02281nas a2200193 4500008004100000245013400041210006900175260000800244300001200252490000700264520155200271100002101823700001801844700001901862700002001881700002601901700002801927856013201955 2022 eng d00aDesign and synthesis of eugenol/isoeugenol glycoconjugates and other analogues as antifungal agents against Aspergillus fumigatus0 aDesign and synthesis of eugenolisoeugenol glycoconjugates and ot cAUG a955-9620 v133 a

Glycoconjugates are biologically significant molecules as they tend to serve a wide range of intra- and extra-cellular processes depending on their size and complexity. The secondary metabolites of the plant Myristica fragrans, eugenol and isoeugenol, have shown antifungal activities (IC50 1900 mu M). Therefore, we envisioned that glycoconjugates based on these two scaffolds could prove to be potent antifungal agents. Triazole-containing compounds have shown prominent activities as antifungal agents. Based on this, we opined that a Cu(i) catalyzed click reaction could serve as the bridging tool between a eugenol/isoeugenol moiety and sugars to synthesize eugenol/isoeugenol based glycoconjugates. In our present work, we have coupled propargylated eugenol/isoeugenol and azido sugar to furnish eugenol/isoeugenol based glycoconjugates. In another approach, we have carried out hydroxylation of the double bond of eugenol and subsequent azidation of a primary alcohol followed by intramolecular coupling reactions leading to various other analogues. All the synthesized compounds were assayed against an opportunistic pathogenic fungus, Aspergillus fumigatus. Among the synthesized compounds, two analogues have exhibited significant antifungal activities with IC50 values of 5.42 and 9.39 mu M, respectively. The study suggested that these two analogues inhibit cell wall-associated melanin hydrophobicity along with the number of conidia. The synthesized compounds were found to be non-cytotoxic to an untransformed cell line.

1 aGoswami, Lakshmi1 aGupta, Lovely1 aPaul, Sayantan1 aVermani, Maansi1 aVijayaraghavan, Pooja1 aBhattacharya, Asish, K. uhttps://library.ncl.res.in/content/design-and-synthesis-eugenolisoeugenol-glycoconjugates-and-other-analogues-antifungal-agents02463nas a2200241 4500008004100000022001400041245019400055210006900249260000800318300000800326490000800334520156100342653002601903653001901929653001501948653002901963653001401992100001802006700001502024700002802039700002602067856012802093 2022 eng d a0302-893300aIsoeugenol affects expression pattern of conidial hydrophobin gene RodA and transcriptional regulators MedA and SomA responsible for adherence and biofilm formation in Aspergillus fumigatus0 aIsoeugenol affects expression pattern of conidial hydrophobin ge cAPR a2140 v2043 a

Aspergillus fumigatus is one of the major pathogenic fungal species, causing life-threatening infections. Due to a limited spectrum of available antifungals, exploration of new drug targets as well as potential antifungal molecules has become pertinent. Rodlet layer plays an important role in adherence of fungal conidia to hydrophobic cell surfaces in host, which also leads to A. fumigatus biofilm formation, contributing factor to fungal pathogenicity. From decades, natural sources have been known for the development of new active molecules. The present study investigates effect of isoeugenol on genes responsible for hydrophobins (RodA), adhesion as well as biofilm formation (MedA and SomA) of A. fumigatus. Minimum inhibitory concentrations (MIC and IC50) of isoeugenol against A. fumigatus were determined using broth microdilution assay. The IC50 results showed reduced hydrophobicity and biofilm formation as well as eradication after treatment with the compound and electron micrograph data corroborated these findings. The qRT-PCR showed a significant downregulation of genes RodA, MedA, SomA and pksP involved in hydrophobicity and biofilm formation. SwissADME studies potentiated drug-like propensity for isoeugenol which formed four hydrogen bonds with low binding energy (- 4.54 kcal/mol) at the catalytic site of RodA protein studied via AutoDock4. Hence, the findings conclude that isoeugenol inhibits conidial hydrophobicity and biofilm formation of A. fumigatus and further investigations are warranted in this direction.

10aAspergillus fumigatus10aHydrophobicity10aIsoeugenol10aTranscription regulators10aVirulence1 aGupta, Lovely1 aSen, Pooja1 aBhattacharya, Asish, K.1 aVijayaraghavan, Pooja uhttps://library.ncl.res.in/content/isoeugenol-affects-expression-pattern-conidial-hydrophobin-gene-roda-and-transcriptional02318nas a2200253 4500008004100000022001400041245009700055210006900152260000900221490000700230520148500237653000601722653001301728653002201741653002601763653002301789653001501812100002101827700001801848700001901866700002601885700002801911856012501939 2023 eng d a1860-717900aDesign and synthesis of 1,3-diynes as potent antifungal agents against aspergillus fumigatus0 aDesign and synthesis of 13diynes as potent antifungal agents aga cMAY 0 v183 a

Eugenol and isoeugenol, secondary metabolites isolated from the plant Myristica fragrans have displayed antifungal activities against Aspergillus fumigatus (IC50 1900 mu M). Compounds having conjugated unsaturation have been of great use as antifungals i. e. amphotericin B, nystatin and terbinafine etc. Hence, in the present study, we have designed and synthesised 1,3-diynes by utilizing Glaser-Hay and Cadiot-Chodkiewicz coupling reactions to furnish possible antifungal agents. Synthesis of 1,6-diphenoxyhexa-2,4-diyne derivatives was achieved by Cu(I) catalysed coupling of propargylated eugenol, isoeugenol, guaiacol, vanillin and dihydrogenated eugenol or eugenol in good to excellent yields. All the synthesized compounds were evaluated against pathogenic fungus A. fumigatus. Among all the synthesized compounds, one of the compounds was found to be exhibiting promising antifungal activity with IC50 value of 7.75 mu M thereby suggesting that this type of scaffold could pave the way for developing new antifungal agents. The most active compound was found to be low cytotoxic when assayed against L-132 cancer cell line. Effect of the most active compound on ergosterol biosynthesis has also been studied. Also, the most active compound exhibited significant anti-biofilm activity although the concentration was found to be higher than its anti-fungal activity. Morphological changes in the biofilm were remarkable under confocal laser scanning microscopy.

10a110a3-Diynes10aAntifungal agents10aAspergillus fumigatus10aCadiot-Chodkiewicz10aGlaser-Hay1 aGoswami, Lakshmi1 aGupta, Lovely1 aPaul, Sayantan1 aVijayaraghavan, Pooja1 aBhattacharya, Asish, K. uhttps://library.ncl.res.in/content/design-and-synthesis-13-diynes-potent-antifungal-agents-against-aspergillus-fumigatus02991nas a2200277 4500008004100000022001400041245018800055210006900243260000900312490000800321520198600329653002602315653002402341653001202365653001902377653002902396653001402425100001802439700001902457700002102476700002102497700001502518700002802533700002602561856012602587 2024 eng d a1364-507200aUnveiling the cell wall-targeting mechanisms and multifaceted virulence modulation by a eugenol glycoconjugate against aspergillus fumigatus: insights from in vitro and in ovo studies0 aUnveiling the cell walltargeting mechanisms and multifaceted vir cJAN 0 v1353 a

Aim The primary objective of this study was to elucidate the putative cell wall-associated targets of compound 6i, a glycoconjugate of eugenol, in Aspergillus fumigatus, while also evaluating its toxicity and assessing histopathologic alterations in the liver, heart, and kidney of compound 6i-treated embryos using an in ovo model.Method To achieve this aim, compound 6i was synthesized, and a series of biochemical assays were performed to determine its impact on the fungal cell wall. Additionally, quantitative real time-PCR and liquid chromatography-mass spectrometry/mass spectrometry analyses were conducted to investigate changes in gene and protein expression profiles associated with melanin biosynthesis, conidiation, siderophore production, transcriptional regulation of beta-glucan biosynthesis, and calcineurin activity in A. fumigatus.Results The experimental findings revealed that compound 6i exhibited notable antifungal activity against A. fumigatus by perturbing cell wall integrity, hindering ergosterol, glucan, and chitin biosynthesis, and inhibiting catalase production. Moreover, relative gene expression and proteomic analyses demonstrated that compound 6i exerted both downregulatory and upregulatory effects on several crucial genes and proteins involved in the aforementioned fungal processes. Furthermore, increased expression of oxidative stress-related proteins was observed in the presence of compound 6i. Notably, the glycoconjugate of eugenol did not elicit cytotoxicity in the liver, heart, and kidney of chick embryos.Conclusion The current investigation elucidated the multifaceted mechanisms by which compound 6i exerts its antifungal effects against A. fumigatus, primarily through targeting cell wall components and signaling pathways. These findings underscore the potential of the eugenol glycoconjugate as a promising antifungal candidate, warranting further exploration and development for combating A. fumigatus infections.

10aAspergillus fumigatus10acell wall integrity10aEugenol10aGlycoconjugate10aTranscription regulators10aVirulence1 aGupta, Lovely1 aVerma, Shalini1 aGoswami, Lakshmi1 aKamboj, Himanshu1 aSen, Pooja1 aBhattacharya, Asish, K.1 aVijayaraghavan, Pooja uhttps://library.ncl.res.in/content/unveiling-cell-wall-targeting-mechanisms-and-multifaceted-virulence-modulation-eugenol02434nas a2200289 4500008004100000022001400041245013600055210006900191260000900260300000800269490000700277520149200284653001601776653001201792653002001804653001701824653001501841653001401856100001501870700001801885700002001903700002101923700002801944700002301972700002601995856012302021 2025 eng d a0301-485100aComprehensive in vitro and in silico assessment of eugenol glycoconjugates against azole and amphotericin B resistant Rhizopus spp.0 aComprehensive in vitro and in silico assessment of eugenol glyco cJUN  a5890 v523 a

Background Rhizopus spp. is a major cause of mucormycosis, a severe infectious disease with high morbidity and mortality. Treatment is challenging due to rising antifungal resistance. Glycosylation is a crucial technique for enhancing the properties of phenolic compounds like eugenol. The present study aims to examine the antifungal efficacy of eugenol glycoconjugates against azole and amphotericin B-resistant Rhizopus isolates. Methods and results Out of 50 soil samples, 12 isolates belonging to Mucorales were obtained, of which 7 were identified as Rhizopus spp. via 18S ITS sequencing. Antifungal susceptibility testing (AST) revealed that all Rhizopus isolates were resistant to amphotericin B (MIC > 1 mu g/mL). Most isolates also showed resistance towards posaconazole (MIC > 1 mu g/mL) and itraconazole (MIC > 2 mu g/mL). AST of eugenol glycoconjugate (coded 6g) showed efficacy against resistant Rhizopus isolates, with MIC values ranging from 6.25 mu g/mL to 25 mu g/mL. Flow cytometry confirmed its fungicidal activity, correlating with MIC data. Compound 6g significantly reduced conidial germination within 24 h and exhibited no cytotoxicity on A549 lung cancer cells. In-silico analysis revealed a negative binding affinity of compound 6g for the spore coat protein CotH3, which could be a potential antifungal target. Conclusion Compound 6g could be an potential antifungal molecule against resistant Rhizopus spp, which requires further studies.

10aAntifungals10aEugenol10aGlycoconjugates10aMucormycosis10aResistance10aVirulence1 aSen, Pooja1 aGupta, Lovely1 aChauhan, Aastha1 aGoswami, Lakshmi1 aBhattacharya, Asish, K.1 aSengupta, Abhishek1 aVijayaraghavan, Pooja uhttps://library.ncl.res.in/content/comprehensive-vitro-and-silico-assessment-eugenol-glycoconjugates-against-azole-and