Three-Dimensional Quantitative Structure−Activity Relationship (QSAR) and Receptor Mapping of Cytochrome P-45014αDM Inhibiting Azole Antifungal Agents

Talele, Tanaji T.; Kulkarni, Vithal M.

doi:10.1021/ci9800413

Cited by 24 publications

(17 citation statements)

References 15 publications

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“…Unfortunately the predictions based on docking analysis in this model could not be confirmed by X-ray crystallography [ 139 ]. Furthermore a three-dimensional quantitative structure-activity model has been described [ 140 ].…”

Section: Mode Of Actionmentioning

confidence: 99%

Conazoles

Heeres¹,

2010

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This review provides a historical overview of the analog based drug discovery of miconazole and its congeners, and is focused on marketed azole antifungals bearing the generic suffix “conazole”. The antifungal activity of miconazole, one of the first broad-spectrum antimycotic agents has been mainly restricted to topical applications. The attractive in vitro antifungal spectrum was a starting point to design more potent and especially orally active antifungal agents such as ketoconazole, itraconazole, posaconazole, fluconazole and voriconazole. The chemistry, in vitro and in vivo antifungal activity, pharmacology, and clinical applications of these marketed conazoles has been described.

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Section: Mode Of Actionmentioning

confidence: 99%

Conazoles

Heeres¹,

2010

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“…The piperazine rings have chair conformations, and the benzene ring is distorted because three atoms of the ring are split on the basis of their thermal parameters [55,56] . Phenylpiperazine ring has no contribution to interact with the heme group CYP51, it interacts with amino acid residues in the substrate access channel [68–73] . The anisotropy and span of the carbon nuclei on the phenylpiperazine ring are low.…”

Section: Resultsmentioning

confidence: 99%

A Description of the Local Structure and Dynamics of Ketoconazole Molecule by Solid‐State NMR Measurements and DFT Calculations: Proposition for NMR Crystallography

Dey

Deshmukh

Ghosh³

2021

ChemistrySelect

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An azole class antifungal agent, ketoconazole, is widely used in the treatment of mucosal fungal infections that arise due to AIDS immunosuppression, organ transplantation, and cancer chemotherapy. The structure and dynamics of various molecular moieties of ketoconazole are thoroughly studied by measuring chemical shift anisotropy tensor and site‐specific spin‐lattice relaxation time. The local correlation time at crystallographically different carbon nuclei sites is also calculated. The chemical shift anisotropy (CSA) parameters at the crystallographically distinct sites of ketoconazole are determined by the two‐dimensional phase‐adjusted spinning sideband (2D PASS) cross‐polarization magic angle spinning (CP‐MAS) solid‐state NMR experiment. The site‐specific spin‐lattice relaxation time is measured by the method outlined by Torchia (T1CP). The values of the principal components of CSA parameters extracted by the 2DPASS CP‐MAS ssNMR experiment are supported by density functional theory (DFT) calculations. The CSA parameters are high for those carbon nuclei, whose spin‐lattice relaxation rate is slow, and it is low for those carbon nuclei whose spin‐lattice relaxation rate is fast. It suggests that the spin‐lattice relaxation mechanism is mainly governed by chemical‐shift anisotropy interaction for these carbon nuclei. A huge variation of the spin‐lattice relaxation time and the local correlation time are observed for numerous carbon nuclei that reside on the side‐chain of the molecule. The spin‐lattice relaxation time varies from 500 s to 8 s, and the order of the local correlation time varies from 10-4 s to 10-7 s. These types of studies in which the chemical shift anisotropy (CSA) parameters and spin‐lattice relaxation time provide information about the electronic configuration and the spin dynamics at the various crystallographic locations of the drug molecule will enrich the field “NMR crystallography.” It will also help to develop the strategies for the administration of antifungal drugs by providing information about the structure and dynamics of various parts of the drug molecule.

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“…5 Indeed, several three-dimensional quantitative structure-activity relationship studies (3D QSAR) have been reported for different datasets of azole derivatives 2,6,[9][10][11][12] however, this strategy afforded models with moderate robustness and local predictive ability only. For instance, Di Santo and co-workers 1 report that their CoMFA model was contradicted by the synthesis and evaluation of novel compounds.…”

Section: Ketoconazole Nystatin Caspofugin Naftifinementioning

confidence: 99%

“…6,7 Nevertheless, some antifungal drugs are either highly toxic (e.g., amphotericin B, AMB) or becoming ineffective against resistant strains that affect mostly hospitalized patients (e.g., flucytosine and azoles). 3 In fact, azole resistance is a major concern in long-course treatment of AIDS patients.…”

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confidence: 99%

2D QSAR studies on a series of bifonazole derivatives with antifungal activity

Mota¹,

Barros²,

Castilho³

2009

J. Braz. Chem. Soc.

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Candida albicans (CA) é considerado como o principal patógeno oportunista em pacientes imunossuprimidos. A maior parte dos fármacos disponíveis para o tratamento de cepas resistentes são altamente tóxicos ou ineficazes. Uma forma de amenizar esse cenário seria através de modificações na estrutura de derivados de azóis que resultassem no aumento da potência e seletividade. Visando esclarecer quais propriedades químicas e estruturais são importantes para atividade antifúngica de derivados de azol, estudos de QSAR 2D clássico e holograma QSAR (HQSAR) foram realizados para um conjunto diverso de 52 derivados de bifonazol com atividade antifúngica. Os descritores topológicos utilizados nos estudos de QSAR 2D clássico originaram modelos com baixa consistência interna (r 2 = 0,38, q 2 = 0,27) e poder preditivo nulo (r 2 pred = −0,6). Por outro lado, a utilização de hologramas moleculares possibilitou a criação de modelos de HQSAR robustos (r 2 = 0,92, q 2 = 0,65) e com bom poder preditivo (r 2 pred = 0,79).Candida albicans (CA) has been identified as the major opportunistic pathogen in immunosuppressed patients. Most of currently available drugs are either highly toxic or becoming ineffective against resistant strains. An approach to overcome this burden relies on azole derivatives with increased potency and selectivity. Aiming at shedding some light on structural and chemical features that are important for the antifungal activity of azole derivatives, classical 2D QSAR and hologram QSAR (HQSAR) studies were performed for a diverse set of 52 bifonazole derivatives with antifungal activity. Topological descriptors, employed in Classical QSAR studies, resulted in models with low correlation (r 2 = 0.38, q 2 = 0.27) and lack of predictive power (r 2 pred = −0.6). On the other hand molecular holograms afforded HQSAR models with good correlation coefficients (r 2 = 0.92, q 2 = 0.65) and good predictive ability (r 2 pred = 0.79).

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Three-Dimensional Quantitative Structure−Activity Relationship (QSAR) and Receptor Mapping of Cytochrome P-450₁₄_α_DM Inhibiting Azole Antifungal Agents

Cited by 24 publications

References 15 publications

Conazoles

Conazoles

A Description of the Local Structure and Dynamics of Ketoconazole Molecule by Solid‐State NMR Measurements and DFT Calculations: Proposition for NMR Crystallography

2D QSAR studies on a series of bifonazole derivatives with antifungal activity

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