Novel Nucleosides As Potential Inhibitors of Fungal Lanosterol 14α-demethylase: an In Vitro and In Silico Study

Abstract

Aim: The global burden of fungal infections has transitioned from a case–specific observation to a major cause of high human mortality. Therefore, novel compounds with innovative methodologies need to be synthesized and evaluated for their antifungal potential to keep pace with the current clinical demands. Results: An efficient synthetic pathway was developed for the synthesis of 21 synthetic novel nucleosides. Two compounds had significant antifungal effect on Aspergillus fumigatus 3007, which was comparable to fluconazole. The experimental data (confocal microscopy, ultrahigh-performance liquid chromatography and flow cytometry) demonstrated the inhibition of fungal lanosterol 14α-demethylase. Conclusion: Owing to the therapeutic relevance of the synthesized nucleosides and simplicity of the procedure, the method may find its potential application for synthesis of antifungal agents.

Exploration of novel TOSMIC tethered imidazo[1,2‐a]pyridine compounds for the development of potential antifungal drug candidate

“…Each flask was inoculated with four fungal mycelia discs (8 mm diameter each) cut from the growing margins of Aspergillus fumigates 3007 and incubated at 30°C for 6 days. The fungal mat thus formed was harvested from the flask and homogenized with a pestle and mortar for ergosterol extraction as reported earlier (Shukla et al, 2019). The fractions were analyzed using UPLC (Waters), with the mobile phase a mixture of 95% methanol: acetonitrile (1:1) with 5% water, and the column used was C18.…”

“…%Radical scavenging activity (Shukla et al, 2019). The fractions were analyzed using UPLC (Waters), with the mobile phase a mixture of 95% methanol: acetonitrile (1:1) with 5% water, and the column used was C18.…”

Exploration of Novel TOSMIC Tethered Imidazo[1,2-a]pyridine Compounds for the Development of Potential Antifungal Drug Candidate.

“…Each ask was inoculated with four fungal mycelia discs (8 mm diameter each) cut from the growing margins of Aspergillus fumigates 3007 and incubated at 30°C for 6 days. The fungal mat thus formed was harvested from the ask and homogenized with a pestle and mortar for ergosterol extraction as reported earlier (18).…”

“…After that the reaction was screened for different solvents. Among the various solvents screened such as non polar (n-Hexane), Halogenated (DCM), polar aprotic (CH 3 CN, THF, CH 3 COCH 3 , DMF, CH 3 COOC 2 H 5 ) and polar protic (MeOH, H 2 O), a decrease in the yield was observed with the use of non polar and polar aprotic solvents (Table 1, entry [15][16][17][18][19] whereas polar protic gave the product in moderate yield (Table 1, entry [20][21][22]. EtOH was found to be appropriate solvent for the present reaction (Table 1, entry 11).…”

“…Encouraged by these observations and in continuation of our research work to discover novel compounds (16,17) and by the lead from our previous publication (18), the authors aimed to synthesize TOSMIC fused imidazo [1,2-a] pyridine compounds by using Groebke-Blackburn-Bienayme (GBB) multicomponent reaction. GBB reaction is a three-component-reaction (3CR) to afford the highly complexed structures by using 2-aminopyridine, aldehyde and an isocyanide and proceeds through subsequent formal [4+1] cycloaddition to form highly substituted heterocyclic compounds.…”