“…It was the highest scoring one and consisted of four chemical features: the coordination interaction (UNA) plus one aromatic ring (RA) and two hydrophobics (HY1 and HY2). Two findings more than any other led us to credit MOD1: first of all, an interaction pattern very similar to the one proposed by this hypothesis had been already determined in a study on a series of obtusifoliol 14α-methyl demethylase azole inhibitors; secondarily, and as expected, the aliphatic substituent on the pyrrole nitrogen of all the most active compounds ( 1b , 1d , 1e , 1f , 1g , 1h ) was found to match one of the two hydrophobic features (HY1). 1 Compound 1g (in yellow), the most active of the whole set, mapped onto the pharmacophore hypothesis MOD1.…”
1-[(Aryl)(4-aryl-1H-pyrrol-3-yl)methyl]-1H-imidazoles were recently reported by our group as potent anti-Candida agents belonging to the antifungal azole class. In the present paper the synthesis, anti-Candida activities, and QSAR studies on a novel series of N-substituted 1-[(aryl)(4-aryl-1H-pyrrol-3-yl)methyl]-1H-imidazole derivatives are reported. The newly synthesized azoles were tested against 12 strains of Candida albicans together with bifonazole, miconazole, itraconazole, fluconazole, and compounds 1a, 1b, 3a, 3b, and 3c used as reference drugs. In general, tested derivatives showed good antifungal activities, and the most potent compound was 1d (MIC(90) = 0.032 microg/mL), which was from 4- to 250-fold more potent than reference drugs. Catalyst software was applied to develop a quantitative pharmacophore model to be used for the rational design of new antifungal azoles. Some key interactions, as well as excluded volumes, further to the coordination bond of azole antifungals with the demethylase enzyme, are highlighted.
“…It was the highest scoring one and consisted of four chemical features: the coordination interaction (UNA) plus one aromatic ring (RA) and two hydrophobics (HY1 and HY2). Two findings more than any other led us to credit MOD1: first of all, an interaction pattern very similar to the one proposed by this hypothesis had been already determined in a study on a series of obtusifoliol 14α-methyl demethylase azole inhibitors; secondarily, and as expected, the aliphatic substituent on the pyrrole nitrogen of all the most active compounds ( 1b , 1d , 1e , 1f , 1g , 1h ) was found to match one of the two hydrophobic features (HY1). 1 Compound 1g (in yellow), the most active of the whole set, mapped onto the pharmacophore hypothesis MOD1.…”
1-[(Aryl)(4-aryl-1H-pyrrol-3-yl)methyl]-1H-imidazoles were recently reported by our group as potent anti-Candida agents belonging to the antifungal azole class. In the present paper the synthesis, anti-Candida activities, and QSAR studies on a novel series of N-substituted 1-[(aryl)(4-aryl-1H-pyrrol-3-yl)methyl]-1H-imidazole derivatives are reported. The newly synthesized azoles were tested against 12 strains of Candida albicans together with bifonazole, miconazole, itraconazole, fluconazole, and compounds 1a, 1b, 3a, 3b, and 3c used as reference drugs. In general, tested derivatives showed good antifungal activities, and the most potent compound was 1d (MIC(90) = 0.032 microg/mL), which was from 4- to 250-fold more potent than reference drugs. Catalyst software was applied to develop a quantitative pharmacophore model to be used for the rational design of new antifungal azoles. Some key interactions, as well as excluded volumes, further to the coordination bond of azole antifungals with the demethylase enzyme, are highlighted.
“…For CYP51 ( 14 α), pharmacophore models have been developed − and homology models have been built on the basis of the CYP 101, 102, and 107A crystal structures. Several ligand-bound and ligand-free crystal structures have been solved, and MD studies have been performed.…”
Table 1. Overview of CYP Pharmacophore and 3D-QSAR Models sets method a training b test c predicted property key features of pharmacophore ref CYP1A2 Combine and GRID/GOLPE + homology model na mutagenicity Inhibitor model includes H-bonding and hydrophobic binding sites (on the protein). Several residues in the homology model are found to interact with the pharmacophore model. 143 CYP2A5 CoMFA na IC50 Substrates and inhibitors have a negative electrostatic potential close to a lactone moiety, steric effects around a methoxy group on methoxasalen, and positive electrostatic potential para to a methoxy group. 171 PLS MS-WHIM na Ki Potent inhibitors have a positive molecular electrostatic potential and a H-bond acceptor. 172 CYP2A6 CoMFA and GRID/GOLPE 5 (ss) IC50 Potent CYP2A6 inhibitors do not include a lactone moiety. 145 CYP2B6 Catalyst and PLS MS-WHIM na (ss) Km, CSP Substrate model includes at least three hydrophobic regions 3.1, 4.6, and 5.3 Å from a H-bond acceptor. 173 Catalyst + homology model 5 (4) Km, CSP Substrate model includes two hydrophobic regions and one H-bond acceptor. Substrate catalytic site is 4.0 and 3.4 Å from two hydrophobic regions and 4.6 Å from a H-bond acceptor in model A and is 4.9, 4.1, and 7.8 Å, in model B. 116 CYP2C8/9/18/19 GRID/CPCA + homology model + docking na na CSP Combined protein-based inverse substrate model includes two hydrophobic and two electropositive binding sites (on the protein). 62 CYP2C8 Catalyst + homology model + docking na CSP Substrate model with H-bond acceptor and a hydrophobic and a cationic region. 117 CYP2C9 manual superposition na CSP Substrate model protein H-bond donor is 7 Å from substrate catalytic site. 174 manual superposition na CSP Substrate model includes anionic site is 7.8 Å from catalytic site, between hydrophobic regions.
36, 175CoMFA + homology model 14 ( 13) Ki, CSP Inhibitor model includes two cationic binding sites, along with an aromatic binding region and a steric region (on the protein). Substrates possess a partial negative charge at 10 Å and an anionic site at 6 Å from the catalytic site. 35 59 Catalyst and PLS-WHIM 14 (10) 14 (12)
“…Alignment of Molecules. The alignment of compounds was based on earlier reports about coordination of similar antifungal azoles to the iron atom of the heme , and previous 3D-QSAR studies . We applied two patterns of superposition.…”
A combination between 3D-QSAR and molecular mechanics (MM)-docking study was used as a tool to detail and model the mechanism of action of 46 antifungal azoles. Two methods of alignment of the ligands were performed: (i) alignment of the main skeleton without substituents and (ii) alignment of a defined substructure. The best model is characterized by q(2) with the values of 0.70 for yeastlike (yeast), 0.66 for filamentous fungi, and 0.70 for the selectivity against filamentous fungi. 3D-QSAR regression maps derived from six models were used to identify the regions responsible for the differences in the compounds activity against yeast and filamentous fungi. The binding energy of the important substructures (Local Binding Energy-LBE) and its standard deviation were calculated in order to demonstrate quantitatively the contribution of substituents reflecting the diversity of the antifungal activity. The comparisons of these results with the same regions of the contour maps indicated a good correspondence between the 3D-QSAR and MM (LBE) approaches allowing association between the maps and the participating residues in the active sites of P450DM of C. albicans and A. fumigatus. The pi-pi interactions of two or more aromatic groups of the ligands with Phe228 and Tyr132 prove to be most important for the differences in activity against C. albicans. In A. fumigatus there was a better occupation of the inner central I-spiral in the areas around the heme. For the activity against A. fumigatus the pi-pi interactions of aromatic groups of the compounds with Phe509, Phe228, and Tyr132 are significant for the activity.
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