AbstractBackgroundDuring the second wave of the COVID-19 pandemic, an unusual increase in cases of mucormycosis was observed in India, owing to immunological dysregulation caused by the SARS-CoV-2 and the use of broad-spectrum antibiotics, particularly in patients with poorly controlled diabetes with ketoacidosis to have contributed to the rise, and it has been declared an epidemic in several states of India. Because of the black colouring of dead and dying tissue caused by the fungus, it was dubbed "black fungus" by several Indian media outlets. In this study, attempts were taken to unmask novel therapeutic options to treat mucormycosis disease. Rhizopus species is the primary fungi responsible for 70% of mucormycosis cases.ResultsWe chose three important proteins from the Rhizopus delemar such as CotH3, Lanosterol 14 alpha-demethylase and Mucoricin which plays a crucial role in the virulence of Mucorales. Initially, we explored the physiochemical, structural and functional insights of proteins and later using AutoDock Vina, we applied computational protein–ligand binding modelling to perform a virtual screening around 300 selected compounds against these three proteins, including FDA-approved drugs, FDA-unapproved drugs, investigational-only drugs and natural bioactive compounds. ADME parameters, toxicity risk and biological activity of those compounds were approximated via in silico methods. Our computational studies identified six ligands as potential inhibitors against Rhizopus delemar, including 12,28-Oxamanzamine A, vialinin B and deoxytopsentin for CotH3; pramiconazole and saperconazole for Lanosterol 14 alpha-demethylase; and Hesperidin for Mucoricin. Interestingly, 12,28-Oxamanzamine A showed a maximum binding affinity with all three proteins (CotH3: − 10.2 kcal/mol Lanosterol 14 alpha-demethylase: − 10.9 kcal/mol Mucoricin: − 8.6 kcal/mol).ConclusionsIn summary, our investigation identified 12,28-Oxamanzamine A, vialinin B, deoxytopsentin, pramiconazole, saperconazole and hesperidin as potent bioactive compounds for treating mucormycosis that may be considered for further optimisation techniques and in vitro and in vivo studies.

2010-05-03·ChemMedChem3区 · 医学

Synthesis and in vitro and in vivo Antifungal Activity of the Hydroxy Metabolites of Saperconazole

3区 · 医学

Article

作者: Stef Leurs ; Luc Van der Eycken ; Leo J. J. Backx ; Lieven Meerpoel ; Andre Van Breda ; Paul Luyts ; Danny Bellens ; Louis J. E. Van der Veken ; Filip A. A. Woestenborghs ; Jan Heeres ; Pascal van Dorsselaer ; Alex De Groot ; Hugo F. Vanden Bossche ; David Corens ; Patrick J. M. G. Marichal ; Frans Van Gerven ; Gustaaf H. M. Willemsens ; Frank C. Odds ; Rob Hendrickx ; Johan Weerts ; Michel Oris

AbstractHerein we describe the scalable diastereoselective and enantioselective syntheses of eight enantiomers of hydroxy metabolites of saperconazole. The in vitro antifungal activity of the eight stereoisomers (compounds 1–8) was compared against a broad panel of Candida spp. (n=93), Aspergillus spp. (n=10), Cryptococcus spp. (n=19), and dermatophytes (n=27). The four 2S isomers 1–4 of the new agent were generally slightly more active than the four 2R isomers 5–8. All eight isomers were tested in a model of experimental A. fumigatus infection in guinea pigs by intravenous inoculation of the fungal conidia. Treatment doses were 1.25 mg kg−1 and 2.5 mg kg−1 per day. Infection severity was measured in terms of mean survival time (MST) after infection and mean tissue burdens in brain, liver, spleen, and kidney at postmortem examination. Among the eight isomers, the 2S diastereomers 1–4 showed a generally higher level of activity than the 2R diastereomers 5–8, revealing compounds 1 and 4 as the most potent overall in eradicating tissue burden and MST. Compared with reference compounds itraconazole and saperconazole, the hydroxy isomers 1–8 are less potent inhibitors of the growth of A. fumigatus in vitro and of ergosterol biosynthesis in both A. fumigatus and C. albicans.

1999-05-01·Journal of Antimicrobial Chemotherapy2区 · 医学

Comparison of the toxicity of fluconazole and other azole antifungal drugs to murine and human granulocyte -macrophage progenitor cells in vitro

2区 · 医学

Article

作者: Kovacs, P. ; Megyeri, A. ; Somogyi, G. ; Kiss, A. ; Kraicsovits, F. ; Benko, I. ; Hernadi, F. ; Tegyey, Z.

We studied the inhibitory effects on colony formation by granulocyte-macrophage colony forming units (cfu-gm) of eight azole antifungal agents in vitro. All agents, except fluconazole, inhibited colony formation dose-dependently with 50% inhibitory concentrations (IC50) in the range of 0.78-49 micromol/L in cultures of murine and human bone marrow. For human cells, the IC50 values were 0.553 mg/L for itraconazole, 1.24 mg/L for saperconazole, 2.58 mg/L for clotrimazole, 5.33 mg/L for miconazole, 6.17 mg/L for econazole, 6.27 mg/L for ketoconazole and 8.38 mg/L for oxiconazole. The IC50 of itraconazole for human cfu-gm in vitro was similar to the plasma level of this drug recommended for systemic antifungal therapy (>0.5 mg/L) thus indicating the potential clinical relevance of our data. The IC50 of ketoconazole for human cfu-gm in vitro may be exceeded by plasma levels produced in vivo by high (> or =400 mg) doses, whereas fluconazole failed to reduce colony formation by 50% even at 100 mg/L, a concentration not reached in vivo even after extremely high doses (2000 mg/day). To most of the drugs studied, murine progenitor cells seemed to be less sensitive than the human ones. There was, however, a close correlation between the murine and human log IC50 values of the drugs (r2 = 0.964, P< 0.001), suggesting that cultures of murine bone marrow may be suitable to predict the in-vitro toxicity of azole antifungals to human cfu-gm.

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KEGG	Wiki	ATC	Drug Bank
D05800	-	-	-

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适应症	最高研发状态	国家/地区	公司	日期
真菌病	临床2期	英国	Cilag AG	-
真菌病	临床2期	美国	Janssen Pharmaceuticals, Inc.	-
真菌病	临床2期	比利时	-	-
真菌病	临床2期	-	Johnson & Johnson	-