Design, synthesis and evaluation of 2-phenylpyrimidine derivatives as novel antifungal agents targeting CYP51 DOI

Zixuan Gao,

Jiachen Zhang,

Kejian Li

et al.

RSC Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 15(2), P. 492 - 505

Published: Nov. 21, 2023

Invasive fungal infections, with high morbidity and mortality, have become one of the most serious threats to human health. There are a few kinds clinical antifungal drugs but large amounts them used, so there is an urgent need for new structural type drug. In this study, we carried out three rounds optimisation modification compound YW-01, which was obtained from preliminary screening group, by using strategy scaffold hopping. A series novel phenylpyrimidine CYP51 inhibitors were designed synthesised.

Language: Английский

The Significance of Mono‐ and Dual‐Effective Agents in the Development of New Antifungal Strategies DOI Creative Commons

Cengiz Zobi,

Öztekin Algül

Chemical Biology & Drug Design, Journal Year: 2025, Volume and Issue: 105(1)

Published: Jan. 1, 2025

ABSTRACT Invasive fungal infections (IFIs) pose significant challenges in clinical settings, particularly due to their high morbidity and mortality rates. The rising incidence of these infections, coupled with increasing antifungal resistance, underscores the urgent need for novel therapeutic strategies. Current drugs target cell membrane, wall, or intracellular components, but resistance mechanisms such as altered drug‐target interactions, enhanced efflux, adaptive cellular responses have diminished efficacy. Recent research has highlighted potential dual inhibitors that simultaneously multiple pathways enzymes involved growth survival. Combining pharmacophores, lanosterol 14α‐demethylase (CYP51), heat shock protein 90 (HSP90), histone deacetylase (HDAC), squalene epoxidase (SE) inhibitors, led development compounds activity reduced resistance. This dual‐target approach, along chemical scaffolds, not only represents a promising strategy combating is also being utilized anticancer agents. review explores new agents employ mono‐, dual‐, multi‐target strategies combat IFIs. We discuss emerging targets, mechanisms, innovative approaches offer hope managing challenging infections.

Language: Английский

Citations

2
Conjugates of amphotericin B to resolve challenges associated with its delivery DOI
Vineet Jain, Keerti Jain, Harvinder Popli

et al.

Expert Opinion on Drug Delivery, Journal Year: 2024, Volume and Issue: 21(2), P. 187 - 210

Published: Jan. 20, 2024

Introduction Amphotericin B (AmB), a promising antifungal and antileishmanial drug, acts on the membrane of microorganisms. The clinical use AmB is limited due to issues associated with its delivery including poor solubility bioavailability, instability in acidic media, intestinal permeability, dose aggregation state dependent toxicity, parenteral administration, requirement cold chain for transport storage, etc.

Language: Английский

Citations

6
Effect of Defined Block Sequence Terpolymers on Antifungal Activity and Biocompatibility DOI Open Access

Hatu Gmedhin,

Sebastian Schaefer,

Nathaniel Corrigan

et al.

Macromolecular Bioscience, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 7, 2025

Invasive fungal infections cause over 3.7 million deaths worldwide annually, underscoring the critical need for new antifungal agents. Developing selective agents is challenging due to shared eukaryotic nature of both and mammalian cells. Toward addressing this, synthetic polymers designed mimic host defense peptides are promising candidates combating infections. This study investigates well-defined multiblock terpolymers with specific arrangements cationic, hydrophobic, hydrophilic groups, as potential The block sequence in these copolymers significantly impacts their minimum inhibition concentration (MIC) against Candida albicans biocompatibility. Furthermore, compared statistical counterparts, exhibit lower MIC values certain instances. Notably, triblock containing a central hydrophobic present an enhanced efficacy These findings highlight sequence-controlled versatile platform developing customized targeted therapies.

Language: Английский

Citations

0
Antifungal Activity and Mechanism of Diaporthein B against Botryosphaeria dothidea in Prevention of Apple Ring Rot DOI

Hui-Fang Du,

Yahui Zhang,

Wan Li

et al.

Journal of Agricultural and Food Chemistry, Journal Year: 2024, Volume and Issue: 72(38), P. 20892 - 20904

Published: Sept. 10, 2024

Apple ring rot, caused by the pathogenic fungus

Language: Английский

Citations

3
Alkyl Tail Variation on Chalcone‐Based Quaternary Pyridinium Salts as Rule‐of‐Thumb for Antimicrobial Activity DOI Creative Commons
Francesca Seghetti, Riccardo Ocello, Alessandra Bisi

et al.

Archiv der Pharmazie, Journal Year: 2025, Volume and Issue: 358(5)

Published: May 1, 2025

ABSTRACT Aiming at developing a new class of quaternary pyridinium salts, the lead compound 1 , characterized by pyridine‐3‐yl chalcone framework, was rationally modified inserting alkyl functions varying from 6 to 18 carbon units. Among set, some valuable compounds were identified. Derivatives 4 – primarily active against Staphylococcus aureus and Candida albicans respectively (MIC = 1.56 3.125 μM). In comparison, analogs 5 showed significant activities Escherichia coli 6.25 Interestingly, antimicrobial property as well their antibiofilm activity, occurred lower concentrations than cyto‐ erythrocyte toxicities, thus ensuring favorable safety profile. Structure–activity relationship analysis highlighted critical role tail length in optimal results observed for moieties ranging 10 14 Molecular dynamics studies performed on 2 modeling them Gram‐positive Gram‐negative membranes that derivatives, upon diffusing across periodic boundary conditions, able intercalate into microbial membranes. The difference diffusion rates provides useful information support diverse potencies newly designed salt.

Language: Английский

Citations

0
Exploring the molecular structure of lipids in the design of artificial lipidated antifungal proteins DOI Creative Commons
Hendra Saputra, Muhammad Safaat,

Kazuki Uchida

et al.

RSC Pharmaceutics, Journal Year: 2024, Volume and Issue: 1(2), P. 372 - 378

Published: Jan. 1, 2024

The antifungal activity of a small chitin-binding domain from chitinase was enhanced by the artificial lipidation with specific alkyl chain length and structure in presence amphotericin B.

Language: Английский

Citations

1
Polyene-Based Derivatives with Antifungal Activities DOI Creative Commons
Kwanele Ngece,

Thabisa L. Ntondini,

Vuyolwethu Khwaza

et al.

Pharmaceutics, Journal Year: 2024, Volume and Issue: 16(8), P. 1065 - 1065

Published: Aug. 14, 2024

Polyenes are a class of organic compounds well known for their potent antifungal properties. They effective due to ability target and disrupt fungal cell membranes by binding ergosterol forming pores. Despite effectiveness as drugs, polyenes have several limitations, such high toxicity the host poor solubility in water. This has prompted ongoing research develop safer more efficient derivatives overcome limitations while enhancing activity. In this review article, we present thorough analysis polyene derivatives, structural modifications, influence on therapeutic effects against various strains. Key studies discussed, illustrating how modifications led improved By evaluating latest advancements synthesis highlight that incorporating amide linkers at carboxylic moiety molecules notably improves properties, evidenced 4, 5, 6G, 18. can help design development novel polyene-based with activities.

Language: Английский

Citations

1
Insights into the antifungal activity and mechanisms of cinnamon components against Aspergillus flavus and Penicillium citrinum DOI

Wanning Liu,

Tao Wang, Erzheng Su

et al.

Food Research International, Journal Year: 2024, Volume and Issue: 197, P. 115291 - 115291

Published: Nov. 5, 2024

Language: Английский

Citations

1
Exploring the molecular structure of lipids in the design of artificial lipidated antifungal proteins DOI Open Access
Hendra Saputra, Muhammad Safaat, Pugoh Santoso

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: March 8, 2024

Abstract Fungal infections have been a concern for decades, yet effective and approved antifungal agents are limited. We recently developed potential method to enhance the activity of small chitin-binding domain (LysM) from Pteris ryukyuensis chitinase A (PrChiA) by site-specific introduction palmitoyl (C16) group catalyzed microbial transglutaminase (MTG). Herein, we attempted conjugation series lipid-peptide substrates with LysM genetically fused C-terminal MTG-reactive Q-tag (LysM-Q) yield LysM-lipid conjugates (LysM-lipids) different lengths (LysM-C12, -C14, -C16) numbers alkyl chains [LysM-(C12) 2 , - (C14) -(C16) ]. The enzymatic proceeded smoothly all LysM-lipids, except LysM-(C16) because low aqueous dispersibility hydrophobic substrate. combination amphotericin B (AmB) LysM-C14 or LysM-C16 exhibited highest performance against Trichoderma viride whereas alterations in number were not enhancing LysM-lipids. Fluorescent microscopic analysis showed that fungal cell wall was stained C14- C16-modified LysM-muGFP fusion proteins when combined AmB, suggesting synergistic action AmB LysM-lipids suitable lipid length. All minimum cytotoxicity toward mammalian cells, could be safe additive development new formulations.

Language: Английский

Citations

0
Evaluation of few bioactive components of spice origin for their antimicrobial potential towards microbes commonly implicated in food spoilage and foodborne pathogenesis DOI Creative Commons
Mamta Bhatia,

Alka Sharma

Journal of Applied and Natural Science, Journal Year: 2024, Volume and Issue: 16(1), P. 308 - 314

Published: March 20, 2024

Natural components isolated from spices are gaining the attention of food researchers to prevent growth microbes associated with spoilage and foodborne pathogenesis meet ever-increasing consumers’ demand for safe wholesome free harmful synthetic preservatives. In present study, five bioactive spice origin, namely, allylisothiocyanate (AITC), cinnamic aldehyde (CIA), cuminic (CUA), eugenol (EU), menthol (MT) were evaluated their antimicrobial potential towards six bacterial strains (Bacillus cereus, Escherichia coli, Pseudomonas aeruginosa, alcaligenes, Shigella sonnei, Staphylococcus aureus) eleven fungal (Alternaria solani, Aspergillus niger, Botrytis cinerea, Cladosporium herbarum, Fusarium oxysporum, Geotrichum candidum, Penicillium citrinum, expansum, Phoma exigua, Rhizopus arrhizus stolonifer), by opting agar well diffusion assay, impregnated paper disc method broth dilution technique. All these seventeen pose deleterious effects on human health. Among compounds, CIA CUA turned out be most potent inhibitors microorganisms, whereas MT was found least effective. Lower concentrations components, ranging 1.95 µL/mL 15.62 µL/mL, needed inhibit fungi, while higher 1000 strains. tested, gram-negative bacteria inhibited at component concentration levels (31.25 µL/mL-1000 µL/mL) compared gram-positive bacteria. The study updates existing information potency natural substances, paving way further research establishing as ‘natural additives’.

Language: Английский

Citations

0