, [Ag2(µ6-hfa)]n (1) and [Ag2(µ4-nda)(H2O)2]n (2), were assembled from Ag2O and homophthalic (H2hfa) or 2,6-naphthalenedicarboxylic (H2nda) acids as unexplored building blocks. Their structures feature 2D metal-organic and supramolecular networks with 3,6L64 or sql topology. Both compounds act as active antimicrobial agents for producing bioCP-doped biopolymer films based on epoxidized soybean oil acrylate (SBO) or potato starch (PS) as model biopolymer materials with a different rate of degradability and silver release. BioCPs and their hybrid biopolymer films (1@[SBO]n, 2@[SBO]n, 1@[PS]n, and 2@[PS]n) with a very low loading of coordination polymer (0.05-0.5 wt %) show remarkable antimicrobial activity against Staphylococcus aureus and Staphylococcus epidermidis (Gram-positive) and Escherichia coli and Pseudomonas aeruginosa (Gram-negative) bacteria. Biopolymer films also effectively impair the formation of bacterial biofilms, allowing total biofilm inhibition in several cases. By reporting on new bioCPs and biopolymer films obtained from renewable biofeedstocks (soybean oil and PS), this study blends highly important research directions and widens a limited antimicrobial application of bioCPs and derived functional materials. This research thus opens up the perspectives for designing hybrid biopolymer films with outstanding bioactivity against bacterial biofilms.

Time-Dependent Self-Assembly of Copper(II) Coordination Polymers and Tetranuclear Rings: Catalysts for Oxidative Functionalization of Saturated Hydrocarbons.

This study describes a time-dependent self-assembly generation of new copper(II) coordination compounds from an aqueous-medium reaction mixture composed of copper(II) nitrate, H3bes biobuffer (N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid), ammonium hydroxide, and benzenecarboxylic acid, namely, 4-methoxybenzoic (Hfmba) or 4-chlorobenzoic (Hfcba) acid. Two products were isolated from each reaction, namely, 1D coordination polymers [Cu3(µ3-OH)2(µ-fmba)2(fmba)2(H2O)2]n (1) or [Cu2(µ-OH)2(µ-fcba)2]n (2) and discrete tetracopper(II) rings [Cu4(µ-Hbes)3(µ-H2bes)(µ-fmba)]·2H2O (3) or [Cu4(µ-Hbes)3(µ-H2bes)(µ-fcba)]·4H2O (4), respectively. These four compounds were obtained as microcrystalline air-stable solids and characterized by standard methods, including the single-crystal X-ray diffraction. The structures of 1 and 2 feature distinct types of metal-organic chains driven by the µ3- or µ-OH- ligands along with the µ-benzenecarboxylate linkers. The structures of 3 and 4 disclose the chairlike Cu4 rings assembled from four µ-bridging and chelating aminoalcoholate ligands along with µ-benzenecarboxylate moieties playing a core-stabilizing role. Catalytic activity of 1-4 was investigated in two model reactions, namely, (a) the mild oxidation of saturated hydrocarbons with hydrogen peroxide to form alcohols and ketones and (b) the mild carboxylation of alkanes with carbon monoxide, water, and peroxodisulfate to generate carboxylic acids. Cyclohexane and propane were used as model cyclic and gaseous alkanes, while the substrate scope also included cyclopentane, cycloheptane, and cyclooctane. Different reaction parameters were investigated, including an effect of the acid cocatalyst and various selectivity parameters. The obtained total product yields (up to 34% based on C3H8 or up to 47% based on C6H12) in the carboxylation of propane and cyclohexane are remarkable taking into account an inertness of these saturated hydrocarbons and low reaction temperatures (50-60 °C). Apart from notable catalytic activity, this study showcases a novel time-dependent synthetic strategy for the self-assembly of two different Cu(II) compounds from the same reaction mixture.

Antimicrobial Activity of Pyrazinamide Coordination Frameworks Synthesized by Mechanochemistry.

The urge for the development of a more efficient antibiotic crystalline forms led us to the disclosure of new antibiotic coordination frameworks of pyrazinamide, a well-known drug used for the treatment of tuberculosis, with some of the novel compounds unravelling improved antimycobacterial activity. Mechanochemistry was the preferred synthetic technique to yield novel compounds, allowing the reproduction of a 1D zinc framework, the synthesis of a novel hydrogen bonding manganese framework, and three new compounds with silver. The structural characterization of the novel forms is presented along with stability studies. The increased antimicrobial activity of the new silver-based frameworks against Escherichia coli, Staphylococcus aureus, and Mycobacterium smegmatis is particularly relevant.

Synthesis of novel pyrazolo[3,4-b]quinolinebisphosphonic acids and an unexpected intramolecular cyclization and phosphonylation reaction.

Novel pyrazolo[3,4-b]quinoline α-ketophosphonic and hydroxymethylenebisphosphonic acid compounds were synthesized using different methodologies, starting from 2-chloro-3-formylquinoline 1. New phosphonic acid compounds were obtained as N-1 derivatives with a side chain with 1 or 3 (n = 1 or 3) methylene groups. All phosphonic acid compounds and their corresponding ester and carboxylic acid precursors were fully characterized, and their structures elucidated by spectroscopic data, using NMR techniques and infrared and high-resolution mass spectroscopy. During the process to obtain the N-1 substituted derivative with two methylene groups (n = 2) in the side chain, an unexpected addition-cyclization cascade reaction was observed, involving the phosphonylation of an aromatic ring and the formation of a new six-member lactam ring to afford a tetracyclic ring system. This was an unexpected result since other pyrazolo[3,4-b]quinoline derivatives and all corresponding pyrazolo[3,4-b]pyridine derivatives already prepared, under similar experimental conditions, did not undergo this reaction. This domino reaction occurs with different phosphite reagents but only affords the six-member ring. The spectroscopic data allowed the identification of the new synthesized tetracyclic compounds and the X-ray diffraction data of compound 11 enabled the confirmation of the proposed structures.

Silver(I) Coordination Polymers Immobilized into Biopolymer Films for Antimicrobial Applications.

This study describes a template-mediated self-assembly synthesis, full characterization, and structural features of two new silver-based bioactive coordination polymers (CPs) and their immobilization into acrylated epoxidized soybean oil (ESOA) biopolymer films for antimicrobial applications. The 3D silver(I) CPs [Ag4(µ8-H2pma)2]n·4nH2O (1) and [Ag5(µ6-H0.5tma)2(H2O)4]n·2nH2O (2) were generated from AgNO3 and pyromellitic (H4pma) or trimesic (H3tma) acid, also using N,N'-dimethylethanolamine (Hdmea) as a template. Both 1 and 2 feature the intricate 3D layer-pillared structures driven by distinct polycarboxylate blocks. Topological analysis revealed binodal nets with the flu and tcj/hc topology in 1 and 2, respectively. These CPs were used for fabricating new hybrid materials, namely, by doping the [ESOA]n biopolymer films with very low amounts of 1 and 2 (0.05, 0.1, and 0.5%). Their antimicrobial activity and ability to impair bacterial biofilm formation were investigated in detail against both Gram-positive (Staphylococcus epidermidis and Staphylococcus aureus) and Gram-negative (Pseudomonas aeruginosa and Escherichia coli) bacteria. Both silver(I) CPs and derived biopolymer films showed activity against all the tested bacteria in a concentration-dependent manner. Compound 1 exhibited a more pronounced activity, especially in preventing biofilm growth, with mean bacterial load reductions ranging from 3.7 to 4.3 log against the four bacteria (99.99% bacterial eradication). The present work thus opens up antibiofilm applications of CP-doped biopolymers, providing new perspectives and very promising results for the design of functional biomaterials.

Cu(ii) and V(iv)O complexes with tri- or tetradentate ligands based on (2-hydroxybenzyl)-l-alanines reveal promising anticancer therapeutic potential.

Four new ligand precursors (H2L1-H2L4), derived from the Mannich condensation of two amino acids (l-Val and l-Phe) and two 3,5-disubstituted phenols (t-Bu or Me), and the corresponding oxidovanadium(iv) (1-4) and copper(ii) (6-7) complexes are synthesized. Two other related compounds (H2L5 and H2L6), containing an additional 2-methyl-pyridine arm, and the corresponding VIVO (5) and CuII (8-9) complexes were also obtained. All metal complexes are monomeric in the solid state, having a solvent molecule or a chloride ion in the coordination sphere. The in vitro cytotoxic activity of all compounds is evaluated against cancer cells from different origins. The IC50 values at 72 h are in the range of 6-15 µM for HeLa cells, 4-17 µM for A-549 cells and >25 µM for MDA-MB-231 cells, except for [VIVOL1(CH3OH)] (1) and [CuL6(H2O)] (9). With the exception of H2L6, overall, the metal complexes are more cytotoxic than the corresponding ligand precursors. Globally, the cellular viability data show that (i) the l-Phe derived compounds are more cytotoxic than the corresponding l-Val complexes; (ii) the presence of the bulkier t-Bu groups increases the cytotoxicity; (iii) the presence of a 2-methyl-pyridine arm increases considerably the cytotoxicity; and (iv) the CuII-complexes are more cytotoxic than the VIVO-compounds. Complexes [VIVOL3(CH3OH)] (3), [CuL3(H2O)] (7) and [CuL5(H2O)] (8) were further evaluated and their mechanism of action was determined to be apoptosis, evidenced by AnnexinV staining and the increase in caspase 3/7 activity. Compounds 3, 7 and 8 also exhibit DNA cleavage activity, involving the formation of reactive oxygen species and were able to induce genomic damage in cells as determined by COMET assay.

Mechanochemistry in Portugal-A Step towards Sustainable Chemical Synthesis.

In Portugal, publications with mechanochemical methods date back to 2009, with the report on mechanochemical strategies for the synthesis of metallopharmaceuticals. Since then, mechanochemical applications have grown in Portugal, spanning several fields, mainly crystal engineering and supramolecular chemistry, catalysis, and organic and inorganic chemistry. The area with the most increased development is the synthesis of multicomponent crystal forms, with several groups synthesizing solvates, salts, and cocrystals in which the main objective was to improve physical properties of the active pharmaceutical ingredients. Recently, non-crystalline materials, such as ionic liquids and amorphous solid dispersions, have also been studied using mechanochemical methods. An area that is in expansion is the use of mechanochemical synthesis of bioinspired metal-organic frameworks with an emphasis in antibiotic coordination frameworks. The use of mechanochemistry for catalysis and organic and inorganic synthesis has also grown due to the synthetic advantages, ease of synthesis, scalability, sustainability, and, in the majority of cases, the superior properties of the synthesized materials. It can be easily concluded that mechanochemistry is expanding in Portugal in diverse research areas.

Silver(I)-Tazobactam Frameworks with Improved Antimicrobial Activity.

Tazobactam (TazoH) is a penicillinate sulfone ß-lactamase inhibitor with negligible antimicrobial activity, commonly used with other antibiotics to provide an effective combination against many susceptible organisms expressing ß-lactamases. Two novel Ag(I)-tazobactam frameworks ([Ag(I)-Tazo] and [Ag(I)-Tazo2]) prepared by mechanochemistry are presented herein as alternative forms to improve the antimicrobial activity of tazobactam by exploring synergistic effects with silver, being the first crystal structures reported of tazobactam coordinating to a metal site. The topological analysis of the 3D ([Ag(I)-Tazo]) and 2D+1D ([Ag(I)-Tazo2]) frameworks revealed underlying nets with the cbs (CrB self-dual) and decorated sql topologies, respectively. These novel frameworks are stable and show an enhanced antimicrobial activity when compared to tazobactam alone. Amongst the tested microorganisms, Pseudomonas aeruginosa is the most sensitive to tazobactam and the new compounds. This study thus unveils novel facets of tazobactam chemistry and opens up its application as a multifunctional linker for the design of antibiotic coordination frameworks and related materials.

The Lisbon Supramolecular Green Story: Mechanochemistry towards New Forms of Pharmaceuticals.

This short review presents and highlights the work performed by the Lisbon Group on the mechanochemical synthesis of active pharmaceutical ingredients (APIs) multicomponent compounds. Here, we show some of our most relevant contributions on the synthesis of supramolecular derivatives of well-known commercial used drugs and the corresponding improvement on their physicochemical properties. The study reflects, not only our pursuit of using crystal engineering principles for the search of supramolecular entities, but also our aim to correlate them with the desired properties. The work also covers our results on polymorphic screening and describes our proposed alternatives to induce and maintain specific polymorphic forms, and our approach to avoid polymorphism using APIs as ionic liquids. We want to stress that all the work was performed using mechanochemistry, a green advantageous synthetic technique.

Bioactivity of Isostructural Hydrogen Bonding Frameworks Built from Pipemidic Acid Metal Complexes.

We report herein three novel complexes whose design was based on the approach that consists of combining commercially available antibiotics with metals to attain different physicochemical properties and promote antimicrobial activity. Thus, new isostructural three-dimensional (3D) hydrogen bonding frameworks of pipemidic acid with manganese (II), zinc (II) and calcium (II) have been synthesised by mechanochemistry and are stable under shelf conditions. Notably, the antimicrobial activity of the compounds is maintained or even increased; in particular, the activity of the complexes is augmented against Escherichia coli, a representative of Gram-negative bacteria that have emerged as a major concern in drug resistance. Moreover, the synthesised compounds display similar general toxicity (Artemia salina model) levels to the original antibiotic, pipemidic acid. The increased antibacterial activity of the synthesised compounds, together with their appropriate toxicity levels, are promising outcomes.