Naiara Chaves Silva

Aspartic proteinases of Candida spp.: role in pathogenicity and antifungal resistance

Fungal infections represent a serious health risk as they are particularly prevalent in immunocompromised individuals. Candida spp. pathogenicity depends on several factors and secreted aspartic proteinases (Sap) are considered one of the most critical factors as they are associated with adhesion, invasion and tissue damage. The production of proteinases is encoded by a family of 10 genes known as SAP, which are distributed differently among the species. The expression of these genes may be influenced by environmental conditions, which generally result in a higher fungal invasive potential. Non‐pathogenic Candida spp. usually have fewer SAP genes, which are not necessarily expressed in the genome. Exposure to subinhibitory concentrations of antifungal agents promotes the development of resistant strains with an increased expression of SAP genes. In general, Candida spp. isolates that are resistant to antifungals show a higher secretion of Sap than the susceptible isolates. The relationship between Sap secretion and the susceptibility profile of the isolates is of great interest, although the role of SAPs in the development of resistance to antifungal agents remains still unclear. This review is the first one to address these issues.

Synthesis and Biological Evaluation of New Eugenol Mannich Bases as Promising Antifungal Agents

New Mannich base‐type eugenol derivatives were synthesized and evaluated for their anticandidal activity using a broth microdilution assay. Among the synthesized compounds, 4‐allyl‐2‐methoxy‐6‐(morpholin‐4‐ylmethyl) phenyl benzoate (7) and 4‐{5‐allyl‐2‐[(4‐chlorobenzoyl)oxy]‐3‐methoxybenzyl}morpholin‐4‐ium chloride (8) were found to be the most effective antifungal compounds with low IC50 values, some of them well below those of reference drug fluconazole. The most significant IC50 values were those of 7 against C. glabrata (1.23 μm), C. albicans and C. krusei (both 0.63 μm). Additionally, the synthesized compounds were evaluated for their in vitro cytotoxic effects on human mononuclear cells. As result, the cytotoxic activity of eugenol in eukaryotic cells decreased with the introduction of the morpholinyl group. Given these findings, we point out compounds 7 and 8 as the most promising derivatives because they showed potency values greater than those of eugenol and fluconazole and they also presented high selectivity indexes.

Synthesis and in vitro evaluation of antifungal and cytotoxic activities of eugenol glycosides

AbstractSix eugenol glycosides were prepared in order to assess their antifungal activity against Candida species. They were synthesized by glycosylation of eugenol with the appropriate glycosyl bromides followed by deacetylation with sodium methoxide in methanol and were evaluated in vitro for their antifungal activity through a Mueller–Hinton broth microdilution method. The peracetyl glycoside (derivative 4) was the most promising one since it was able to inhibit growth of C. albicans, C. tropicalis and C. glabrata with IC50 values much lower than that of the prototype eugenol. Derivative 4 showed to be 160.0 and 3.4 times more potent than eugenol and fluconazole, respectively, against C. glabrata with low cytotoxity (selectivity index of 45). Moreover, it was possible to verify the positive effect of gluco configuration and lipophilicity on antifungal activity, since glucose peracetyl derivatives were more active than the free sugars of galacto configuration.

Synthesis and antimicrobial activity of 6-triazolo-6-deoxy eugenol glucosides.

A new series of 1,2,3-triazole eugenol glucosides were synthesized. The new compound structures were confirmed by MS, (1)H NMR and (13)C NMR. All of the synthesized compounds were screened for antimicrobial and cytotoxic activity. Five compounds exerted significant activity against the Gram-negative bacteria Salmonella typhimurium with low IC50 values (49.73-68.53 μΜ), and seven compounds were active against the Gram-positive bacteria Micrococcus luteus (42.89-210.94 μM). In vitro cytotoxicity on mouse spleen cells was also evaluated. One compound bearing a phenyl substituent at the triazole ring showed good activity against Salmonella typhimurium (49.73 μM) and low toxicity to normal cells (CC50=157.83 μM). Thus, the compounds herein can be considered for further modification for improving their antibacterial activity or obtaining novel antibacterial drug candidates.

Candida glabrata among Candida spp. from environmental health practitioners of a Brazilian Hospital

The incidence of the species Candida albicans and non-albicans Candida was evaluated in a Brazilian Tertiary Hospital from the environment and health practitioners. In a 12-month period we had a total positivity of 19.65% of Candida spp. The most recurring non-albicans Candida species was C. glabrata (37.62%), generally considered a species of low virulence, but with a higher mortality rate than C. albicans. Subsequently, C. parapsilosis (25.74%) and C. tropicalis (16.86%) were the second and third most commonly isolated species. Considering the total samples collected from the emergency room and from the inpatient and the pediatric sector, 19.10% were positive for Candida spp., with the predominance of non-albicans Candida species (89.42%). The high percentage of positivity occurred in the hands (24.32%) and the lab coats (21.88%) of the health care assistants. No sample of C. albicans presented a profile of resistance to the drugs. All the non-albicans Candida species presented a decreased susceptibility to miconazole and itraconazole, but they were susceptible to nystatin. Most of the isolates were susceptible to fluconazole and amphotericin B. As expected, a high resistance rate was observed in C. glabrata and C. krusei, which are intrinsically less susceptible to this antifungal agent. The contamination of environmental surfaces by Candida spp. through hand touching may facilitate the occurrence of Candida infections predominantly in immunocompromised patients. In addition to that, the antifungal agents used should be carefully evaluated considering local epidemiologic trends in Candida spp. infections, so that therapeutic choices may be better guided.

New Eugenol Glucoside-based Derivative Shows Fungistatic and Fungicidal Activity against Opportunistic Candida glabrata.

A new series of glucosides modified in their saccharide units were synthesized, evaluated against Candida sp., and compared to prototype 1, an eugenol tetracetyl glucoside previously synthesized and shown to be active against Candida glabrata. Among the new glucosides, benzyl derivative 5 was the most promising, showing fungistatic activity at IC50 18.1 μm against Candida glabrata (threefold higher than fluconazole) and fungicidal activity with a low IC90 value of 36.2 μm. Moreover, the cytotoxic activity of compound 5 (CC50: 580.9 μm), tested in peripheral blood mononuclear cells, suggests its potential as an agent to treat Candida glabrata infections, with a selectivity index of 32. The new eugenol glucoside 5 may be considered as a novel structural pattern in the development of new anti‐Candida drugs.

Synthesis of piplartine analogs and preliminary findings on structure–antimicrobial activity relationship

In this work it is described the synthesis, characterization and antimicrobial and toxicity evaluation of a series of analogs of piplartine, a piperamide found in Piper sp. The compounds structures were confirmed by infrared spectroscopy, 1H, 13C nuclear magnetic resonance, high resolution mass spectroscopy and were evaluated against strains of Candida spp., Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa. Derivative 24 was almost four-fold more potent (IC50: 48.83 μM) and five-fold less toxic (SI > 3) than piplartine (IC50: 189.2 μM; SI: 0.21) against Candida krusei, as well as two-fold more potent than fluconazole (IC50: 104.48 μM). This compound was also active against Candida tropicalis at 97.67 μM. Benzoyl derivative 17 was three-fold more potent (IC50: 85.2 μM) and more than five-fold less toxic (CC50: 231.71 μM) than piplartine (IC50: 315.33 μM and CC50: 41.14 μM) against Staphylococcus aureus. Given these findings, we have found analogs of piplartine which can be assumed as prototypes for the optimization and the development of new antimicrobial (compounds 24 and 17) agents.

Antifungal Activity of New Eugenol-Benzoxazole Hybrids against Candida spp.

Eugenol is a natural allylphenol responsible for a wide range of biological activities, especially antimicrobial. Benzoxazoles are heterocycles with recognized antimicrobial activities. This paper describes the design, synthesis, and the biological results for benzoxazole type derivatives of eugenol as antifungal agents. The products were obtained in good yields by a four-step synthetic sequence involving aromatic nitration, nitroreduction, amide formation, and cycle condensation. They were evaluated against species of Candida spp. in microdilution assays, and four products (5a, 5b′, 5c, and 5d′) were about five times more active than eugenol against C. albicans and C. glabrata. Two of them (5b′ and 5d′) showed good activity against C. krusei, a species which is naturally resistant to fluconazole. Furthermore, the active products were more selective than eugenol against human blood cells, showing that they are interesting substances for further optimization.