Formation and Cleavage of C–C Bonds by Enzymatic Oxidation–Reduction Reactions

Chemical Reviews, Journal Year: 2018, Volume and Issue: 118(14), P. 6573 - 6655

Published: June 22, 2018

Many oxidation–reduction (redox) enzymes, particularly oxygenases, have roles in reactions that make and break C–C bonds. The list includes cytochrome P450 other heme-based monooxygenases, dioxygenases, nonheme iron mono- flavoproteins, radical S-adenosylmethionine copper peroxidases. Reactions involve steroids, intermediary metabolism, secondary natural products, drugs, industrial agricultural chemicals. bonds are formed via either (i) coupling of diradicals or (ii) generation unstable products rearrange. cleavage several themes: rearrangement oxidized produced by the oxidation collapse radicals cations rearrangement, (iii) oxygenation to yield readily hydrolyzed (iv) activation O2 systems which binding a substrate facilitates activation. enzymes metals, but these, is clearly predominant.

Language: Английский

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History of the development of antifungal azoles: A review on structures, SAR, and mechanism of action

Bioorganic Chemistry, Journal Year: 2020, Volume and Issue: 104, P. 104240 - 104240

Published: Aug. 28, 2020

Language: Английский

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The Fungal CYP51s: Their Functions, Structures, Related Drug Resistance, and Inhibitors

Frontiers in Microbiology, Journal Year: 2019, Volume and Issue: 10

Published: April 24, 2019

CYP51 (Erg11) belongs to the cytochrome P450 monooxygenase (CYP) superfamily and mediates a crucial step of synthesis ergosterol, which is fungal-specific sterol. It also target azole drugs in clinical practice. In recent years, researches on fungal have stepped into new stage attributing discovery crystal structures homologs C. albicans, neoformans A. fumigatus. This review summarizes functions, proteins, inhibitors targeting these homologs. particular, several drug-resistant mechanisms associated with CYP51s are introduced. The sequences proteins different species compared. These will provide insights for advancement research antifungal agents.

Language: Английский

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Molecular mechanisms governing antifungal drug resistance

npj Antimicrobials and Resistance, Journal Year: 2023, Volume and Issue: 1(1)

Published: July 17, 2023

Abstract Fungal pathogens are a severe public health problem. The leading causative agents of systemic fungal infections include species from the Candida , Cryptococcus and Aspergillus genera. As opportunistic pathogens, these fungi generally harmless in healthy hosts; however, they can cause significant morbidity mortality immunocompromised patients. Despite profound impact pathogenic on global human health, current antifungal armamentarium is limited to only three major classes drugs, all which face complications, including host toxicity, unfavourable pharmacokinetics, or spectrum activity. Further exacerbating this issue growing prevalence antifungal-resistant emergence multidrug-resistant pathogens. In review, we discuss diverse strategies employed by evolve resistance, drug target alterations, enhanced efflux, induction cellular stress response pathways. Such mechanisms resistance occur through genetic point mutations, aneuploidy formation, epigenetic changes given plasticity observed many genomes. Additionally, highlight recent literature surrounding governing emerging auris glabrata . Advancing our knowledge molecular adapt challenge exposure imperative for designing therapeutic tackle threat resistance.

Language: Английский

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Fungal Drug Response and Antimicrobial Resistance

Journal of Fungi, Journal Year: 2023, Volume and Issue: 9(5), P. 565 - 565

Published: May 12, 2023

Antifungal resistance is a growing concern as it poses significant threat to public health. Fungal infections are cause of morbidity and mortality, especially in immunocompromised individuals. The limited number antifungal agents the emergence have led critical need understand mechanisms drug resistance. This review provides an overview importance resistance, classes agents, their mode action. It highlights molecular including alterations modification, activation, availability. In addition, discusses response drugs via regulation multidrug efflux systems drug–target interactions. We emphasize understanding develop effective strategies combat highlight for continued research identify new targets development explore alternative therapeutic options overcome Overall, its will be indispensable field clinical management fungal infections.

Language: Английский

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Indole clubbed 2,4‐thiazolidinedione linked 1,2,3‐triazole as a potent antimalarial and antibacterial agent against drug‐resistant strain and molecular modeling studies

Archiv der Pharmazie, Journal Year: 2024, Volume and Issue: 357(4)

Published: Jan. 21, 2024

Abstract In the face of escalating challenges microbial resistance strains, this study describes design and synthesis 5‐({1‐[(1 H ‐1,2,3‐triazol‐4‐yl)methyl]‐1 ‐indol‐3‐yl}methylene)thiazolidine‐2,4‐dione derivatives, which have demonstrated significant antimicrobial properties. Compared with minimum inhibitory concentrations (MIC) values ciprofloxacin on respective compounds 5a , 5d 5g 5l 5m exhibited potent antibacterial activity MIC ranging from 16 to 25 µM. Almost all synthesized showed lower compared standards against vancomycin‐resistant enterococcus methicillin‐resistant Staphylococcus aureus strains. Additionally, majority remarkable antifungal activity, Candida albicans Aspergillus niger as nystatin, griseofulvin, fluconazole. Furthermore, notable effects Plasmodium falciparum strain, having IC 50 1.31 2.79 μM standard quinine (2.71 μM). Cytotoxicity evaluation 5a–q SHSY‐5Y cells at up 100 μg/mL no adverse effects. Comparison control groups highlights their noncytotoxic characteristics. Molecular docking confirmed compound binding target active sites, stable protein–ligand complexes displaying drug‐like molecules. dynamics simulations revealed dynamic stability interactions. Rigorous tests molecular modeling unveil effectiveness drug‐resistant microbes, providing hope for new potential safety.

Language: Английский

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Current treatment options for vulvovaginal candidiasis caused by azole-resistant Candida species

Expert Opinion on Pharmacotherapy, Journal Year: 2018, Volume and Issue: 19(9), P. 971 - 977

Published: June 13, 2018

Clinicians are increasingly challenged by patients with refractory vulvovaginal candidiasis (VVC) caused azole-resistant Candida species. Fluconazole resistant C.albicans is a growing and perplexing problem following years of indiscriminate drug prescription unnecessary exposure for which there few therapeutic alternatives. Regrettably, although the azole class drugs has expanded, new classes antifungal have not been forthcoming, limiting effective treatment options in vaginitis.This review covers published data on epidemiology, pathophysiology women VVC.Fluconazole adds to challenge non-albicans spp. Both issues follow fluconazole exposure. Although an understanding resistance yeast established, this knowledge translated into useful advantage. Treatment such symptoms extremely limited. New strategies urgently needed meet resistance.

Language: Английский

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Emerging New Targets for the Treatment of Resistant Fungal Infections

Journal of Medicinal Chemistry, Journal Year: 2018, Volume and Issue: 61(13), P. 5484 - 5511

Published: Jan. 2, 2018

With the increasing morbidity and mortality of invasive fungal infections emergence severe antifungal drug resistance, new targets novel agents are urgently needed. Recently, better understanding pathogenesis has contributed to rapid potential targets. This perspective aims provide a comprehensive review medicinal chemistry efforts toward inhibitor discovery. Particular focus will be placed on druggability their treat resistant infections. Innovative strategies for next generation therapy, such as virulence factors, protein-protein interactions, immune response-based proteins, also highlighted.

Language: Английский

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A comprehensive overview of the medicinal chemistry of antifungal drugs: perspectives and promise

Chemical Society Reviews, Journal Year: 2020, Volume and Issue: 49(8), P. 2426 - 2480

Published: Jan. 1, 2020

The emergence of new fungal pathogens makes the development antifungal drugs a medical imperative that in recent years motivates talents numerous investigators across world.

Language: Английский

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CYP51 as drug targets for fungi and protozoan parasites: past, present and future

Parasitology, Journal Year: 2018, Volume and Issue: 145(14), P. 1820 - 1836

Published: April 12, 2018

Abstract The efficiency of treatment human infections with the unicellular eukaryotic pathogens such as fungi and protozoa remains deeply unsatisfactory. For example, mortality rates from nosocomial fungemia in critically ill, immunosuppressed or post-cancer patients often exceed 50%. A set six systemic clinical azoles [sterol 14 α -demethylase (CYP51) inhibitors] represents first-line antifungal treatment. All these drugs were discovered empirically, by monitoring their effects on fungal cell growth, though it had been proven that they kill cells blocking biosynthesis ergosterol at stage -demethylation sterol nucleus. This review briefs history azoles, outlines situation current azole-based drugs, describes attempts repurposing for protozoan parasites that, similar to fungi, also produce endogenous sterols, discusses most recently acquired knowledge CYP51 structure/function inhibition. It is our belief this information should be helpful shifting traditional phenotypic screening actual target-driven drug discovery paradigm, which will rationalize substantially accelerate development new, more efficient pathogen-oriented inhibitors.

Language: Английский

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