ABSTRACT
OBJECTIVES: In this study we investigated the in vitro fungistatic and fungicidal activities of CPA18 and CPA109, two azole compounds with original structural features, alone and in combination with fluconazole against fluconazole-susceptible and -resistant Candida albicans strains. METHODS: Antifungal activities were measured by MIC evaluation and time-kill studies. Azole binding analysis was performed by UV-Vis spectroscopy. Hyphal growth inhibition and filipin and propidium iodide staining assays were used for morphological analysis. An analysis of membrane lipids was also performed to gauge alterations in membrane composition and integrity. Synergism was calculated using fractional inhibitory concentration indices (FICIs). Evaluation of cytotoxicity towards murine macrophages was performed to verify selective antifungal activity. RESULTS: Even though their binding affinity to C. albicans Erg11p is comparable to that of fluconazole, CPA compounds are active against resistant strains of C. albicans with a mutation in ERG11 sequences and/or overexpressing the ABC transporter genes CDR1 and CDR2, which encode ATP-dependent efflux pumps. Moreover, CPA18 is fungistatic, even against the two resistant strains, and was found to be synergistic with fluconazole. Differently from fluconazole and other related azoles, CPA compounds induced marked changes in membrane permeability and dramatic alterations in membrane lipid composition. CONCLUSIONS: Our outcomes suggest that CPA compounds are able to overcome major mechanisms of resistance in C. albicans. Also, they are promising candidates for combination treatment that could reduce the toxicity caused by high fluconazole doses, particularly in immunocompromised patients.
Subject(s)
Antifungal Agents/pharmacology , Azoles/pharmacology , Candida albicans/drug effects , Animals , Antifungal Agents/toxicity , Azoles/toxicity , Candida albicans/growth & development , Candida albicans/physiology , Cell Membrane/drug effects , Cell Membrane/physiology , Cell Survival/drug effects , Drug Synergism , Filipin/metabolism , Hyphae/drug effects , Hyphae/growth & development , Hyphae/physiology , Macrophages/drug effects , Mice , Microbial Sensitivity Tests , Microbial Viability/drug effects , Propidium/metabolism , Staining and LabelingABSTRACT
A series of novel 4-phenylquinazoline-2-carboxamides (1-58) were designed as aza-isosters of PK11195, the well-known 18 kDa translocator protein (TSPO) reference ligand, and synthesized by means of a very simple and efficient procedure. A number of these derivatives bind to the TSPO with K(i) values in the nanomolar/subnanomolar range, show selectivity toward the central benzodiazepine receptor (BzR) and exhibit structure-affinity relationships consistent with a previously published pharmacophore/topological model of ligand-TSPO interaction.
Subject(s)
Carrier Proteins/metabolism , Quinazolines/chemical synthesis , Receptors, GABA-A/metabolism , Animals , Binding, Competitive , Cell Line, Tumor , Cell Survival/drug effects , Inhibitory Concentration 50 , Molecular Structure , Quinazolines/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
The anthranilic acid diamides represent the most recent class of nonpeptide CCK(1) receptor (CCK(1)-R) antagonists. Herein we describe the second phase of the anthranilic acid C-terminal optimization using nonproteinogenic amino acids containing a phenyl ring in their side chain. The Homo-Phe derivative 2 (VL-0797) enhanced 12-fold the affinity for the rat CCK(1)-R affinity and 15-fold for the human CCK(1)-R relative to the reference compound 12 (VL-0395). The eutomer of 2 (6) exhibited a nanomolar range affinity toward the human CCK(1)-R and was at least 400-fold selective for the CCK(1)-R over the CCK(2)-R. Molecular docking in the modeled CCK(1)-R and its validation by site-directed mutagenesis experiments showed that the 6 binding site overlaps that occupied by the C-terminal bioactive region of the natural agonist CCK. Owing to their interesting properties, new compounds provided by this study represent a solid basis for further advances aimed at synthesis of clinically valuable CCK(1)-R antagonists.
Subject(s)
Aminobutyrates/pharmacology , Heterocyclic Compounds/pharmacology , Receptor, Cholecystokinin A/antagonists & inhibitors , ortho-Aminobenzoates/chemistry , ortho-Aminobenzoates/pharmacology , Aminobutyrates/chemistry , Aminobutyrates/metabolism , Animals , Binding Sites/genetics , Binding, Competitive , COS Cells , Cerebral Cortex/metabolism , Chlorocebus aethiops , Gallbladder/drug effects , Gallbladder/physiology , Guinea Pigs , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/metabolism , Humans , In Vitro Techniques , Indoles/chemistry , Indoles/metabolism , Indoles/pharmacology , Male , Models, Molecular , Molecular Structure , Muscle Contraction/drug effects , Mutagenesis, Site-Directed , Mutation , Pancreas/metabolism , Rats , Rats, Sprague-Dawley , Receptor, Cholecystokinin A/genetics , Receptor, Cholecystokinin A/metabolism , Sincalide/metabolism , Sincalide/pharmacology , Structure-Activity Relationship , ortho-Aminobenzoates/metabolismABSTRACT
Several derivatives out of a series of antifungal agents exhibited a good inhibitory potency against aromatase as well as a fairly good selectivity toward CYP17, even if lacking H-bond accepting substituents. Their common structural feature is a flexible backbone that did not fit into previously reported CYP19 models. Thus, a ligand-based approach was exploited to develop a novel statistically robust, self-consistent and predictive 3D-QSAR model herein proposed as a helpful tool to design new aromatase inhibitors.
Subject(s)
Antifungal Agents/pharmacology , Aromatase Inhibitors/pharmacology , Drug Design , Steroid 17-alpha-Hydroxylase/antagonists & inhibitors , Antifungal Agents/chemical synthesis , Aromatase Inhibitors/chemical synthesis , Ligands , Quantitative Structure-Activity RelationshipABSTRACT
A new series of 3-phenyl-1-(1,1'-biphenyl-4-yl)-2-(1H-imidazol-1-yl)propane derivatives 2a-l (related to the antifungal bifonazole) was synthesized and tested for antimicrobial activity. A number of substituents on the phenyl ring were chosen to compare the relative biological properties with those of corresponding aza-analogues, previously described by us. The in vitro antifungal activities of the newly synthesized azoles were tested against several pathogenic fungi responsible for human disease. Test pathogens included representatives of yeasts (Candida albicans, Candida parapsilosis, Criptococcus neoformans), dermathophytes (Tricophyton verrucosum, Tricophyton rubrum, Microsporum gypseum) and moulds (Aspergillus fumigatus). Bifonazole and miconazole were used as reference drugs. Title compounds were prepared by alkylation of 1-biphenyl-4-yl-2-imidazol-1-yl-ethanone with the proper arylmethyl halide and subsequent reduction of corresponding ketones applying the Huang-Minlon modification of the Wolff-Kishner reaction.
Subject(s)
Amines/chemical synthesis , Antifungal Agents/chemical synthesis , Antifungal Agents/pharmacology , Propane/analogs & derivatives , Propane/pharmacology , Amines/chemistry , Amines/pharmacology , Antifungal Agents/chemistry , Aspergillus fumigatus/drug effects , Aza Compounds/chemistry , Aza Compounds/pharmacology , Benzene Derivatives/chemistry , Benzene Derivatives/pharmacology , Cell Line , HIV-1/drug effects , Humans , Imidazoles/chemical synthesis , Imidazoles/chemistry , Imidazoles/pharmacology , Miconazole/pharmacology , Microbial Sensitivity Tests , Microsporum/drug effects , Propane/chemical synthesis , Structure-Activity Relationship , Trichophyton/drug effects , Yeasts/drug effectsABSTRACT
In the course of a study on 1H-imidazol-1-amine derivatives as antifungal agents, we found that N-[(1,1'-biphenyl)-4-ylmethyl]-N-[(2,4-dichlorophenyl)methyl]-1H-imidazol-1-amine (1a) exhibited promising activities. In order to explore more in detail the structure-activity relationship of this new class of antifungal agents, we report now the synthesis and the biological activity of new analogues (1b-k) of compound 1a. The synthesis was performed using N-[(1,1'-biphenyl)-4-ylmethyl]-1H-imidazol-1-amine as starting material which was reacted with the proper arylmethyl halide. Most of the newly synthesized imidazolamines exhibited both fungal growth inhibition activity and cellular selectivity.
