JOURNAL OF MOLECULAR STRUCTURE
·
2026
·
IF 4.7
Meiling Nie,Ting Jiao,Lin Wang,Chiyi Wang,Jiahan Jin,Jialu Hu,Yang Li,Hailu Zhang
The study of pharmaceutical cocrystal polymorphism is attracting increasing interest, as variations in intermolecular interactions and packing arrangements between an active pharmaceutical ingredient (API) and the same cocrystal former (CCF) directly impact the extent to which cocrystals can tailor the API’s properties. However, the number of reported cases of cocrystal polymorphism remains relatively limited. Herein, we propose that orientational variability of hydrogen bond donors or acceptors on either the API or the CCF may drive the formation of cocrystal polymorphs. To substantiate this hypothesis, 5-fluorocytosine (5-FC) and L -malic acid ( L -MAL) were selected as the model cocrystallization system, and two distinct 2:1 polymorphs (form Ⅰ and form Ⅱ) were ultimately identified. Crystal structural analysis revealed that the two cocrystals share consistent supramolecular interactions; however, the divergent orientations of carbonyl and hydroxyl groups in L -MAL induce distinguishable hydrogen bonding configurations and molecular stacking patterns, which strongly validates the proposed origin of cocrystal polymorphism. Lattice energy calculations, polymorphic transformation studies, and melting point data collectively confirmed that these two polymorphs exhibit a monotropic thermodynamic relationship, with the high- Z ’ form Ⅱ ( Z ’ = 2) being the thermodynamically stable crystalline phase. Under higher relative humidity condition (90 % RH), an obvious phase transformation of form Ⅰ was observed within one week, whereas form Ⅱ maintains its phase stability for at least four weeks. Such performance difference between these two cocrystals further underscores the practical significance of cocrystal polymorph screening.
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mBio
·
2022
·Vol. 14
·期 1
·
IF 7.786
Hui Lu,Wanqian Li,Malcolm Whiteway,Hongkang Wang,Shuo Zhu,Zhe Ji,Yanru Feng,Lan Yan,Ting Fang,Liping Li,Tingjunhong Ni,Xiaolong Zhang,Quanzhen Lv,Zichao Ding,Lijuan Qiu,Dazhi Zhang,Yuanying Jiang
Fluconazole (FLC) is widely used to prevent and treat invasive fungal infections. However, FLC is a fungistatic agent, allowing clinical FLC-susceptible isolates to tolerate FLC. Making FLC fungicidal in combination with adjuvants is a promising strategy to avoid FLC resistance and eliminate the persistence and recurrence of fungal infections. Here, we identify a new small molecule compound, CZ66, that can make FLC fungicidal. The mechanism of action of CZ66 is targeting the C-4 sterol methyl oxidase, encoded by the ERG251 gene, resulting in decreased content of sterols with the 14α-methyl group and ultimately eliminating FLC tolerance of Candida albicans. CZ66 most likely interacts with Erg251 through residues Glu195, Gly206, and Arg241. Establishing Erg251 as a synergistic lethal target protein of FLC should direct research to identify specific small molecule inhibitors of 14α-methylsterol synthesis and open the way to abolishing fungal FLC tolerance.IMPORTANCE Fluconazole (FLC) tolerance increases the frequency of acquired FLC resistance, and a high FLC tolerance level is associated with persistent candidemia. Multiple functional proteins, such as calcineurin, heat shock protein 90 (Hsp90), and ADP ribosylation factor, are essential for the survival of C. albicans exposed to FLC, but how these factors increase the fungicidal activity of FLC remains to be determined. In this study, we found that 14α-methylsterols replace ergosterol to allow C. albicans to survive FLC, but Erg251 inactivated by CZ66 results in loss of 14α-methylsterol synthesis and cell death of C. albicans treated with FLC. Establishing Erg251 as a synergistic lethal target protein of FLC should direct research to identify specific small molecule inhibitors of 14α-methylsterol synthesis and open the way to abolishing fungal FLC tolerance.
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高影响因子
JOURNAL OF MOLECULAR STRUCTURE
·
2022
·
IF 3.841
Fan-Zhi Bu,Yue-Ming Yu,Yu-Li Shen,Zhi-Yong Wu,Yan-Tuan Li
The present investigation aims to fully exploit the structural dominance and liver protective efficacy of phenolic acid nutraceutical ferulic acid (FUA) towards decreasing antifungal drug 5-fluorocytosine (FTS) in solubility and dissolution rate through a cocrystallization stratagem, thereby achieving some fire-new understandings for addressing the side effects generated by the fast and inappropriate absorption from FTS. Toward this end, the cocrystalline complex of FTS with FUA, viz . FTS-FUA, as the first cocrystal of FTS with phenolic acid nutrient of hydroxycinnamic acid subgroup is directionally assembled and fully characterized. The crystal structure determined by the single-crystal X-ray diffraction method demonstrates that FUA molecules in the lattice seize the polar sites in situ of FTS founded on the compact hydrogen-bond interaction, therefore leading to the formation of a rigid S-shaped module (RSM) with hydrophobic potentials, which induces a simultaneous down-regulation of the cocrystal in solubility and intrinsic dissolution rate versus raw drug FTS itself. The experimental outcomes are strongly verified by relevant theoretical investigations. The molecular electrostatic potential and the mutual penetration distance authenticate that the RSM's polarity in the cocrystal is lower than that of FTS per se, which complies with the abatement in polarity attributable to the reinforced hydrogen-bonds energy as per topology analysis with atoms in molecules theory, thus giving a remarkable improvement in hydrophobicity for the cocrystal. As a result, the current contribution not only provides a new crystallization form for FTS, but also exemplifies the feasibility of cocrystallization clue from integrated experimental with a systematic theoretical approach to overcome intractable adverse effects of the antifungal agent.
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CRYSTENGCOMM
·
2022
·Vol. 24
·期 15
·2777-2790
·
IF 3.756
Fan-Zhi Bu,Yue-Ming Yu,Yu-Li Shen,Lu Liu,Cui-Wei Yan,Zhi-Yong Wu,Yan-Tuan Li
The current research takes advantage of the low solubility and hepatoprotective activity of the phenolic acid nutrient vanillic acid (VAA) to reduce the solubility and dissolution rate of the antifungal drug 5-fluorocytosine (FCY) via a cocrystallization strategy, thus gaining new insights into surmounting the dose-limited hepatotoxicity caused by the rapid and almost complete absorption of FCY. An FCY-phenolic acid nutraceutical cocrystal, namely, FCY–VAA–H2O, was directionally self-assembled and structurally characterized. The single-crystal X-ray structural analysis showed that water and VAA molecules occupy the polar sites of FCY in situ through strong hydrogen-bonding interplays, establishing a key plane structure (KPS) with hydrophobicity, which down-regulates the solubility and dissolution rate of the cocrystal as compared with FCY itself. The conclusion is supported by systematic theoretical studies. Molecular electrostatic potential (MEP) calculations revealed a polarity decrease in KPS in the cocrystal relative to free FCY, in accordance with the polarity diminution induced by intensive hydrogen-bonding energy, through the reduced density gradient (RDG) analysis, implying an obvious potentiation in hydrophobicity. Thereby, the theoretical calculations achieved positive correlations with the experimental measurements.
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MICROCHEMICAL JOURNAL
·
2021
·
IF 4.821
Zuoling Zhang,Min Xia,Pengfei Huang,Bin Di,Mengxiang Su
New stationary-phase materials are of great interest for use in hydrophilic interaction liquid chromatography (HILIC), a relatively new technique capable of separating highly polar compounds. In this study, a new strategy was established to prepare a novel Sil-Bac stationary phase by bonding bacitracin to silanised silica particles using hexamethylene diisocyanate as a spacer arm. The obtained material was characterised by Fourier transform infrared spectroscopy, Brunauer–Emmett–Teller analysis, transmission electron microscopy (TEM), and elemental analysis. The network layers observed through TEM and change in specific surface area from 315.0820 to 169.6758 m 2 ·g −1 after modification reflected the addition of bacitracin. The chromatographic behaviour of the Sil-Bac column showed that it can be used for HILIC. The influence of the chromatographic conditions on substance retention was explored by varying the acetonitrile content, column temperature, buffer concentration, and pH of the mobile phase. Using cytosine, uracil, nicotinamide, and isonicotinic acid as probes, the Sil-Bac column was demonstrated to have acceptable repeatability and stability, with a relative standard deviation of the retention time in the ranges of 0.05–0.18% for intra-day precision ( n = 3) and 0.16–3.28% for inter-day precision ( n = 3). Finally, the stationary phase was applied in separating basic nucleosides, water-soluble vitamins, and amino acids. A variety of bases and nucleosides could be separated within 7 min in a mobile phase of ACN/ammonium acetate (pH 3.0) = 90/10 (v/v), T = 30 °C. The Sil-Bac column was also compared with three commercial columns, and the results indicated that the analytes retained on the Sil-Bac column showed better retention and selectivity from an overall view. This novel stationary phase has a good separation ability and selectivity in HILIC mode and provides new ideas for the separation of polar compounds.
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JOURNAL OF CHEMICAL AND ENGINEERING DATA
·
2021
·
IF 2.694
Yang Cong,Cunbin Du,Meng Wang,Zhouyu Jiang,Mingliang Wang
In this work, the phase equilibrium solubility of 5-fluorocytosine (5-FC) in dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), 1-butanol, acetonitrile, 1-propanol, 1,4-dioxane, acetone, ethyl acetate, 2-propanol, 2-butanone, and mixture systems (DMSO + 2-propanol and DMF + 2-propanol) at a series of temperatures (283.15–323.15 K) is determined, and model correlation, solvent effect, and preferential solvation analysis are researched. The solubility of 5-FC is related to temperature, which decreases with decreasing temperature. For monosolvent systems, the mole solubility order is DMSO > DMF > 1-butanol > 1-propanol > 2-propanol > acetone > 2-butanone > 1,4-dioxane > acetonitrile > ethyl acetate. The solvent effect has been studied in monosolvents, hydrogen-bonding acceptor (HBA) interactions and nonspecific dipolarity/polarizability interactions favor dissolution, and solvent self-cohesiveness is not beneficial to dissolution. For two mixture systems, the mole solubility of 5-FC in DMSO + 2-propanol solvent systems is higher than that in DMF + 2-propanol solvent systems. A dimensionless parameter (δ) is defined to observe the deviation from ideality of mixed solvents whose values are all greater than zero. The equilibrium constant of the solvent exchange process (Kps) can be used to evaluate the preferential solvation of 5-FC. DMSO or DMF dissolves 5-FC in the local region around 5-FC preferentially. The equilibrium solubility data is correlated by four correlation models (modified Apelblat, λh, CNIBS/R-K, and Jouyban–Acree models). The greatest relative average deviation (RAD) and root-mean-square deviation (RMSD) values are 2.01% and 11.87 × 10–5 in pure solvent systems and 2.20% and 5.99 × 10–5 in mixture systems, respectively. These four models show excellent correlation with the experimental solubility data.
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NEW JOURNAL OF CHEMISTRY
·
2022
·Vol. 47
·期 3
·1328-1341
·
IF 3.925
Fan-Zhi Bu,Yue-Ming Yu,Yu Yu,Cui-Wei Yan,Zhi-Yong Wu,Yan-Tuan Li
The current work aims to take full advantage of the structural superiority and hepatoprotective effect of the nutrient trans-p-coumaric acid (TPCA) to decrease the solubility and dissolution rate of the antimycotic agent 5-fluorocytosine (FLCY) by using a co-crystallization strategy, thereby giving a novel understanding into conquering the dose-limiting hepatotoxicity induced by the quick and almost complete absorption of FLCY. To that end, FLCY–TPCA, as the first cocrystal of FLCY and phenolic acid (a nutrient of the hydroxycinnamic acid type), is orientationally self-assembled and fully characterized. The single crystal structure shows that TPCA molecules in the crystal lattice locate at the polar sites in situ of FLCY via robust hydrogen bond interaction, thus creating a vital planar construction (VPC) possessing hydrophobicity, which results in the simultaneous down-regulation for the cocrystal of solubility and dissolution rate versus the parent FLCY. The outcomes of the experiment are strongly supported by related theory research. Molecular electrostatic potential (MEP) calculation showed that the VPC polarity in the cocrystal is lower than that of free FLCY, which conforms with the reduction in polarity due to intensifying hydrogen-bond energy based on topology analysis with atoms in molecules (AIM) theory, hence conferring a conspicuous improvement in hydrophobicity on the cocrystal. Furthermore, the molecular planarity analysis based on Multiwfn's wave function calculation module confirms the convergence in planarity at a two-dimensional infinite level, which undoubtedly contributes to forming a tight three-dimensional supramolecular superposition landscape, corresponding with the coinstantaneous reinforcement of π–π stacking interaction evidenced by the reduced density gradient (RDG), and all these results further support the fact that the hydrophobicity of the FLCY–TPCA cocrystal is significantly enhanced. As a result, the current contribution exemplifies a feasible cocrystallization strategy using integrated experimental and systematic theoretical approaches to overcome the intractable toxicity issues of antifungal agents.
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CRYSTENGCOMM
·
2023
·Vol. 25
·期 13
·1951-1964
·
IF 3.1
Fan-Zhi Bu,Yue-Ming Yu,Lin-Lin Zhang,Cui-Wei Yan,Zhi-Yong Wu,Yan-Tuan Li
The goal of the present work is to elucidate the ability of protocatechuic acid (PCA) in downregulating the dissolubility property and gain an innovative insights into conquering adverse reactions of the antifungal drug 5-fluorocytosine (FYT) by a salification strategy. The strategy highlights the feature of adjacent 3,4-substituted phenolic groups on PCA molecule that establishes the helical morphology to attain the hydrophobic molecular salt by facilitating proton exchange reaction between PCA and FTY, thus decreasing FYT's dissolution capacity; moreover, it can also play to PCA's strengths with hepatoprotective effect and antifungal potential as a phenolic acid nutrient, all of which benefit in overcoming the adverse drug reactions caused by the fast and inappropriate absorption of FYT. Taking the strategy as a guideline, the first FTY's molecular salt, FTY–PCA, with hydrophobic characteristics has been successfully synthesized and thoroughly characterized by multiple analytical approaches. The single-crystal X-ray diffraction technology verifies that the newly obtained FTY–PCA consists of an unusual hydrophobic triple helix structure (THS) that is dexterously wound by three strands single helix structure (SHS) via robust hydrogen-bonding interplays and electrostatic forces, which endows the ability of concurrent downregulation of the solubility and dissolution rate, with the maximum reduction being, respectively, 31.23% and 60.49% relative to the parent drug FYT. The experimental outcomes are strongly confirmed by relevant theoretical studies. The molecular electrostatic potential confirms that the THS motif constructed by the SHS forms serves a crucial role in reducing the polarity of the molecular salt and complies with the abatement in polarity, attributable to the reinforced hydrogen-bonding energy as per the electron density difference as well as topology analysis of atoms in molecules, thereby clarifying the hydrophobic property of the molecular salt at theoretical levels. Thereby, the current contribution not only exemplifies the first hydrophobic molecular salt of FYT with a rare triple-helical structure, filling the gaps in the application of hydrophobic molecular salt in antifungal drugs, but also supplies some novel insights into the salinization strategy aiming at overcoming the adverse effects caused by the fast and almost entire absorption of some drugs by ameliorating the dissolubility behaviors.
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CHEMICAL ENGINEERING JOURNAL
·
2023
·
IF 15.1
Meng Wang,Yanwen Zhou,Zhaohui Wang
The critical shortage of antifungal drugs and increasingly emerged resistant fungi urgently call for the development of novel fungicidal agents with translational potential. Although nanodrugs compose a new antifungal arsenal, the fungicidal efficacy barely exceeds clinical molecules. In this study, a CuFeSe 2 -PVP nano-blade, is unexpectedly discovered with ultrapotent intrinsic fungicidal efficacy. This nanostructure is facilely fabricated by a specific aqueous precipitation method with the nucleation of tetragonal eskebornite CuFeSe 2 at PVP chains. The unique semiconductor CuFeSe 2 -PVP demonstrates superior antifungal activity than the commonly used small-molecule drugs and metal nanoparticles in both planktonic fungi and biofilm. Intriguingly, electron microscopy visualizes that the nano-blades cut fungal membranes with fungi surfaces inserted by the blades. Such a membrane-piercing effect results in the loss of important intracellular components, including nucleic acids , proteins, and potassium ions. Increased intracellular reactive oxygen species (ROS) is also observed. Encouragingly, in mice with subcutaneous fungal infection, the nanodrug achieves absolute fungi clearance, effectively alleviating inflammation and promoting collagen fiber recovery. Moreover, the excellent biocompatibility of CuFeSe 2 -PVP promises great potential for further translation. This study not only provides a novel fungicidal drug candidate, but also inspires the future design of anti-fungal nanomedicine .
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JOURNAL OF THERMAL ANALYSIS AND CALORIMETRY
·
2015
·Vol. 123
·期 3
·2485-2497
·
IF 2.042
Wang Xue-jie,You Jin-zong
The thermal decomposition of capecitabine (CAP) was measured with thermogravimetry, differential scanning calorimetry, and thermogravimetric analysis coupled with Fourier transform infrared spectroscopy. The IR spectra, high-performance liquid chromatography, and liquid chromatography–mass spectrometry of CAP and the residue of its thermal decomposition at various temperatures were determined. The molecular bond orders were calculated using an ab initio method from the GAMESS program of quantum chemistry. The mode of thermal decomposition for CAP was discussed. The kinetic parameters for thermal decomposition such as activation energy E
a and the pre-exponential factor A were obtained using the Ozawa method. The prospective lifetime of CAP was estimated using the Dakin equation. The results indicated that the thermal decomposition of CAP is a three-step process, and the first mass loss stage is to lose pentyl formate. The initial decomposition temperature in either nitrogen or air is 120 °C. For decomposition in nitrogen, the E
a and A for the initial thermal decomposition are 105.1 kJ mol −1 and 9.12 × 10 11 min −1 , respectively. For decomposition in air, the corresponding E
a and A are 105.1 kJ mol −1 and 9.55 × 10 11 min −1 , respectively. The CAP has poor thermal stability under routine temperature.
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高影响因子
JOURNAL OF ANALYTICAL AND APPLIED PYROLYSIS
·
2015
·
IF 3.564
Xue-Jie Wang,Jin-zong You,Feng Yu
The thermal decomposition of emtricitabine (FTC) was measured with thermogravimetry (TG), differential scanning calorimetry (DSC), and thermogravimetric analysis coupled with Fourier transform infrared spectroscopy (TG-FTIR). The infrared (IR) spectra, high performance liquid chromatography (HPLC), and liquid chromatography mass spectrometry (LC–MS) of FTC and the residues of its thermal decomposition at various temperatures were determined. The molecular bond orders were calculated with an ab initio method from the GAMESS program. The mechanism of thermal decomposition of FTC was discussed. The kinetic parameters of thermal decomposition such as activation energy E a and the pre-exponential factor A were obtained with the Ozawa method. The prospective lifetime of FTC was estimated with the Dakin equation. The results indicated that the thermal decomposition of FTC is a two-step process. In the thermal decomposition process, most of FTC decomposes directly to small molecules and insoluble substance due to the fracture of the N C bond of amide in the 5-fluorocytosine ring, a small amount of FTC decomposes to 5-fluorocytosine due to the fracture of the N -glycosidic bond, and a small amount of 5-fluorouracil and 2′,3′-dideoxy-5-fluoro-3′-thiauridine are generated due to the oxidation reaction. The initial decomposition temperature either nitrogen or air is 200 °C. For decomposition in nitrogen, the E a and A for the initial thermal decomposition are 142.4 kJ mol −1 and 2.09 × 10 13 min −1 , respectively. For decomposition in air, the corresponding E a and A are 140.7 kJ mol −1 and 1.62 × 10 13 min −1 , respectively. The thermal stability of FTC is very good under routine temperatures.
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Nature Communications
·
2025
·Vol. 16
·期 1
·1-18
·
IF 15.7
Li Wanqian,Whiteway Malcolm,Hang Sijin,Yu Jinhua,Lu Hui,Jiang Yuanying
Azole effectiveness against candidiasis can be compromised by Candida albicans resistance and tolerance, and unfortunately, few clinically useful compounds can enhance azole antifungal activities. We find that the amino acids V234, F235 and L238 of Erg11 are critical for its interaction with Ncp1, and the Ncp1-Erg11 association is important in azole response. Ellipticine and its analog phiKan 083 block this Erg11-Ncp1 interaction by targeting Ncp1, and boost antifungal effects of fluconazole in vitro and in vivo. A series of steps influencing this process—an initial elevation in reactive oxygen species, leading to protein oxidation and misfolding in the endoplasmic reticulum (ER) that causes ER stress. This stress leads to Ca 2+ release from the ER, mitochondrial Ca 2+ accumulation and dysfunction, increased ROS production, and apoptosis of C. albicans cells. Overall, disrupting the Erg11-Ncp1 interaction in C. albicans can serve as a useful approach to enhancing the antifungal properties of azoles.
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高影响因子
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