Antimicrobial activity of clove oil and its potential in the treatment of vaginal candidiasis

In the present study, we evaluated antimicrobial activity of clove oil against a range of fungal pathogens including that responsible for urogenital infection. Clove oil was found to possess strong antifungal activity against opportunistic fungal pathogens such as Candida albicans, Cryptococcus neoformans and Aspergillus fumigatus, etc. The oil was found to be extremely successful in the treatment of experimental murine vaginitis in model animals. On evaluating various formulations, topical administration of the liposomized clove oil was found to be most effective against treatment of vaginal candidiasis.     

Structure-based design, synthesis, and antifungal activity of new triazole derivatives

A series of new antifungal triazole derivatives with phenylacetamide side chain were rational designed and synthesized on the basis of the structural information of lanosterol 14‐demethylase (CYP51). In vitro antifungal activity assay indicated that several compounds showed higher activity than fluconazole. Especially, compound 8h showed excellent inhibitory activity against Candida albicans and Cryptococcus neoformans (MIC = 0.0156 μg/mL), suggesting that it is a promising lead for the development of novel antifungal agents. The binding mode of compound 8h was investigated by flexible molecular docking. It interacted with CACYP51 through hydrophobic and van der Waals interactions.     

In vitro andin vivo antifungal activities of 6-[(N-4-bromophenyl) amino]-7-chloro-5,8-quinolinediones

Antifungal activities of 6-[(N-4-bromophenyl)amino]-7-chloro-5,8-quinolinedione (RCK7) were tested. The MIC values of RCK7 were determined for antifungal suceptibility,in vitro againstAspergillus niger, Cryptococcus neoformans andTrichophyton mentagrophyte by standard agar streak method.In vitro, RCK7 showed more potent antifungal activity than fluconazole and ketoconazole. Also, RCK7 was tested forin vivo antifungal activity in the treatment of systemic infection withCandida albicans in normal mice. The therapeutic potential of RCK7 had been assessed by evaluating their survival rate against systemic infections compared with that of ketoconazole. ED₅₀ of intraperitoneally administered RCK7 was 2.05±0.30 mg/kg but that of ketoconazole was 8.00±0.73 mg/kg, respectively. When RCK7 was administered intravenously at the ED₅₀ (2.05 mg/kg), the colony counts ofCandida albicans in the liver after 7 days and 14 days were reduced as likely as ketoconazole at the ED₅₀ (8.00 mg/kg), and the better survival rates than ketoconazole’s were achieved after 14 days. The results suggest that RCK7 may be a potent antifungal agent.     

Immunomodulator tuftsin increases the susceptibility of Cryptococcus neoformans to liposomal amphotericin B in immunocompetent BALB/c mice

The co-administration of immunomodulators and antibiotics has been proved very successful for treatment of opportunistic infectious diseases. In the present study, we evaluated the combination of liposomal amphotericin B (lip-Amp B) and immunomodulator tuftsin to cure Cryptococcus neoformans infection in BALB/c mice. Mice infected with C. neoformans were treated with Amp B deoxycholate and tuftsin free or tuftsin-loaded Amp B liposomes. The results of the present study demonstrated higher efficacy of tuftsin-loaded Amp B liposomes against experimental murine cryptococcosis, in terms of enhanced survival rate and reduced fungal burden in organs (lungs and brain) of the treated mice. Interestingly, pre-treatment of mice with liposomal tuftsin before challenging them with the C. neoformans infection resulted in 100% survival of the treated animals followed by treatment with lip-Amp B. Immunomodulator-based therapy seems likely to be more beneficial for treatment of fungal infectious diseases.     

Chloroquine Blood Levels After Administration of the Liposome-Encapsulated Drug in Relation to Therapy of Murine Malaria

In a previous report (P. A. M. Peeters, C. W. E. M. Huiskamp, W. M. C. Eling, and D. J. A. Crommelin. Parasitology, 1989, in press) an increase in therapeutic and prophylactic potential was found when chloroquine (CQ) was encapsulated in fluid-state liposomes (lipCQ) and tested in Plasmodium berghei-infected mice in comparison to intraperitoneal (i.p.) administration of the free drug. In this study, the same model was used to demonstrate that encapsulation of CQ into gel-state liposomes further increased the preventive and therapeutic effect considerably. CQ determinations in whole blood, plasma, and red blood cells (RBC) after i.p. administration of fluid- or gel-state lipCQ revealed a prolonged availability of the drug in comparison to administration of free CQ. The CQ concentrations were related to the CQ levels needed for prevention or therapy of Plasmodium berghei infections in mice.     

Enhanced Immunostimulant Activity and Protective Effect of a Synthetic Lipopeptide after Liposomization Against Plasmodium berghei Infection in Mice

The immunostimulant activity of non-pyrogenic, sugar-free immunomodulator lipopeptide, Ala-D-Glu(Gly-Lys-CO. C₁₁H₂₃)-NH₂ (comp. no 84/201), and its iiposomized formulation has been studied. Liposomization of this lipopeptide significantly enhanced its antigen specific as well as nonspecific immune responses, as compared to the free lipopeptide. The liposomized formulation of lipopeptide significantly stimulated both the antibody and delayed-type hypersensitivity responses in Balb/c mice, and also enhanced nonspecifically the macrophage migration index, phagocytic activity and incorporation of ¹⁴C glucosamine in peritoneal macrophages of the mice that received pretreatment with this preparation. Further, the mice that received pretreatment with the liposomized preparation strongly resisted lethal P. berghei infection and consequently survived for longer period of times. These results indicate that liposomization of the compound no 84/201 significantly improves its ability to enhance not only antigen-specific immune response but also the nonspesific host's resistance against infections.     

Allylamine Type Xanthone Antimycotics

A number of xanthone derivatives bearing the basic chain of naftifine and butenafine antimycotics in 1, 2, 3, and 4 nuclear positions are described. The in vitro antifungal activity against representative strains of molds and yeasts is reported. Only butenafine xanthone analogues show significant activity against, Cryptococcus neoformans, in particular the regioisomer 4d (1.5 μg/ml).     

吩嗪类衍生物的抗真菌活性研究

目的 研究吩嗪类衍生物的抗真菌活性。方法 利用微量液基稀释法考察吩嗪类衍生物的体外抗真菌活性;利用棋盘式微量稀释法检测吩嗪类衍生物与氟康唑合用对常见临床耐药菌的抗真菌活性;在菌丝诱导条件下考察吩嗪衍生物对白念珠菌菌丝形成的抑制效果。结果 吩嗪类衍生物单用对临床常见条件致病真菌白念珠菌没有明显抗真菌活性;吩嗪衍生物-17与氟康唑合用有显著抗白念珠菌活性;吩嗪衍生物-17与氟康唑合用可以明显抑制白念珠菌菌丝生长。结论 筛选获得了与氟康唑合用具有抗真菌活性的吩嗪类衍生物-17,为抗真菌药物研发和克服真菌耐药提供了新思路。     

Efficient Synthesis and Biological Evaluation of a Novel Series of 1,5‐Benzodiazepine Derivatives as Potential Antimicrobial Agents

A series of novel 1,5‐benzodiazepine derivatives were rationally designed and synthesized following the principle of the superposition of bioactive substructures by the combination of 1,5‐benzodiazepine, pyridine (phenyl), and an ester group. The structures of the target compounds were determined by ¹H NMR, ¹³C NMR, MS, IR, and elemental analysis. All the synthesized compounds were evaluated for their antimicrobial activities in vitro against the fungi C. neoformans, C. neoformans clinical isolates (ATCC 32264), C. albicans (ATCC 10231), Gram‐negative bacterium E. coli (ATCC 44752), and Gram‐positive bacterium S. aureus (ATCC 25923). The results of the bioactive assay demonstrated that most of the tested compounds exhibited variable inhibitory effects on the growth of the tested microorganisms. All the active compounds showed better antifungal activity than antibacterial activity. Notably, compound 2b displayed the highest activity (MIC = 30 μg/mL) against C. neoformans and (MIC = 31 μg/mL) against C. neoformans clinical isolates. In addition, compound 2a also showed excellent activity against C. neoformans and C. neoformans clinical isolates with minimum inhibitory concentration of 35 and 36 μg/mL, respectively. Compounds 2a and 2b were further studied by evaluating their cytotoxicities, and the results showed that they have relatively low level cytotoxicity for BV2 and 293T cell. Preliminary structure‐activity relationship study on three diverse sets (C‐2, C‐3, and C‐8 positions) of 1,5‐benzodiazepines was performed. The results revealed that the presence of a ‐CH₃ group at the C‐8 position had a positive effect on the inhibitory activity of these compounds. Additionally, the 2‐pyridyl group at the C‐2 position may be a pharmacophore and ‐COOC₂H₅ at C‐3 position is the best substituent for the maintenance of antimicrobial activities.     

Design and Synthesis of a New Class of 4‐Aminoquinolinyl‐ and 9‐Anilinoacridinyl Schiff Base Hydrazones as Potent Antimalarial Agents

A series of novel 4‐aminoquinolinyl and 9‐anilinoacridinyl Schiff base hydrazones have been synthesized and evaluated for their antimalarial activity. All compounds were evaluated in vitro for their antimalarial activity against chloroquine‐sensitive strain 3D7 and the chloroquine‐resistant K1 strain of Plasmodium falciparum and for cytotoxicity toward Vero cells. Compounds 17 , 20 , and 21 displayed good activity against the 3D7 strain with IC₅₀ values ranging from 19.69 to 25.38 nm . Moreover, compounds 16 , 17 , 21 , 24 , 32, and 33 exhibited excellent activities (21.64–54.26 nm ) against K1 strain and several compounds displayed β‐hematin inhibitory activity, suggesting that they act on the heme crystallization process such as CQ. Compounds were also found to be non‐toxic with good selectivity index.     

Synergic effect of combination of glycyrol and fluconazole against experimental cutaneous candidiasis due to <Emphasis Type="Italic">Candida albicans</Emphasis>

In this study, we investigated the anti-fungal activity of glycyrol, a coumarine isolated from licorice (Glycyrrhizae Radix), in a murine model of cutaneous candidiasis caused by Candida albicans. Compared to the infected sites, located on the mice’s back, of the untreated control mice, the infected sites treated with glycyrol had reduced CFU (colony forming unit) values up to 60 and 85.5 % at 20 and 40 μg/mouse of glycyrol, respectively (P < 0.01). The antifungal activity of glycyrol was synergistically increased when glycyrol (10 μg/mouse) was combined with fluconazole (10 μg/mouse), demonstrating that the combination therapy is approximately 4 times more effective than fluconazole alone at 20 μg/mouse (P < 0.01). Additionally, the combination activity was 1.65 times greater than the antifungal activity of fluconazole alone at 40 μg/mouse (P < 0.05). In seeking glycyrol’s antifungal mechanism, we determined that glycyrol inhibited hyphal induction and cell wall adherence of C. albicans. Thus, it is very likely that, by damaging the cell wall, glycyrol helps fluconazole invade C. albicans more readily and attack fluconazole’s target in the fungus membrane. In summary, our data indicate that glycyrol may contribute to the development of a novel agent that possesses antifungal activity against cutaneous candidiasis.     

新型三唑类化合物的设计、合成和抗真菌活性研究

目的 基于唑类药物合理优化的分子设计模型,设计新型三唑类化合物,并测试其对常见致病真菌的抑制活性。方法 采用环氧化物开环法合成目标化合物,通过¹H NMR和MS确证其化学结构,经微量液基稀释法测试体外抗真菌活性。结果 合成了2个含三唑酮侧链的新型唑类化合物,它们均显示了优秀的广谱抗真菌活性。结论 目标化合物对白色念珠菌的活性优于对照药氟康唑和酮康唑,值得进一步深入构效关系研究。     

Synthesis, molecular docking, and biological evaluation of novel triazole derivatives as antifungal agents

Twenty-eight novel triazole derivatives (compounds 1a-v, 2a-f) have been synthesized for structure–activity relationship studies as antifungal agents. The compounds were designed on the basis of the structure of fluconazole and molecular modeling of the active site of the cytochrome P450 14α-demethylase (CYP51). All of them are reported for the first time. Their chemical structures are characterized by ¹H NMR, ¹³C NMR, LC-MS, and elemental analysis. The antifungal activities have been evaluated in vitro by measuring the minimal inhibitory concentrations (MICs). Compounds 1a-v exhibited higher activity against nearly all fungi tested except Aspergillus fumigatus (A. fum) than fluconazole (FCZ). The computational molecular docking experiments indicated that the inhibition of CYP51 involves a coordination bond with iron of the heme group, a hydrophilic H-bonding region, a hydrophobic region, and a narrow hydrophobic binding cleft.     

Reversal of fluconazole resistance induced by a synergistic effect with Acca sellowiana in Candida glabrata strains

Context: The increased incidence of non-albicans Candida (NAC) resistant to fluconazole (FLZ) makes it necessary to use new therapeutic alternatives. Acca sellowiana (O.berg) Burret (Myrtaceae) is a guava with several proven biological activities. The interaction with fluconazole can be a feasible alternative to overcome this resistance.

Objective: This study evaluates the in vitro antifungal activity of fractions obtained from the lyophilized aqueous extract of the leaves of A. sellowiana against resistant strains of NAC.

Materials and methods: The antifungal activity of the fractions was evaluated at 500?μg/mL by microdilution method. Checkerboard assay was performed to determine the effect of the combination of the F2 fraction and antifungal at concentrations: MIC/4, MIC/2, MIC, MIC?×?2 and MIC?×?4.

Results: Candida glabrata showed the lowest MIC values (500–3.90?μg/mL) and the F2 active fraction was the most effective. The association of F2 with FLZ showed a strong synergistic effect (FICI?≤?0.5) against 100% of C. glabrata resistant isolates. Moreover, the F2 active fraction has demonstrated that probably acts in the cell wall of these yeasts. There was no observed acute dermal toxicity of lyophilized aqueous extract of leaves of A. sellowiana on pig ear skin cells.

Discussion and conclusion: The interaction between substances present in the F2 active fraction is possibly responsible for the antifungal activity presented by this fraction. This study is unprecedented and suggests that the combination of F2 active fraction and FLZ might be used as an alternative treatment for mucocutaneus infections caused by C. glabrata resistant.     

Investigation of the antifungal activity of carvacrol against strains of Cryptococcus neoformans

Background: Cryptococcus neoformans is the etiologic agent of opportunistic systemic fungal infection cryptococcosis, which affects individuals with compromised immune systems. Thus, natural products research has become important, since monoterpenes such as carvacrol, a promising molecule in the search antifungal agents, have shown significant biological activity.

Objective: The study aimed to investigate the antifungal activity and mode of action of carvacrol against strains of C. neoformans.

Methods: The minimum inhibitory concentration (MIC) was determined by microdilution method. Minimum fungicidal concentration (MFC) was performed by seeding technique on solid media. Studying the mode of action was performed using broth microdilution.

Results: The MIC ranged from 25 to 81?μg/mL and the MFC ranged from 25 to 102?μg/mL. Carvacrol bonded to exogenous ergosterol and cholesterol.

Discussion: The results suggest that carvacrol has antifungal activity against C. neoformans and its mode of action is related to fungal membrane instability.

Conclusions: The phytoconstituent carvacrol may eventually become a drug; however, further studies are needed to elucidate its mechanism.     

Fluconazole,caspofungin, voriconazole in combination with amphotericin B

Combined antifungal therapy has been suggested to enhance the efficacy and reduce the toxicity of antifungal agents. The aim of the study was to investigate the in vitro synergistic activity of caspofungin, voriconazole, and fluconazole with amphotericin B against ten isolates of Candida parapsilosis and Candida albicans strains which were resistant to azoles or amphotericin B. Three different antifungal combinations (amphotericin B [AP] — caspofungin [CS], amphotericin B — fluconazole [FL], and AP — voriconazole [VO]) were evaluated for in vitro synergistic effect by the microdilution checkerboard and E-test methods. For the majority of strains, the combination test showed indifferent activity. Via the E-test method, synergistic activity was seen in 3 strains in response to AP-CS combination treatment and in one strain after administration of AP-FL; however, no synergy was observed in response to combination treatment with P-VO. Antagonistic activity was the result in 1 strain treated with AP-CS as well as in 6 strains treated with AP-FL and AP-VO combinations. Via the microdilution test, no synergistic activity was seen after treatment with all 3 combinations. Antagonistic activity was the result in 2 strains with AP-CS, in 6 strains with AP-VO and in 5 strains with AP-FL combinations. Agreement between the checkerboard and E-test methods was observed to be approximately 72%. These combinations may be used in the case of antifungal resistance.     

Ascorbic acid decreases the antifungal effect of fluconazole in the treatment of candidiasis

• 1 The aim of the present study was to investigate the effects of ascorbic acid (AA) on the antifungal activity of fluconazole (FCZ) in a systemic murine candidiasis model as well as in vitro.
• 2 The murine model was established by infusion of Candida albicans via the tail vein. Control mice received no further treatment. Other groups of mice were injected with FCZ (0.5 mg/kg, i.p.) and then treated or not with 50 or 500 mg/kg AA intragastrically (i.g.) or i.p. In all groups, FCZ was administered i.p. 2 h after fungal inoculation, whereas AA was administered 6 h after fungal inoculation. Survival rate, kidney fungal burden and renal pathological changes were evaluated.
• 3 The in vitro effects of AA (5, 1 and 0.2 mmol/L) on the growth of various Candida strains in the presence of FCZ (0.125–64 µg/mL) were also investigated. The in vitro effects of two anti‐oxidants, namely N‐acetylcysteine (NAC; 5, 1 and 0.2 mmol/L) and reduced glutathione (GSH; 5, 1 and 0.2 mmol/L), on FCZ activity were evaluated to determine the mechanism of action of AA.
• 4 Intragastric administration of AA (50 or 500 mg/kg) significantly decreased the antifungal effect of 0.5 mg/kg FCZ. Although i.p. administration of AA (50 or 500 mg/kg) had no significant effect on the survival of mice, it dose‐dependently inhibited the activity of FCZ, with significant inhibition observed with 500 mg/kg AA.
• 5 In vitro, AA decreased the activity of FCZ against various Candida strains. Both NAC and GSH dose‐dependently decreased the activity of FCZ.
• 6 The results of the present study indicate that AA inhibits the antifungal activity of FCZ, suggesting that the two should not be used together clinically for the treatment of candidiasis.

     

Antifungal activity of Allamanda polyantha seed extract and its iridoids promote morphological alterations in Cryptococcus spp.

Cryptococcosis, caused by Cryptococcus spp., is an invasive fungal infection of the central nervous system, associated with high mortality, affecting mainly immunocompromised patients. Due to the development of resistance to the current therapy, there is an urgent need for less toxic and more effective antifungal agents. In this study, we describe the antifungal activity against Cryptococcus spp. of an aqueous seed extract from Allamanda polyantha (ASEAP) and two iridoids, plumieride and plumieridine, isolated from this extract with an antifungal activity. The capsule formation and the morphological alterations were evaluated using fluorescent microscopy. The cytotoxic activity was also investigated. The minimal inhibitory concentration (MIC) values of ASEAP for Cryptococcus gattii were 70 and 36 µg/ml (for the R265 and R272 strains, respectively) and 563 µg/ml for Cryptococcus neoformans H99. ASEAP inhibited C. neoformans H99 capsule formation, an important virulence factor, and decreased the cell body size for both the C. gattii strains. H99 cells also presented morphological alterations, with defects in bud detachment and nuclear fragmentation. Plumieride and plumieridine presented higher MIC values than ASEAP, indicating that other compounds might contribute to antifungal activity and/or that combination of the compounds results in a higher antifungal activity.     

Novel Carboline Derivatives as Potent Antifungal Lead Compounds: Design,Synthesis, and Biological Evaluation

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Discovery of 5-Nitro-6-thiocyanatopyrimidines as Inhibitors of Cryptococcus neoformans and Cryptococcus gattii

Opportunistic infections from pathogenic fungi present a major challenge to healthcare because of a very limited arsenal of antifungal drugs, an increasing population of immunosuppressed patients, and increased prevalence of resistant clinical strains due to overuse of the few available antifungals. Cryptococcal meningitis is a life-threatening opportunistic fungal infection caused by one of two species in the Cryptococcus genus, Cryptococcus neoformans and Cryptococcus gattii. Eighty percent of cryptococcosis diseases are caused by C. neoformans that is endemic in the environment. The standard of care is limited to old antifungals, and under a high standard of care, mortality remains between 10 and 30%. We have identified a series of 5-nitro-6-thiocyanatopyrimidine antifungal drug candidates using in vitro and computational machine learning approaches. These compounds can inhibit C. neoformans growth at submicromolar levels, are effective against fluconazole-resistant C. neoformans and a clinical strain of C. gattii, and are not antagonistic with currently approved antifungals.