Delving into the Latest Updates on Bifonazole with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

(+-)-1-(p,alpha-Diphenylbenzyl)imidazole, 1-((4-Biphenylyl)phenylmethyl)-1H-imidazole, 1-(alpha-(4-Biphenylyl)benzyl)imidazole

+ [22]

Target

fungal CYP51A1

Mechanism

fungal CYP51A1 inhibitors(Fungal CYP51A1 inhibitors)

Therapeutic Areas

Infectious DiseasesSkin and Musculoskeletal Diseases

Active Indication

CandidiasisTinea PedisTinea Versicolor+ [1]

Inactive Indication

Onychomycosis

Originator Organization

Bayer Yakuhin Ltd.

Active Organization

Bayer Yakuhin Ltd.

Inactive Organization

Bayer AG

Drug Highest PhaseApproved

First Approval Date

JP (08 May 2009),

CandidiasisTinea PedisTinea Versicolor

Regulation-

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Structure

Molecular FormulaC22H18N2

InChIKeyOCAPBUJLXMYKEJ-UHFFFAOYSA-N

CAS Registry60628-96-8

Esophageal squamous cell carcinoma (ESCC), a malignancy of the digestive system, is highly prevalent and the primary cause of cancer-related deaths worldwide due to the lack of early diagnostic biomarkers and effective therapeutic targets. Dysregulated ribonucleotide reductase (RNR) expression has been confirmed to be causally linked to tumorigenesis. This study demonstrated that ribonucleotide reductase small subunit M2 (RRM2) is significantly upregulated in ESCC tissue and that its expression is negatively correlated with clinical outcomes. Mechanistically, HuR promotes RRM2 mRNA stabilization by binding to the adenine/uridine (AU)-rich elements (AREs) within the 3'UTR, resulting in persistent overexpression of RRM2. Furthermore, bifonazole is identified as an inhibitor of HuR via computational screening and molecular docking analysis. Bifonazole disrupts HuR-ARE interactions by competitively binding to HuR at F65, R97, I103, and R153 residues, resulting in reduced RRM2 expression. Furthermore, bifonazole exhibited antitumor effects on ESCC patient-derived xenograft (PDX) models by decreasing RRM2 expression and the dNTP pool. In summary, this study reveals the interaction network among HuR, RRM2, and bifonazole and demonstrated that bifonazole is a potential therapeutic compound for ESCC through inhibition of the HuR/RRM2 axis.

01 Oct 2024·Protein Science

Multiresolution molecular dynamics simulations reveal the interplay between conformational variability and functional interactions in membrane‐bound cytochrome P450 2B4

Article

Author: Wade, Rebecca C. ; Teuffel, Jonathan ; Han, Sungho Bosco ; Mukherjee, Goutam

AbstractCytochrome P450 2B4 (CYP 2B4) is one of the best‐characterized CYPs and serves as a key model system for understanding the mechanisms of microsomal class II CYPs, which metabolize most known drugs. The highly flexible nature of CYP 2B4 is apparent from crystal structures that show the active site with either a wide open or a closed heme binding cavity. Here, we investigated the conformational ensemble of the full‐length CYP 2B4 in a phospholipid bilayer, using multiresolution molecular dynamics (MD) simulations. Coarse‐grained MD simulations revealed two predominant orientations of CYP 2B4's globular domain with respect to the bilayer. Their refinement by atomistic resolution MD showed adaptation of the enzyme's interaction with the lipid bilayer, leading to open configurations that facilitate ligand access to the heme binding cavity. CAVER analysis of enzyme tunnels, AquaDuct analysis of water routes, and Random Acceleration Molecular Dynamics simulations of ligand dissociation support the conformation‐dependent passage of molecules between the active site and the protein surroundings. Furthermore, simulation of the re‐entry of the inhibitor bifonazole into the open conformation of CYP 2B4 resulted in binding at a transient hydrophobic pocket within the active site cavity that may play a role in substrate binding or allosteric regulation. Together, these results show how the open conformation of CYP 2B4 facilitates the binding of substrates from and release of products to the membrane, whereas the closed conformation prolongs the residence time of substrates or inhibitors and selectively allows the passage of smaller reactants via the solvent and water channels.

01 Sep 2024·Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy

Bifonazole caffeate: The first molecular salt of bifonazole with enhanced biopharmaceutical property based on experiments and quantum chemistry research

Article

Author: Wang, Ling-Yang ; Li, Yan-Tuan ; Wu, Zhi-Yong ; Meng, Su-Su ; Bu, Fan-Zhi

In order to make novel breakthroughs in molecular salt studies of BCS class-IV antifungal medication bifonazole (BIF), a salification-driven strategy towards ameliorating attributes and aiding augment efficiency is raised. This strategy fully harnesses structural characters together attributes and benefits of caffeic acid (CAF) to concurrently enhance dissolvability and permeability of BIF by introducing the two ingredients into the identical molecular salt lattice through the salification reaction, which, coupled with the aroused potential activity of CAF significantly amplifies the antifungal efficacy of BIF. Guided by this route, the first BIF-organic molecular salt, BIF-CAF, is directionally designed and synthesized with satisfactorily structural characterizations and integrated theoretical and experimental explorations on the pharmaceutical properties. Single-crystal X-ray diffraction resolving confirms that there is a lipid-water amphiphilic sandwich structure constructed by robust charge-assistant hydrogen bonds in the salt crystal, endowing the molecular salt with the potential to enhance both dissolvability and permeability relative to the parent drug, which is validated by experimental evaluations. Remarkably, the comprehensive DFT-based theoretical investigations covering frontier molecular orbital, molecular electrostatic potential, Hirshfeld surface analysis, reduced density gradient, topology, sphericity and planarity analysis strongly support these observations, thereby allowing some positive relationships between macroscopic properties and microstructures of the molecular salt can be made. Intriguingly, the optimal properties, together with the stimulated activity of CAF markedly augment in vitro antifungal ability of the molecular salt, with magnifying inhibition zones and reducing minimum inhibitory concentrations. These findings fill in the gaps on researches of BIF-organic molecular salt, and adequately exemplify the feasibility and validity by integrating theoretical and experimental approaches to resolve BIF's problems via the salification-driven tactic.

100 Deals associated with Bifonazole

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External Link

KEGG	Wiki	ATC	Drug Bank
D01775	Bifonazole	D01AC10	DB04794

R&D Status

Approved

10 top approved records.

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Indication	Country/Location	Organization	Date
Candidiasis	JP	Bayer Yakuhin Ltd.	08 May 2009
Tinea Pedis	JP	Bayer Yakuhin Ltd.	08 May 2009
Tinea Versicolor	JP	Bayer Yakuhin Ltd.	08 May 2009
Mycoses	-	-	-

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Tinea Pedis	Phase 2	DE	Bayer AG	01 Dec 2009
Onychomycosis	Phase 2	DE	Bayer AG	01 Oct 2008
Onychomycosis	Phase 2	CZ	Bayer AG	01 Oct 2008
Onychomycosis	Phase 2	PL	Bayer AG	01 Oct 2008