Synergic Effect of Phthalide Lactones and Fluconazole and Its New Analogues as a Factor Limiting the Use of Azole Drugs against Candidiasis

The resistance of Candida albicans and other pathogenic yeasts to azole antifungal drugs has increased rapidly in recent years and is a significant problem in clinical therapy. The current state of pharmacological knowledge precludes the withdrawal of azole drugs, as no other active substances have yet been developed that could effectively replace them. Therefore, one of the anti-yeast strategies may be therapies that can rely on the synergistic action of natural compounds and azoles, limiting the use of azole drugs against candidiasis. Synergy assays performed in vitro were used to assess drug interactions Fractional Inhibitory Concentration Index. The synergistic effect of fluconazole (1) and three synthetic lactones identical to those naturally occurring in celery plants—3-n-butylphthalide (2), 3-n-butylidenephthalide (3), 3-n-butyl-4,5,6,7-tetrahydrophthalide (4)—against Candida albicans ATCC 10231, C. albicans ATCC 2091, and C. guilliermondii KKP 3390 was compared with the performance of the individual compounds separately. MIC90 (the amount of fungistatic substance (in µg/mL) inhibiting yeast growth by 90%) was determined as 5.96–6.25 µg/mL for fluconazole (1) and 92–150 µg/mL for lactones 2–4. With the simultaneous administration of fluconazole (1) and one of the lactones 2–4, it was found that they act synergistically, and to achieve the same effect it is sufficient to use 0.58–6.73 µg/mL fluconazole (1) and 1.26–20.18 µg/mL of lactones 2–4. As fluconazole and phthalide lactones show synergy, 11 new fluconazole analogues with lower toxicity and lower inhibitory activity for CYP2C19, CYP1A2, and CYP2C9, were designed after in silico testing. The lipophilicity was also analyzed. A three-carbon alcohol with two rings was preserved. In all compounds 5–15, the 1,2,4-triazole rings were replaced with 1,2,3-triazole or tetrazole rings. The hydroxyl group was free or esterified with phenylacetic acid or thiophene-2-carboxylic acid chlorides or with adipic acid. In structures 11 and 12 the hydroxyl group was replaced with the fragment -CH2Cl or = CH2. Additionally, the difluorophenyl ring was replaced with unsubstituted phenyl. The structures of the obtained compounds were determined by 1H NMR, and 13C NMR spectroscopy. Molecular masses were established by GC-MS or elemental analysis. The MIC50 and MIC90 of all compounds 1–15 were determined against Candida albicans ATCC 10231, C. albicans ATCC 2091, AM 38/20, C. guilliermondii KKP 3390, and C. zeylanoides KKP 3528. The MIC50 values for the newly prepared compounds ranged from 38.45 to 260.81 µg/mL. The 90% inhibitory dose was at least twice as high. Large differences in the effect of fluconazole analogues 5–15 on individual strains were observed. A synergistic effect on three strains—Candida albicans ATCC 10231, C. albicans ATCC 2091, C. guilliermondii KKP 339—was observed. Fractional inhibitory concentrations FIC50 and FIC90 were tested for the most active lactone, 3-n-butylphthalide, and seven fluconazole analogues. The strongest synergistic effect was observed for the strain C. albicans ATCC 10231, FIC 0.04–0.48. The growth inhibitory amount of azole is from 25 to 55 µg/mL and from 3.13 to 25.3 µg/mL for 3-n-butylphthalide. Based on biological research, the influence of the structure on the fungistatic activity and the synergistic effect were determined

HS⇆LS Transition in Iron(II) Two-Dimensional Coordination Networks Containing Tris(tetrazol-1-ylmethyl)methane As Triconnected Building Block

Novel tripodal ligand 1,1′,1″-tris­(tetrazol-1-ylmethyl)­methane (<b>111tz</b>) and products of its reactions with perchlorate as well as with tetrafluoroborate salts of iron­(II) are presented. The isostructural complexes, [Fe­(<b>111tz</b>)₂]­(ClO₄)₂ and [Fe­(<b>111tz</b>)₂]­(BF₄)₂, were isolated as two-dimensional (2D) coordination networks revealing a honeycomb-like pattern with cages occupied by disordered anions. <b>111tz</b> molecules act as a tridentate ligand bridging three adjacent Fe­(II) ions, and the nitrogen N4 atom of six tetrazole rings (tz) is placed in octahedron vertices of FeN₆ chromophores. The complexes, crystallizing in the <i>P</i>3̅ space group, were characterized by variable-temperature single-crystal X-ray diffraction and variable-temperature magnetic susceptibility measurements. Variable-temperature magnetic susceptibility measurements show that both systems undergo abrupt and complete spin transition with <i>T</i>_1/2^↑ = <i>T</i>_1/2^↓ = 176 K for perchlorate and <i>T</i>_1/2^↑ = 193.8 and <i>T</i>_1/2^↓ = 192.8 K for the tetrafluoroborate analogue. Change of spin state in both complexes is accompanied by a thermochromic effect. The HS→LS transition in [Fe­(<b>111tz</b>)₂]­(ClO₄)₂ involves shortening of the Fe–N4 bond lengths from 2.171(2) Å (293 K) to 2.002(1) Å (100 K). In [Fe­(<b>111tz</b>)₂]­(BF₄)₂, lowering of temperature from 293 to 100 K is accompanied by shortening of the Fe–N4 distances from 2.179(2) to 1.987(2) Å, respectively. Perchlorate in [Fe­(<b>111tz</b>)₂]­(ClO₄)₂ or tetrafluoroborate anions in [Fe­(<b>111tz</b>)₂]­(BF₄)₂ are engaged in the formation of intermolecular contacts within as well as with the neighboring 2D layer

HS⇆LS Transition in Iron(II) Two-Dimensional Coordination Networks Containing Tris(tetrazol-1-ylmethyl)methane As Triconnected Building Block

Novel tripodal ligand 1,1′,1″-tris­(tetrazol-1-ylmethyl)­methane (<b>111tz</b>) and products of its reactions with perchlorate as well as with tetrafluoroborate salts of iron­(II) are presented. The isostructural complexes, [Fe­(<b>111tz</b>)₂]­(ClO₄)₂ and [Fe­(<b>111tz</b>)₂]­(BF₄)₂, were isolated as two-dimensional (2D) coordination networks revealing a honeycomb-like pattern with cages occupied by disordered anions. <b>111tz</b> molecules act as a tridentate ligand bridging three adjacent Fe­(II) ions, and the nitrogen N4 atom of six tetrazole rings (tz) is placed in octahedron vertices of FeN₆ chromophores. The complexes, crystallizing in the <i>P</i>3̅ space group, were characterized by variable-temperature single-crystal X-ray diffraction and variable-temperature magnetic susceptibility measurements. Variable-temperature magnetic susceptibility measurements show that both systems undergo abrupt and complete spin transition with <i>T</i>_1/2^↑ = <i>T</i>_1/2^↓ = 176 K for perchlorate and <i>T</i>_1/2^↑ = 193.8 and <i>T</i>_1/2^↓ = 192.8 K for the tetrafluoroborate analogue. Change of spin state in both complexes is accompanied by a thermochromic effect. The HS→LS transition in [Fe­(<b>111tz</b>)₂]­(ClO₄)₂ involves shortening of the Fe–N4 bond lengths from 2.171(2) Å (293 K) to 2.002(1) Å (100 K). In [Fe­(<b>111tz</b>)₂]­(BF₄)₂, lowering of temperature from 293 to 100 K is accompanied by shortening of the Fe–N4 distances from 2.179(2) to 1.987(2) Å, respectively. Perchlorate in [Fe­(<b>111tz</b>)₂]­(ClO₄)₂ or tetrafluoroborate anions in [Fe­(<b>111tz</b>)₂]­(BF₄)₂ are engaged in the formation of intermolecular contacts within as well as with the neighboring 2D layer

Does the Structural Preorganization Contribute to the “Two-Way” Spin Crossover in 1,1′-Di(tetrazol-1-ylo)methane-Based Fe(II) Coordination Polymer Containing Conformationally Labile Adiponitrile Coligand?

The reaction between 1,1′-di(tetrazol-1-ylo)methane (1ditz) and iron(II) tetrafluoroborate carried out in the presence of adiponitrile (ADN) afforded the coordination compound [Fe2(μ-1ditz)4(μ-ADN)(ADN)2](BF4)4·2ADN. The 1ditz molecules bridge the Fe(II) ions in two directions, resulting in a polymeric layer, whereas adiponitrile molecules join 1ditz-based units, extending the structure into the three-dimensional network. One of the two axial coordination sites of Fe(II) is occupied by monodentately coordinating adiponitrile. Dinitrile can also act as guest molecules occupying the area between the 1ditz-based layers. Cooling from room temperature triggers the structural phase transitions HS(P1; a, b, c) → HS(P2; 2a, b, c) → LS(P3; a, b, c) (P, phase; HS, high spin; and LS, low spin) associated with the conformational changes of the adiponitrile molecules. In the cooling mode, T1/2↓ = 160 K, while in the heating mode T1/2↑ is equal to 185 K. Depending on the further path of change of the temperature, it is possible (i) to perform the same cooling/heating cycle (T1/2↓ = 160 K; T1/2↑ = 185 K) after the sample is reheated above 240 K or (ii) to execute the cooling with T1/2↓ = 167 K after the heating is stopped at 190 K, where the phase with superlattice (P2) does not appear. Both ways are reversible, and they are managed by conformational changes of the adiponitrile molecules

Physical and Structural Characterization of Imidazolium-Based Organic–Inorganic Hybrid: (C₃N₂H₅)₂[CoCl₄]

(C₃N₂H₅)₂[CoCl₄] (ICC) was characterized in a wide temperature range by the single-crystal X-ray diffraction method. Differential scanning calorimetry revealed two structural phase transitions: continuous at 245.5 K (from phase I to II) and a discontinuous one at 234/237 K (cooling/heating) (II → III). ICC adopts monoclinic space groups <i>C</i>2/<i>c</i> and <i>P</i>2₁/<i>c</i> in phase (I) and (III), respectively. The intermediate phase (II) appears to be incommensurately modulated. Dynamic properties of polycrystalline ICC were studied by means of dielectric spectroscopy and proton magnetic resonance (¹H NMR). The presence of a low frequency dielectric relaxation process in phase III reflects libration motion of the imidazolium cations. The temperature dependence of the ¹H spin–lattice relaxation time indicated two motional processes with similar activation energies that are by about an order of magnitude smaller than the activation energy obtained from dielectric studies. There are no abrupt changes in the ¹H relaxation time at the phase transitions indicating that the dynamics of the imidazolium rings gradually varies with temperature; that is, it does not change suddenly at the phase transition. Negative values of the Weiss constant and the intermolecular exchange parameter were obtained, confirming the presence of a weak antiferromagnetic interaction between the nearest cobalt centers. Moreover, the magnitude of zero field splitting was determined. The AC susceptibility measurements show that a slow magnetic relaxation is induced by small external magnetic field