Synthesis and evaluation of thiophene-based guanylhydrazones (iminoguanidines) efficient against panel of voriconazole-resistant fungal isolates

A series of new thiophene-based guanylhydrazones (iminoguanidines) were synthesized in high yields using a straightforward two-step procedure. The antifungal activity of compounds was evaluated against a wide range of medicaly important fungal strains including yeasts, molds, and dermatophytes in comparison to clinically used drug voriconazole. Cytotoxic properties of compounds were also determined using human lung fibroblast cell line and hemolysis assay. All guanylhydrazones showed significant activity against broad spectrum of clinically important species of Candida spp., Aspergillus fumigatus, Fusarium oxysporum, Microsporum canis and Trichophyton mentagrophytes, which was in some cases comparable or better than activity of voriconazole. More importantly, compounds 10, 11, 13, 14, 18 and 21 exhibited excellent activity against voriconazole-resistant Candida albicans CA5 with very low minimal inhibitory concentration (MIC) values <2 μg mL⁻¹. Derivative 14, bearing bromine on the phenyl ring, was the most effective compound with MICs ranging from 0.25 to 6.25 μg mL⁻¹. However, bis-guanylhydrazone 18 showed better selectivity in terms of therapeutic index values. In vivo embryotoxicity on zebrafish (Danio rerio) showed improved toxicity profile of 11, 14 and 18 in comparison to that of voriconazole. Most guanylhydrazones also inhibited C. albicans yeast to hyphal transition, essential for its biofilm formation, while 11 and 18 were able to disperse preformed Candida biofilms. All guanylhydrazones showed the equal potential to interact with genomic DNA of C. albicans in vitro, thus indicating a possible mechanism of their action, as well as possible mechanism of observed cytotoxic effects. Tested compounds did not have significant hemolytic effect and caused low liposome leakage, which excluded the cell membrane as a primary target. On the basis of computational docking experiments using both human and cytochrome P450 from Candida it was concluded that the most active guanylhydrazones had minimal structural prerequisites to interact with the cytochrome P450 14α-demethylase (CYP51). Promising guanylhydrazone derivatives also showed satisfactory pharmacokinetic profile based on molecular calculations.     

Novel potentially antifungal hybrids of 5-flucytosine and fluconazole: Design,synthesis and bioactive evaluation

A series of novel potentially antifungal hybrids of 5-flucytosine and fluconazole were designed, synthesized and characterized by ¹H NMR, ¹³C NMR, IR and HRMS spectra. Bioactive assay manifested that some prepared compounds showed moderate to good antifungal activities in comparison with fluconazole and 5-flucytosine. Remarkably, the 3,4-dichlorobenzyl hybrid 7h could inhibit the growth of C. albicans ATCC 90023 and clinical resistant strain C. albicans with MIC values of 0.008 and 0.02?mM, respectively. The active molecule 7h could not only rapidly kill C. albicans but also efficiently permeate membrane of C. albicans. Molecular docking study revealed that compound 7h could interact with the active site of CACYP51 through hydrogen bond. Quantum chemical studies were also performed to explain the high antifungal activity. Further preliminary mechanism research suggested that molecule 7h could intercalate into calf thymus DNA to form a steady supramolecular complex, which might block DNA replication to exert the powerful bioactivities.     

Antimicrobial,anticoagulant, and cytotoxic evaluation of multidrug resistance of new 1,4-dihydropyridine derivatives

A new series of 1,4-dihydropyridine derivatives (2a–h, 3a–e, and 4a–e) were systematically designed and synthesized via ultrasound irradiation methods with easy work-up and good yields. Compounds structures were confirmed by IR, ¹H NMR, ¹³C NMR, and mass spectra. The synthesized compounds were screened for both antimicrobial and anticoagulant activities. Compound 2e (MIC: 0.25?μg/mL) was highly active against Escherichia coli and compound 2c (MIC: 0.5?μg/mL) was also highly active against Pseudomonas aeruginosa compared with ciprofloxacin. (MIC: 1?μg/mL) The antifungal activity of 2c (MIC: 0.5?μg/mL) against Candida albicans was high relative to that of clotrimazole (MIC: 1?μg/mL). Anticoagulant activity was determined by activated partial thromboplastin time (APTT) and prothrombin time (PT) coagulation assays. Compound 4-(4-hydroxyphenyl)-2,6-dimethyl-N³,N⁵-bis(5-phenyl-1,3,4-thiadiazol-2-yl)-1,4-dihydropyridine-3,5-dicarboxamide 3d (>1000?s in APTT assays) was highly active in anticoagulant screening compared with the reference of heparin.Cytotoxicity was evaluated using HepG2 (liver), HeLa (cervical), and MCF-7 (breast) cancer cell lines, with high toxicities observed for 2c (GI₅₀?=?0.02?μm) against HeLa cell line and 2e (GI₅₀?=?0.03?μm) equipotant against MCF-7 cell line. Therefore, the compounds 2e, 2c and 3d can serve as lead molecules for the development of new classes of antimicrobial and anticoagulant agent.     

Synthesis and anti-Candidal activity of N-(4-aryl/cyclohexyl)-2-(pyridine-4-yl carbonyl) hydrazinecarbothioamide

Eighteen N-(4-aryl/cyclohexyl)-2-(pyridine-4-yl carbonyl) hydrazinecarbothioamide derivatives were synthesized, evaluated against ten clinical isolates of Candida spp. and compared with itraconazole. Introduction of p-chloro (2c), p-iodo (2q), m-chloro (2l) and o-nitro (2r) substitution at phenyl ring of thiosemicarbazide enhanced the anti-Candida activity. Compound (2c) bearing p-cholorophenyl ring was found to be the most effective against Candida albicans ATCC 66027, Candida spp. 12810 (blood) and Candida spp. 178 (HVS) with MIC value of 0.09–0.78 μg/mL, whereas itraconazole exhibits the inhibitory activity with MIC value of 0.04–1.56 μg/mL against all tested strains. There is a correlation between anti-Candidal activity and p-chloro substitution at phenyl ring of thiosemicarbazide. All synthesized compounds were investigated for their potential cytotoxicity against non cancer cell line MCF-10A. The active compounds 2c, 2r and 2a were further investigated for their cytotoxic effects on three cancer cell lines; HT1080 (skin), HepG2 (liver) and A549 (lung). The active compounds showed minimal cytotoxic activity against non cancer cell line and all three cancer cell lines. Moreover, compound 2c displaying better activity against C. albicans ATCC66027 and Candida spp. [blood] compared to reference drug (itraconazole), represents a good lead for the development of newer, potent and broad spectrum anti-Candidal agents.     

Efficiency of newly prepared thiazole derivatives against some cutaneous fungi

A series of fourteen novel synthesized arylazothiazole and arylhydrazothiazole derivatives were tested for their antifungal activity and structure-activity relationship. The activity of the compounds depends mainly on the side chains of the nucleus compound. The antifungal activity was more significant when both side chains are aromatic?>?one aromatic and one aliphatic and substituted aromatic with CH₃ or OCH₃?>?non-substituted?>?substituted aromatic with chloro- or nitro-groups. Thiazole derivatives 7a, 7c, 7e, 7f, 7?g, 7i, 7?m, and 11a showed the most effective as antifungal compounds and were comparable with fluconazole as antifungal reference drug when investigated against Candida albicans, Microsporum gypseum and Trichophyton mentagrophytes. The minimum inhibitory concentration (MIC) reached 2?µg/mL in the case of C. albicans for compounds 7a, 7b, 7c and 11a and measured 4?µg/mL in the case of M. gypseum and T. mentagrophytes for the same compounds. The minimum fungicidal concentration (MFC) for the same compounds was 4?µg/mL for C. albicans and ranged from 8 to 32?µg/mL for the other two fungi. The results revealed that compounds 7c and 11a were the most antifungal compounds against the test fungi regarding keratinase activity and ergosterol biosynthesis. The in vivo efficacy of synthesized thiazoles 7c and 11a applied at their respective MFC was more effective in the treatment of skin infection of guinea pigs previously inoculated with the test fungi as compared with fluconazole. The Molecular Operating Environment (MOE) software was used to analyze the docking poses and binding energies of compound 11a and keratinase. The computational studies supported the biological activity results.     

Antifungal activity of magnoflorine against <Emphasis Type="Italic">Candida</Emphasis> strains

Candida albicans is a major invasive pathogen, and the development of strains resistant to conventional antifungal agents has been reported in recent years. We evaluated the antifungal activity of 44 compounds against Candida strains. Magnoflorine showed the highest growth inhibitory activity of the tested Candida strains, with a minimum inhibitory concentration (MIC) of 50 μg/mL based on microdilution antifungal susceptibility testing. Disk diffusion assay confirmed the antifungal activity of magnoflorine and revealed that this activity was stable over 3 days compared to those of berberine and cinnamaldehyde. Cytotoxicity testing showed that magnoflorine could potentially be used in a clinical setting because it didn’t have any toxicity to HaCaT cells even in 200 μg/mL of treatment. Magnoflorine at 50 μg/mL inhibited 55.91?±?7.17% of alpha-glucosidase activity which is required for normal cell wall composition and virulence of Candida albicans. Magnoflorine also reduced the formation of C. albicans’ biofilm. Combined treatment with magnoflorine and miconazole decreased the amount of miconazole required to kill various Candida albicans. Therefore, magnoflorine is a good candidate lead compound for novel antifungal agents.     

New potent antifungal triazole alcohols containing N-benzylpiperazine carbodithioate moiety: Synthesis,in vitro evaluation and in silico study

A number of 1H-1,2,4-triazole alcohols containing N-(halobenzyl)piperazine carbodithioate moiety have been designed and synthesized as potent antifungal agents. In vitro bioassays against different Candida species including C. albicans, C. glabrata, C. parapsilosis, C. krusei, and C. tropicalis revealed that the N-(4-chlorobenzyl) derivative (6b) with MIC values of 0.063–0.5 µg/mL had the best profile of activity, being 4–32 times more potent than fluconazole. Docking simulation studies confirmed the better fitting of compound 6b in the active site of lanosterol 14α-demethylase (CYP51) enzyme, the main target of azole antifungals. Particularly, the potential of compound 6b against fluconazole-resistant isolates along with its minimal toxicity against human erythrocytes and HepG2 cells make this prototype compound as a good lead for discovery of potent and safe antifungal agents.     

Design and total synthesis of (-)-codonopsinine, (-)-codonopsine and codonopsinine analogues by O-(2-oxopyrrolidin-5-yl)trichloroacetimidate as amidoalkylating agent with improved antimicrobial activity via solid lipid nanoparticle formulations

A general strategy towards total synthesis of (-)-codonopsinine, (-)-codonopsine and codonopsinine analogues has been developed from (D)-tartaric acid via the intermediate (3S,4R)-1-methyl-2-oxo-5-(2,2,2-trichloroacetamido)pyrrolidinediacetate (7). α-amidoalkylation studies of 7 with electron rich benzene derivative 8a-g as C-nucleophiles afforded (aryl derivatives) 9a-g. The target compounds 1, 2 and 13c-g were readily obtained from 10a-g via Grignard addition to the homochiral lactam which was produced by deoxygenation using Lewis-acid followed by deacetylation. The synthesized compounds were loaded onto solid lipid nanoparticle formulations (SLNs) prepared by hot emulsification-ultrasonication technique using Compritol as solid lipid and Pluronic f68 as surfactant. SLNs were fully evaluated and the permeation of synthesized compound from SLNs was assayed against non-formulated compounds through dialysis membranes using Franz cell. The data indicated good physical characteristics of the prepared SLNs, sustaining of release profiles and significant improvement of permeation ability when compared to the non-formulated compounds. The antibacterial and antifungal activities of 1, 2 and 13c-g were determined by disc diffusion and microbroth dilution method to determine the minimum inhibitory concentrations (MIC) against seven microorganisms (Staphyloccus aureus, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Acinetobacter baumannii and Candida albicans). The most active compounds against the Gram positive S. aureus were 1, 13C, 13d, and 13g. Also, 13c, 13d, and 13e had antibacterial activity but not 13f against some Gram negative organisms (E. coli, and P. mirabilis). MIC concentrations against P. aeruginosa, and K. pneumoniae were?≥512?μg/ml, while that against A. baumannii was?≥128?μg/ml except for nanoformulae of 13e and 13f that were 16 and 64?μg/ml, respectively. No antifungal activity against Candida albicans was recorded for all compounds and their nanoformulae (MIC?>?1024?μg/ml). SLNs were found to decrease the MIC values for some of the compounds with no effect on the antifungal activity. In conclusion, we demonstrated a novel, straight-forward and economical procedure for the total synthesis of (-)-codonopsinine 1, (-)-codonopsine 2 and codonopsinine analogues 13c-g from simple and commercially available starting materials; d-tartaric acid; with antimicrobial activities against Gram positive and Gram-negative organisms that were improved by SLNs formulations.     

Synthesis and antimicrobial activity of novel amphiphilic aromatic amino alcohols

We report in this work the preparation and in vitro antimicrobial evaluation of novel amphiphilic aromatic amino alcohols synthesized by reductive amination of 4-alkyloxybenzaldehyde with 2-amino-2-hydroxymethyl-propane-1,3-diol. The antibacterial activity was determined against four standard strains (Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Pseudomonas aeruginosa) and 21 clinical isolates of methicillin-resistant Staphylococcus aureus. The antifungal activity was evaluated against four yeast (Candida albicans, Candida tropicalis, Candida glabrata and Candida parapsilosis). The results obtained showed a strong positive correlation between the lipophilicity and the antibiotic activity of the tested compounds. The best activities were obtained against the Gram-positive bacteria (MIC = 2–16 μg ml^?1) for the five compounds bearing longer alkyl chains (4c–g; 8–14 carbons), which were also the most active against Candida (MIC = 2–64 μg ml^?1). Compound 4e exhibited the highest levels of inhibitory activity (MIC = 2–16 μg ml^?1) against clinical isolates of MRSA. A concentration of twice the MIC resulted in bactericidal activity of 4d against 19 of the 21 clinical isolates.     

β-lactam substituted polycyclic fused pyrrolidine/pyrrolizidine derivatives eradicate C. albicans in an ex vivo human dentinal tubule model by inhibiting sterol 14-α demethylase and cAMP pathway

BackgroundFurther quest for new anti-fungal compounds with proven mechanisms of action arises due to resistance and dose limiting toxicity of existing agents. Among the human fungal pathogens C. albicans predominate by infecting several sites in the body and in particular oral cavity and root canals of human tooth.MethodsIn the present study, we screened a library of β-lactam substituted polycyclic fused pyrrolidine/pyrrolizidine compounds against Candida sp. Detailed molecular studies were carried out with the active compound 3 on C. albicans. Morphological damage and antibiofilm activity of compound 3 on C. albicans was studied using scanning electron microscopy (SEM). Biochemical evidence for membrane damage was studied using flow cytometry. In silico docking studies were carried out to elucidate the mechanism of action of compound 3. Further, the antifungal activity of compound 3 was evaluated in an ex vivo dentinal tubule infection model.ResultsScreening data showed that several new compounds were active against Candida sp. Among them, Compound 3 was most potent and exerted time kill effect at 4 h, post antifungal effect up to 6 h. When used in combination with fluconazole or nystatin, compound 3 revealed an minimum inhibitory concentration (MIC) decrease by 4 fold for both drugs used. In-depth molecular studies with compound 3 on C. albicans showed that this compound inhibited yeast to hyphae (Y-H) conversion and this involved the cAMP pathway. Further, SEM images of C. albicans showed that compound 3 caused membrane damage and inhibited biofilm formation. Biochemical evidence for membrane damage was confirmed by increased propidium iodide (PI) uptake in flow cytometry. Further, in silico studies revealed that compound 3 docks with the active site of the key enzyme 14-α-demethylase and this might inhibit ergosterol synthesis. In support of this, ergosterol levels were found to be decreased by 32 fold in compound 3 treated samples as analyzed by high performance liquid chromatography (HPLC). Further, the antifungal activity of compound 3 was evaluated in an ex vivo dentinal tubule infection model, which mimics human tooth root canal infection. Confocal laser scanning microscopy studies showed 83% eradication of C. albicans and a 6 log reduction in colony forming unit (CFU) after 24 h treatment in the infected tooth samples in this model.ConclusionCompound 3 was found to be very effective in eradicating C. albicans by inhibiting cAMP pathway and ergosterol biosynthesis.General SignificanceThe results of this study can pave the way for developing new antifungal agents with well deciphered mechanisms of action and can be a promising antifungal agent or medicament against root canal infection.     

Synthesis,biological evaluations and computational studies of N-(3-(-2-(7-Chloroquinolin-2-yl)vinyl) benzylidene)anilines as fungal biofilm inhibitors

In the present investigation, new chloroquinoline derivatives bearing vinyl benzylidene aniline substituents at 2nd position were synthesized and screed for biofilm inhibitory, antifungal and antibacterial activity. The result of biofilm inhibition of C. albicans suggested that compounds 5j (IC₅₀ value?=?51.2?μM) and 5a (IC₅₀ value?=?66.2?μM) possess promising antibiofilm inhibition when compared with the standard antifungal drug fluconazole (IC₅₀?=?40.0?μM). Two compounds 5a (MIC?=?94.2?μg/mL) and 5f (MIC?=?98.8?μg/mL) also exhibited good antifungal activity comparable to standard drug fluconazole (MIC?=?50.0?μg/mL). The antibacterial screening against four strains of bacteria viz. E. coli, P. aeruginosa, B. subtilis, and S. aureus suggested their potential antibacterial activity and especially all the compounds except 5g were found more active than the standard drug ciprofloxacin against B. subtilis. To further gain insights into the possible mechanism of these compounds in biofilm inhibition through the agglutinin like protein (Als), molecular docking and molecular dynamics simulation studies were carried out. Molecular modeling studies suggested the clear role in inhibition of this protein and the resulting biofilm inhibitory activity.     

Evaluation of Antifungal Susceptibility Testing with Microdilution and Etest Methods of <Emphasis Type="Italic">Candida</Emphasis> Blood Isolates

Candida species that show an increasing number of clinical and/or microbiological resistance to several antifungals and are the most common agents of invasive fungal infections. The aim of this study was to investigate the in vitro susceptibility of Candida blood isolates to antifungal agents (amphotericin B, fluconazole, itraconazole, and voriconazole) by comparative use of the CLSI reference microdilution method and Etest. Four hundred Candida blood isolates (215 Candida albicans, 185 non-albicans Candida strains) were included in the study. The broth microdilution test was performed according to the CLSI M27 A2 document. Etest was carried out according to the manufacturer’s instructions. The MIC results obtained with reference microdilution were compared with those obtained with the Etest by using percent and categorical agreements. According to MIK₉₀ values, voriconazole was the most active and itraconazole was the least active drug in vitro against all Candida species. Other than voriconazole, statistically significant differences were found when the susceptibility of Candida albicans and non-albicans Candida spp. to amphotericin B, fluconazole, and itraconazole were compared. These antifungal agents were found to be more active to C. albicans. Among the non-albicans Candida species, the lowest MIC values were obtained for Candida parapsilosis isolates. When the standard method was compared with Etest, the total agreement was higher for C. albicans than for non-albicans species, especially for fluconazole and voriconazole. In view of the findings, it was concluded that itraconazole showed the lowest activity against all Candida species. Etest could be an alternative method in assessing the in vitro antifungal susceptibility of Candida spp., but it is more convenient to use the microdilution method for studying in vitro susceptibility of non-albicans species, in particular for those possessing high MIC values against azoles.     

Cananginones A-I, linear acetogenins from the stem bark of Cananga latifolia

Nine linear C23 and C21 acetogenins, named cananginones A–I (1–9), were isolated from stem bark of Cananga latifolia. Their structures were established by spectroscopic methods. These compounds showed cytotoxicity against three cancer cell lines (KB, MCF7 and NCI-H187) with IC₅₀ values in the range 16.6–129.7 μM. Only 5 showed weak antimalarial activity against Plasmodium falciparum. In addition, 8 and 9 exhibited weak antifungal activity against Candida albicans.     

Anti-inflammatory and antimicrobial activities of novel pyrazole analogues

A new sequence of pyrazole derivatives (1–6) was synthesized from condensation technique under utilizing ultrasound irradiation. Synthesized compounds were characterized from IR, ¹H NMR, ¹³C NMR, Mass and elemental analysis. Synthesized compounds (1–6) were screened for antimicrobial activity. Among the compounds 3 (MIC: 0.25 μg/mL) was exceedingly antibacterially active against gram negative bacteria of Escherichia coli and compound 4 (MIC: 0.25 μg/mL) was highly active against gram positive bacteria of Streptococcus epidermidis compared with standard Ciprofloxacin. Compound 2 (MIC: 1 μg/mL) was highly antifungal active against Aspergillus niger proportionate to Clotrimazole. Synthesized compounds (1–6) were screened for anti-inflammatory activity and the compound 2-((5-hydroxy-3-methyl-1H-pyrazol-4-yl)(4-nitrophenyl)methyl)hydrazinecarboxamide (4) was better activity against anti-inflammatory when compared with standard drugs (Diclofenac sodium). Compounds (2, 3 and 4) are the most important molecules and hence the need to develop new drugs of antibacterial, antifungal and anti-inflammatory agents.     

Design,synthesis, characterization and biological evaluation of novel pyrazole integrated benzophenones

A series of novel pyrazole integrated benzophenones (9a–j) have been designed, synthesized from 1-methyl-5-(2,4,6-trimethoxy-phenyl)-1H-pyrazole 6. The structures of the regioisomers 6 and 7 were determined by 2D ¹H–¹H COSY, ¹H–¹³C HSQC and ¹H–¹³C HMBC experiments. The newly synthesized compounds (9a–j) were evaluated for in vivo anti-inflammatory activity by carrageenan paw edema in rats and in vitro COX-1/COX-2 inhibition and antioxidant potential. Among the synthesized compounds, compounds 9b, 9d and 9f, were found to be active anti-inflammatory agents in addition to having potent antioxidant activity.     

Candida inhibitory effects of six commercial mouthwashes

TheCandida inhibitory activities of commercial mouthwashes with various, active ingredients — fluoride (FLO), cethylpyridinium chloride (CPC), chlorhexidine gluconate (CHX), triclosan (TRI) and herbal extracts: Twin Lotus (TLO) and Herbric concentrated (HBC) — were determined. TheCandida activities included growth, germ tube formation and adhesion ofCandida albicans to human buccal mucosa. This study showed that TRI, TLO and CHX mouthwashes had growth inhibitory effects toC. albicans with the MIC of 1/64, 1/64 and 1/32, respectively. CHX, TRI, TLO, HBC and CPC mouthwashes had ability to inhibit adhesion ofC. albicans ATCC 10231 by approximately 85, 80, 70, 65 and 55%, respectively. Germ tube formation, or mycelial conversion, ofC. albicans was inhibited by approximately 90, 85 and 80% after treatment with 20% mouthwashes containing CHX, TRI and CPC, respectively. Fluoride mouthwash showed the weakest in all inhibitory activities. These results suggested that CHX and triclosan mouthwashes were effective in reducing oralCandida activities.     

D319 induced antifungal effects through ROS-mediated apoptosis and inhibited isocitrate lyase in Candida albicans

BackgroundCandida albicans (C. albicans) is an opportunistic pathogen that can cause superficial and life-threatening systemic infections in immunocompromised patients. However, the available clinically antifungals are limited. Therefore, the development of effective antifungal agents and therapies is urgently needed. Quinoline type of compounds were reported to possess potent anti-fungal effect. A series of quinoline derivatives were synthesized. Moreover their inhibitory activities and mechanisms on C. albicans were evaluated in this study.MethodsThe structure of D319 was identified by extensive spectroscopic analysis. The antifungal activity of D319 on C. albicans was evaluated using conventional methods, including the inhibition zone diameters with filter paper, Clinical Laboratory Standard Institute (CLSI) broth microdilution method in vitro, and in a murine model in vivo. Flow cytometry, fluorescence microscopy, western blot, knockout mutant and revertant strain techniques, and molecular modeling were applied to explore the mechanism of action of D319 in anti-Candida.ResultsD319 exhibited potent anti-Candida activity with Minimum Inhibitory Concentration value of 2.5 μg/mL in vitro. D319 significantly improved survival rate and reduced fungal burden compared to vehicle control in a murine model in vivo. The treatment of C. albicans with D319 resulted in fungal apoptosis through reactive oxygen species (ROS) accumulation in C. albicans. Furthermore, D319 inhibited the glyoxylate enzyme isocitrate lyase (ICL) of C. albicans, which was also confirmed by docking analysis.ConclusionsQuinoline compound D319 exhibited strong anti-Candida activities in vitro and in vivo models through inhibiting ICL activity and ROS accumulation in C. albicans.General significanceThis study showed that compound D319 as a novel isocitrate lyase inhibitor, would be a promising anti-Candida lead compound, which provided a potential application of this type of compounds in fighting clinical fungal infections. Furthermore, this study also supported ICL as a potential target for anti-Candida drug discovery.     

Pseudomembranous Candidiasis in HIV/AIDS Patients in Cali, Colombia

Candida albicans is the most frequently isolated yeast from the oral cavity of HIV/AIDS individuals. The use of fluconazole has increased the number of resistant or less-sensitive Candida species different than C. albicans. The purpose of this study was to identify the Candida species producing pseudomembranous candidiasis in patients suffering from AIDS, their relationship with CD4⁺ counts and their sensitivity to fluconazole and itraconazole. We studied 71 patients at a hospital in the city of Cali. Samples of white plaque were seeded on CHROMagar Candida, yeast identification was done with API 20C Aux, and susceptibility testing was determined by E test. Ninety-three yeast isolates were obtained, 52 single and 41 mixed. C. albicans was the most isolated, followed by C. glabrata. An increased frequency of isolates and variety of Candida species occurred in patients with a CD4⁺ cell count ≤100 cells/mm³ without significant differences (p = 0.29). The susceptibility study showed that 8 (8.6 %) isolates were resistant to fluconazole and 11 (11.8 %) to itraconazole, while 6 (8.8 %) C. albicans were simultaneously resistant. No association was found between the isolates of C. albicans or Candida species different than C. albicans and the use of fluconazole (p = 0.21). The results of this study indicate that in the tested population, fluconazole continues to be the best treatment option for oropharyngeal candidiasis in patients suffering from AIDS (HIV/AIDS); however, susceptibility tests are necessary in patients who present therapeutic failure.     

Inhibition of protein tyrosine phosphatase 1B (PTP1B) and α-glucosidase by xanthones from Cratoxylum cochinchinense, and their kinetic characterization

Cratoxylum cochinchinense displayed significant inhibition against protein tyrosine phosphatase 1B (PTP1B) and α-glucosidase, both of which are key target enzymes to attenuate diabetes and obesity. The compounds responsible for both enzymes inhibition were identified as twelve xanthones (1–12) among which compounds 1 and 2 were found to be new ones. All of them simultaneously inhibited PTP1B with IC₅₀s of (2.4–52.5?µM), and α-glucosidase with IC₅₀ values of (1.7–72.7?µM), respectively. Cratoxanthone A (3) and γ-mangostin (7) were estimated to be most active inhibitors against both PTP1B (IC₅₀?=?2.4?µM for 3, 2.8?µM for 7) and α-glucosidase (IC₅₀?=?4.8?µM for 3, 1.7?µM for 7). In kinetic studies, all isolated xanthones emerged to be mixed inhibitors of α-glucosidase, whereas they behaved as competitive inhibitors of PTP1B. In time dependent experiments, compound 3 showed isomerization inhibitory behavior with following kinetic parameters: K_i^app?=?2.4?µM; k₅?=?0.05001?µM^?1?S^?1 and k₆?=?0.02076?µM^?1?S^?1.     

Antimicrobial phenolic metabolites from the aerial parts of Orthosiphon aristatus

Two new compounds oraristatin A (1) and oraristatinoside A (2), one new natural compound (2 S)-methyl-6,7-dihydroxytropate (3), and 11 known phenolic metabolites were isolated from the aerial parts of Orthosiphon aristatus. Their chemical structures were identified by 1D- and ²D NMR and HRESIMS spectroscopic analyses. The absolute configurations of 1 and 3 were determined by TD-DFT ECD spectroscopic analyses. Of the isolates, compound 2 weakly inhibited both Gram-positive and -negative bacteria (MIC = 150–300 μM), while 6 and 7 suppressed the growth of three Gram-positive bacteria and a yeast (MIC = 75–150 μM). This is the first report of the isolation of 6 − 9, 12, and 14 from the genus Orthosiphon and the antimicrobial effects of compounds 3, 7, 9, 12, and 14.