Synthesis of 25-aminosterols, new antifungal agents

Beuchet, P.; Dherbomez, Michel; Elkiel, L.; Charles, G.; Letourneux, Yves

doi:10.1016/s0960-894x(99)00233-4

Cited by 14 publications

(5 citation statements)

References 11 publications

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“…A group of triterpene and steroids were also found including epidihydrocholesterin, androstenediol, and methandriol. Several reports of related structures for these compounds also support our findings as hit candidates [60–65]. Two tropane derivatives were also found, they are structurally related to benzotropine which has been reported as active [57].…”

Section: Resultssupporting

confidence: 88%

Similarity searching for anticandidal agents employing a repurposing approach

Rodríguez‐Villar,

Cortés‐Benítez,

Palacios‐Espinosa

et al. 2024

Molecular Informatics

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Fungal infections caused by Candida are still a public health concern. Particularly, the resistance to traditional chemotherapeutic agents is a major issue that requires efforts to develop new therapies. One of the most interesting approaches to finding new active compounds is drug repurposing aided by computational methods. In this work, two databases containing anticandidal agents and drugs were studied employing cheminformatics and compared by similarity methods. The results showed 36 drugs with high similarities to some candicidals. From these drugs, trimetozin, osalmid and metochalcone were evaluated against C. albicans (18804), C. glabrata (90030), and miconazole‐resistant strain C. glabrata (32554). Osalmid and metochalcone were the best, with activity in the micromolar range. These findings represent an opportunity to continue with the research on the potential antifungal application of osalmid and metochalcone as well as the design of structurally related derivatives.

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Section: Resultssupporting

confidence: 88%

Similarity searching for anticandidal agents employing a repurposing approach

Rodríguez‐Villar,

Cortés‐Benítez,

Palacios‐Espinosa

et al. 2024

Molecular Informatics

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“…The fungal ability to Cmethylate sterols is the only proven difference in sterol synthetic pathways between humans and opportunistic pathogens; as such, the SMT is considered to be a unique target for rational drug design (7)(8)(9). Cultures of Saccharomyces cereVisiae, Candida albicans, or Gibberella fujikori in the presence of SMT inhibitors such as 25-azalanosterol 5 result in the decreased production of ergosterol 4, the accumulation of zymosterol 2, and the inhibition of growth, supporting its identification as a critical step (Scheme 1) (10)(11)(12)(13)(14)(15).…”

mentioning

confidence: 96%

Sterol Methyltransferase: Functional Analysis of Highly Conserved Residues by Site-Directed Mutagenesis

et al. 2003

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Sterol methyltransferase (SMT), the enzyme from Saccharomyces cerevisiae that catalyzes the conversion of sterol acceptor in the presence of AdoMet to C-24 methylated sterol and AdoHcy, was analyzed for amino acid residues that contribute to C-methylation activity. Site-directed mutagenesis of nine aspartate or glutamate residues and four histidine residues to leucine (amino acids highly conserved in 16 different species) and expression of the resulting mutant proteins in Escherichia coli revealed that residues at H90, Asp125, Asp152, Glu195, and Asp276 are essential for catalytic activity. Each of the catalytically impaired mutants bound sterol, AdoMet, and 25-azalanosterol, a high energy intermediate analogue inhibitor of C-methylation activity. Changes in equilibrium binding and kinetic properties of the mutant enzymes indicated that residues required for catalytic activity are also involved in inhibitor binding. Analysis of the pH dependence of log kcat/Km for the wild-type SMT indicated a pH optimum for activity between 6 and 9. These results and data showing that only the mutant H90L binds sterol, AdoMet, and inhibitor to similar levels as the wild-type enzyme suggest that H90 may act as an acceptor in the coupled methylation-deprotonation reaction. Circular dichroism spectra and chromatographic information of the wild-type and mutant enzymes confirmed retention of the overall conformation of the enzyme during the various experiments. Taken together, our studies suggest that the SMT active center is composed of a set of acidic amino acids at positions 125, 152, 195, and 276, which contribute to initial binding of sterol and AdoMet and that the H90 residue functions subsequently in the reaction progress to promote product formation.

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“…Other reports on lanosterol derivatives with amine functionality in the side chain to assess their potency as anti-fungal agents have been described. [35][36][37][38] The majority of research has documented strong antifungal activity in vitro with C-3 and C-24 derivatives.…”

Section: Introductionmentioning

confidence: 99%