Search Results (511)

A series of Group 10 metal dithiocarbonate complexes [M(S₂COⁱPr)₂] (M = Ni 1, Pd 2, Pt 3) was prepared following procedures from the literature and cocrystallized with the ditopic σ/π-hole donor 1,4-diiodotetrafluorobenzene. Single-crystal X-ray diffraction revealed a consistent I···S halogen bonding motif alongside a remarkable diversity in metal-involving interactions across the Ni–Pd–Pt triad. While nickel(II) exhibits strong electrophilic M···S semicoordination, the palladium(II) center displays ambiphilic behavior, and platinum(II) acts exclusively as a nucleophile via π-hole···M bonding. Comprehensive density functional theory studies, including molecular electrostatic potential (MEP) mapping, quantum theory of atoms in molecules/noncovalent interaction plot analyses, and energy decomposition analysis, were used to quantify this competitive balance. The results demonstrate that the increasing nucleophilicity from Ni to Pt, supported by shifting MEP minima and stronger π-hole stabilization energies, dictates the preference for nucleophilic over electrophilic metal-centered contact. Full article

Ten compounds have been prepared among them six different dioxido(pyridine-2,6-dicarboxylato)vanadate(V) compounds with piperazinium (H₂pip²⁺) (1·6H₂O), methylpiperazinium (H₂mepip²⁺) (2·5H₂O), ethylpiperazinium (H₂etpip²⁺) (3·3H₂O), isopropylpiperazinium (H₂isopip²⁺) (4·H₂O), phenylpiperazinium (Hphepip⁺) (5∙H₂O) and thiomorpholinium 1-oxide (HtmorO⁺) (6·2,6-H₂pydc·2H₂O) cations as counterions as well as methylpiperazinium (H₂mepip²⁺) salt of a mixed valence vanadium [VO(2,6-pydc)-(μ-O)-VO(H₂O)(2,6-pydc)]⁻ complex (7), thiomorpholin-4-ium vanadate (Htmor)VO₃ (8), hexa(thiomorpholin-4-ium) decavanadate hexahydrate (Htmor)₆[V₁₀O₂₈]·6H₂O (9·6H₂O) and organic salt cocrystal thiomorpholin-4-ium 6-carboxypicolinate pyridine-2,6-dicarboxylic acid (Htmor)⁺(2,6-Hpydc)⁻∙(2,6-H₂pydc)·2H₂O (10·2H₂O) via different pathways starting either from pyridine-2,6-dicarboxylic acid or its esters, and were structurally characterized by single-crystal X-ray diffraction. Extended hydrogen bonding interactions are present due to the presence of organic cations as well as due to the diverse roles of water molecules in the hydrogen bonding network. Centrosymmetric hydrogen bonding was found to be an important motif, and diverse supramolecular patterns were also observed due to a wide variety of C–H···O and π···π interactions stabilizing the crystal lattices. Full article

Background: Hepatitis B virus (HBV) infection continues to be a major public health concern, especially in sub-Saharan Africa, where widespread epidemics and restricted availability of long-term antiviral therapies result in higher mortality and morbidity rates. Drug repurposing represents a strategic approach to accelerate the discovery of effective therapies by leveraging agents with demonstrated antiviral and immunomodulatory activity. Product Nkabinde (PN) is a patented African polyherbal formulation initially developed for the treatment of HIV. Recent experimental studies demonstrate PN’s potent anti-HIV activity and significant immunomodulatory effects in human immune cells, implicating host-directed mechanisms relevant to chronic viral infections. This study combines an integrative application of network pharmacology and molecular docking to evaluate the repurposing potential of PN as a multi-target agent in HBV. Method: Bioactive components of PN were screened, and compound-associated targets were intersected with HBV-associated genes (proteins) to construct a protein–protein interaction (PPI) network. Topological analysis identified 10 hub targets (STAT1, STAT3, SRC, HCK, EGFR, SYK, PIK3CA, PIK3CB, PIK3R1, and PTPN11). Gene Ontology and KEGG pathway enrichment were performed with an FDR cut-off < 0.05. Significantly enriched pathways included JAK–STAT signaling, chemokine signaling, EGFR-TKI resistance, PI3K complex signaling, and viral infection pathways, particularly those related to Kaposi sarcoma virus and HSV-1, indicating immunoregulatory and antiviral roles. Molecular docking was performed using AutoDock Vina 1.1.2 to evaluate binding affinity and interaction mode of key PN phytochemicals against the hub proteins, and results were compared to their respective co-crystallized ligands. Results: Molecular docking indicated that major phytochemicals from PN exhibited significant binding affinities across all 10 hub host targets, typically outperforming or closely matching their respective co-crystallized ligands. The strongest contacts were observed for β-sitosterol–PIK3CB (−14.2 kcal/mol) and oleanolic acid–SYK (−14.0 kcal/mol), which were significantly stronger than the co-crystallized ligands (−7.9 and −8.3 kcal/mol, respectively), indicating robust stabilization within catalytic and regulatory pockets. Procyanidin B2 toward HCK (−10.5 vs. −7.9 kcal/mol) and PIK3CA (−9.5 vs. −7.3 kcal/mol), quercetin toward PIK3R1 (−10.6 vs. −8.2 kcal/mol) and PTPN11 (−9.2 vs. −7.5 kcal/mol), rutin toward SRC (−10.5 vs. 7.8 kcal/mol), and diosgenin toward EGFR (−9.4 vs. 8.4 kcal/mol). Procyanidin B2 maintained robust multi-hydrogen bonding networks, demonstrating significant binding, despite STAT1 and STAT3 docking showing identical affinities to co-crystals. Conserved hydrogen bonds, π–cation interactions, and significant hydrophobic packing at ATP-binding clefts and regulatory domains supported these interaction patterns, indicating competitive suppression of host signaling nodes taken over by HBV. Conclusions: Together, these results demonstrate that the components of PN possess strong multitarget binding capabilities across the PI3K/AKT, JAK–STAT, SRC-family kinase, EGFR, and SYK pathways, supporting their potential repurposing as host-directed HBV therapeutics with the ability to impede immune evasion, viral persistence, and HBV-associated oncogenic progression. Full article

This review summarizes innovative co-formulation strategies for non-marketed dry powder inhalers (DPIs), enabling the simultaneous pulmonary delivery of multiple active pharmaceutical ingredients (APIs). Key approaches include co-amorphous systems (COAMS) and co-crystals, which combine two APIs into a single particle, improving aerodynamic properties, solubility, dissolution, and patient compliance while reducing manufacturing complexity. Core–shell microparticles, produced via spray drying, allow spatial separation and controlled release of APIs, minimizing drug–drug interactions and enabling tailored pharmacokinetics. Co-spray drying of dual APIs can yield particles with superior aerosolization and stability, though examples remain limited. Nanoparticle-based systems offer enhanced lung deposition and cellular uptake but face challenges in device compatibility, scalability, and regulatory approval. Each technology presents unique advantages and limitations regarding manufacturability, dose flexibility, and clinical translation. This review also highlights advances in in vitro toxicity testing, including air–liquid interface cultures, organoids, lung-on-chip models, and precision-cut lung slices, which are increasingly important as alternatives to animal studies. The importance of using an aerosol exposure system for the testing is highlighted. Ultimately, the choice of co-formulation platform should balance scientific innovation with practical considerations of manufacturing and regulatory requirements to maximize therapeutic benefit and commercial viability for future DPI combination products. Full article

Tramadol acts via μ-opioid receptor agonism and monoamine reuptake inhibition but is clinically limited by metabolic dependence, interindividual variability, and addiction risks. Structural modification aims to resolve these limitations. This review systematically summarizes tramadol’s structure–activity relationships and mechanisms, focusing on key strategies for structural optimization. Major advances include: (i) synergistic strategies, such as tramadol–celecoxib cocrystals (tramadol and celecoxib coexist in the supramolecular crystal network at a 1:1 molar ratio), achieving multimodal analgesia at lower doses; (ii) mechanism-balancing strategies such as tapentadol (derivatives of tramadol with a dual mechanism of action), which enhance μ-opioid agonism and norepinephrine reuptake inhibition while attenuating serotonergic effects to improve efficacy; (iii) metabolic optimization utilizing M1 analogues to circumvent CYP2D6 polymorphisms (tramadol is metabolized by this enzyme into the active metabolite M1 to exert analgesic effects); and (iv) pharmacophore optimization leveraging tramadol–morphine homology and “message–address” concepts to design selective ligands. Novel derivatives demonstrate improved potency and metabolic stability but continue to face challenges regarding opioid risks and clinical translation. Future research should integrate rational drug design, delivery systems, and personalized medicine to facilitate the development of safer next-generation analgesics. Full article

Three multicomponent crystals of metformin were investigated to elucidate factors governing crystal architecture. Structures were determined by X-ray diffraction and analyzed using the Atoms-in-Molecules (AIM) approach, focusing on critical points and electron density topology. Three types of crystals were obtained: salt, cocrystal salt solvate and mixed salt with both organic and inorganic anions. Protonation of nitrogen atoms in metformin alters bond lengths and electron density, while strong intramolecular hydrogen bonds in hydrogenmaleate anions stabilize the structures and define the preferred anion geometry. Comparison with monoprotonated metformin revealed similar topological features despite differing protonation states. Mechanochemical synthesis via liquid-assisted grinding (LAG) enabled selective formation of specific crystalline forms, with the solvent type and acid polymorph influencing product distribution. These results highlight the critical roles of protonation, hydrogen bonding, and synthetic methodology in designing and controlling multicomponent metformin crystal structures. Full article

The present study investigates the co-crystallization process of rivaroxaban (RIV), a poorly water-soluble potent oral anticoagulant, with niacinamide (NIA), a highly soluble and pharmaceutically acceptable co-crystal former, in two different molar ratios (1:1 and 1:2). The aim was to enhance the physicochemical and biopharmaceutical properties of rivaroxaban such as dissolution rate and aqueous solubility, by forming stable co-crystals through a solvent evaporation technique. The resulting co-crystals (RIV-NIA, 1:1 co-crystallization compound, F1 and RIV-NIA, 1:2 co-crystallization compound, F3) were characterized using scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FTIR), powder X-ray diffraction (XRD) and thermal analysis, which confirmed the formation of a new rivaroxaban–niacinamide co-crystalline phase. In vitro dissolution studies confirmed a significant enhancement in the dissolution rate of the two obtained co-crystals. These findings suggest that stoichiometric variation plays an important role in co-crystal performance and in improving solubility compared with the pure drug. Also, the obtained results suggest that niacinamide is an effective coformer for improving the dissolution and physicochemical properties of rivaroxaban. Full article

Two novel cocrystals of zwitterionic trimethylglycine (TMG) with 2,6-dichlorophenol [TMG•2,6-dichlorophenol] (1:1) and 2,6-dibromophenol [TMG•2,6-dibromophenol] (1:2) are synthesized and structurally characterized using single crystal X-ray diffraction. To estimate the energy of various intermolecular interactions, periodic DFT calculations were performed followed by Bader analysis of the crystalline electron density. TMG molecules form dimers in [TMG•2,6-dichlorophenol] (1:1). Its supramolecular structure is governed by the primary charge-assisted H-bonds (~60 kJ/mol) and supported by C–H∙∙∙O contacts (~12 kJ/mol). Cl/Br substitution introduces a more potent halogen-bonding donor. The Br∙∙∙O⁻ interaction (~10 kJ/mol) is strong enough to reorganize the packing into a catemeric motif. As a result, TMG molecules form infinite chains in [TMG•2,6-dibromophenol] (1:2). This illustrates that “fine tuning” is not merely about changing distances, but about shifting the entire energy hierarchy of the crystal. Two-dimensional fingerprint diagrams (2D diagrams) obtained from the Hirshfeld surface and Bader’s analysis of the crystalline electron density give significantly different values of the contributions of the H∙∙∙H contacts, 28% vs. 5% respectively. The main reason for this discrepancy is the large number of relatively short intermolecular H∙∙∙H contacts without a critical bond point in trimethylglycine cocrystals. Full article

Calcium oxalate (CaOx) crystals in plants can form naturally within their idioblasts but may also be induced by other factors, such as environmental pollution. Here, we report qualitative and semiquantitative results obtained using scanning electron microscopy (SEM) and energy-dispersive X-ray (EDX) from two experiments in which tomato seedlings were moderately irrigated with Sulfamethoxazole (SMX) and Amoxicillin (AMX) solutions (0.25 mM). Abundant prismatic CaOx co-crystals appeared on the leaf surface induced by these two antibiotics compared to the distilled water (DW) control. Applying a non-thermal plasma (NTP) treatment for 20 min (T20) to the SMX initial solution led to a dramatic suppression of these crystals, with a shift toward spherical structures. Furthermore, the investigation into the composition of both crystal types, indicated different percentual levels of O, C, Ca, K, Mg, S, and Mn as main constituent minerals involved in crystal formation. However, crystal morphology was affected by each applied experimental condition, while detecting their constituent elements depended on their mineral homogeneity at the micro- or macro-field scales. Although both antibiotics induced crystal formation and T20 phenotypically reduced the abundance of the acicular–prismatic crystals by removing the effects of SMX, their mode of action has not yet been clarified. Full article

Phenothiazine is a heteroaromatic molecule capable of various noncovalent interactions, including halogen bonding and π-stacked association. Despite its broad use in functional materials and pharmaceutical ingredients, a systematic comparison of these interaction modes has been lacking. Here, we report a combined experimental and computational study of intermolecular interactions of phenothiazine with a prototypical halogen-bond (HaB) donor (tetrabromomethane), planar π-electron acceptors (tetracyanopyrazine and tetrafluoro-p-benzoquinone), and multifunctional species capable of both interaction types (iodo- and bromo-3,5-dinitrobenzenes). X-ray structural analysis revealed that CBr₄ forms exclusively C–Br···π halogen bonds with the aromatic rings of phenothiazine, whereas all π-acceptors yield alternating donor–acceptor stacks characterized by multiple short contacts indicative of multicenter interactions. Notably, co-crystals of iodo- and bromodinitrobenzenes with phenothiazine display only π-stacked architectures. Density-functional calculations showed that isolated HaB complexes involving N, S, or π sites of phenothiazine possess comparable binding energies (≈−3 kcal mol⁻¹), whereas π-stacked complexes are substantially stronger (≈−9–12 kcal mol⁻¹). QTAIM, NCI, NBO, and energy-decomposition analyses indicated that while amounts of charge transfer in halogen-bonded and π-stacked complexes are comparable, the enhanced stability of the latter originates primarily from a large dispersion contribution. These results rationalize the solid-state preference for π-stacking over halogen bonding in systems where both motifs are accessible and clarify the hierarchy and physical origin of noncovalent interactions involving phenothiazine, providing guidance for the design of supramolecular assemblies and functional materials based on this versatile electron donor. Full article

Background/Objectives: Cocrystallisation is a well-established path for altering the physicochemical properties and bioavailability of active pharmaceutical ingredients (APIs). A common side effect of anti-tubercular medicines is the depletion of group B vitamin reserves in TB patients. Co-administration of supplements such as pyridoxine (vitamin B₆) during TB therapy may be used to ameliorate the harmful side effects of vitamin B₆ deficiency. Methods: Mechanochemical grinding and solvent evaporation experiments using pyridoxine (PN) with 4-aminosalicylic acid (PAS) and separately with pyrazinecarboxylic acid (PCBA) were conducted. The bulk powder and crystal analysis was performed using FTIR, PXRD, DSC, TGA and SCXRD. Results: The isolation and characterization of two multicomponent salts containing pyridoxine, i.e., PN-PAS·H₂O and PN-PCBA, were completed. Mechanochemistry is an efficient method for the preparation of cocrystals. Conclusions: The drug–vitamin combinations may be useful for the development of new treatment regimens with potentially improved therapeutic outcomes and reduced adverse effects. Full article

Betaine, a simple natural zwitterion, is currently attracting widespread attention. Although historically labeled as an osmoregulator in agriculture and a methyl donor in animal nutrition, the molecule is now being repositioned at the forefront of green chemistry and materials science due to its unique physicochemical structure. This review critically explores the expanding horizon of betaine applications, bridging the gap between its established biological functions and its emerging roles in recently reported technologies, such as deep eutectic solvents (DESs), cocrystal engineering, and sustainable polymer synthesis. Beyond summarizing its versatile functionality across biomedicine, food science, and industrial formulations, we provide a comprehensive bibliometric analysis to map the evolution of research trends, identifying a clear focus toward industrial ecology and advanced materials. By synthesizing current advancements and discussing potential future directions, this work highlights betaine not merely as a supplement, but as a versatile molecular component with potential applications in sustainable materials and chemical engineering processes. Full article

This study contains a combination of a review and a related individual case study, which discusses the possibility of predicting the success of enantiomers’ optical separation using fractional crystallization of diastereomeric salts. The key idea is to use relatively simple and rapid experimental methods, such as differential scanning calorimetry (DSC) and powder X-ray diffraction (XRD), to construct ternary melting diagrams. These diagrams can be used for visualization and predicting compositional conditions favorable for successful separation. The main limitations are also mentioned, such as the ideal eutectic behavior of components and the need to identify all crystalline phases in the system. For demonstration, three novel studies, attempts in ternary resolution systems of racemic o- and p-chloromandelic acids with chiral 1-cyclohexylethylamine or pregabalin, resulting in either declined or promising aspects for a successful resolution, were completed, and the corresponding individual ternary phase diagrams have been compiled and presented, as well. In addition, indexing and modeling of one of the diastereomeric salts’ unit cells have been successfully carried out by means of powder X-ray diffraction, using the DASH software package. Full article

Papain-like protease (PLpro), a crucial functional domain of the SARS-CoV-2 non-structural protein 3 (nsp3), plays a dual role in both hydrolyzing viral polyprotein precursors and modulating host immune responses. These critical functions position PLpro as a key target in the ongoing development of antiviral therapies for SARS-CoV-2. This review analyzes more than 100 PLpro-ligand co-crystal structures and summarizes the major binding modes between these ligands and PLpro. Most of these ligands bind to sites analogous to those targeted by the classical non-covalent inhibitor GRL0617, primarily involving the P3 and P4 subsites and the BL2 loop. Based on these structural insights, optimized inhibitors have expanded targeting beyond the canonical binding site to auxiliary regions such as the BL2 groove and the Val70 site, and in some cases toward the catalytic Cys111 buried within a narrow pocket. Certain ligands identified through various screening approaches bind to non-canonical or allosteric regions, such as the S1 and S2 sites or the zinc-finger domain, engaging PLpro through distinct interaction modes and thereby offering additional opportunities for PLpro inhibitor design. The review also discusses potential strategies for future PLpro inhibitor development informed by recent structural advances. Taken together, these structural and functional insights support ongoing efforts in the structure-guided design and optimization of PLpro inhibitors. Full article

Pharmaceutical cocrystals are a well-established class of solid-state forms that can modulate the solubility, dissolution, stability, and bioavailability of active pharmaceutical ingredients without altering their molecular identity. Although traditional oral formulations have demonstrated translational potential, recent research has emphasized the importance of integrating cocrystals into emerging drug-delivery technologies. This review systematically analyzes recent advances in conventional and innovative cocrystal-based platforms, critically evaluating their therapeutic relevance. A comprehensive literature search was conducted, focusing on publications from the last decade, with emphasis on studies from 2020 to 2025, including peer-reviewed articles, patents, and regulatory documents. Evidence was organized into traditional oral, inhalable, intranasal, and transdermal formulations, followed by emerging platforms such as 3D printing, nano-cocrystals, and microneedles. Case studies and preclinical/clinical data were critically assessed to identify strengths, limitations, and future directions. Advancements in formulation science and novel delivery technologies are allowing pharmaceutical cocrystals to transition from laboratory innovations to clinical applications. Despite challenges in scalability, stability, and regulatory clarity, the application of cocrystals into emerging platforms highlights their potential as transformative tools in next-generation therapeutics. Full article