Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 10 de 10
Filter
Add more filters










Publication year range
1.
Acta Crystallogr E Crystallogr Commun ; 78(Pt 11): 1089-1096, 2022 Nov 01.
Article in English | MEDLINE | ID: mdl-36380902

ABSTRACT

Three hexa-hydro-quinoline derivatives were synthesized and crystallized in an effort to study the structure-activity relationships of these calcium-channel antagonists. The derivatives are ethyl 4-(2-meth-oxy-phen-yl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexa-hydro-quinoline-3-carboxyl-ate, C22H27NO4, (I), ethyl 4-(4-meth-oxy-phen-yl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexa-hydro-quinoline-3-carb-ox-yl-ate, C22H27NO4, (II), and ethyl 4-(3,4-di-hydroxy-phen-yl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexa-hydro-quinoline-3-carboxyl-ate, C21H24NO5, (III). In these hexa-hydro-quinoline derivatives, common structural features such as a flat-boat conformation of the 1,4-di-hydro-pyridine (1,4-DHP) ring, an envelope conformation of the fused cyclo-hexa-none ring, and a substituted phenyl group at the pseudo-axial position are retained. Hydrogen bonds are the main contributors to the packing of the mol-ecules in these crystals.

2.
Acta Crystallogr E Crystallogr Commun ; 76(Pt 2): 125-131, 2020 Feb 01.
Article in English | MEDLINE | ID: mdl-32071733

ABSTRACT

The title compound I, 2,2'-[(2-nitro-phen-yl)methyl-ene]bis-(3-hy-droxy-5,5-di-methyl-cyclo-hex-2-enone), C23H27NO6, features a 1,3-ketone-enol conformation which is stabilized by two intra-molecular hydrogen bonds. The most prominent inter-molecular inter-actions in compound I are C-H⋯O hydrogen bonds, which link mol-ecules into a two-dimensional network parallel to the (001) plane and a chain perpendicular to (11). Both title compounds II, ethyl 4-(4-hy-droxy-3,5-di-meth-oxy-phen-yl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexa-hydro-quinoline-3-carb-oxyl-ate, C23H29NO6, and III, ethyl 4-(anthracen-9-yl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexa-hydro-quinoline-3-carboxyl-ate, C29H29NO3, share the same structural features, such as a shallow boat conformation of the di-hydro-pyridine group and an orthogonal aryl group attached to the di-hydro-pyridine. Inter-molecular N-H⋯O bonding is present in the crystal packing of both compound II and III.

3.
Acta Crystallogr E Crystallogr Commun ; 74(Pt 10): 1417-1420, 2018 Oct 01.
Article in English | MEDLINE | ID: mdl-30319791

ABSTRACT

In the title racemic compound, ethyl 4-(4-di-methyl-amino-phen-yl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexa-hydro-quinoline-3-carboxyl-ate, the common structural features in this type of compound, such as the flat-boat conformation of the 1,4-di-hydro-pyridine (1,4-DHP) ring, the envelope conformation of the fused cyclo-hexa-none, and the substituted phenyl ring at the pseudo-axial position and orthogonal to the 1,4-DHP ring, are present. In the crystal, mol-ecules are linked via N-H⋯O and C-H⋯O hydrogen bonds, forming layers parallel to the (10) plane.

4.
Bioorg Med Chem ; 25(12): 3223-3234, 2017 06 15.
Article in English | MEDLINE | ID: mdl-28434782

ABSTRACT

A series of dimeric isoxazolyl-1,4-dihydropyridines (IDHPs) were prepared by click chemistry and examined for their ability to bind the multi-drug resistance transporter (MDR-1), a member of the ATP-binding cassette superfamily (ABC). Eight compounds in the present study exhibited single digit micromolar binding to this efflux transporter. One monomeric IDHP m-Br-1c, possessed submicromolar binding of 510nM at MDR-1. Three of the dimeric IDHPs possessed <1.5µM activity, and 4b and 4c were observed to have superior binding selectivity compared to their corresponding monomers verses the voltage gated calcium channel (VGCC). The dimer with the best combination of activity and selectivity for MDR-1 was analog 4c containing an m-Br phenyl moiety in the 3-position of the isoxazole, and a tether with five ethyleneoxy units, referred to herein as Isoxaquidar. Two important controls, mono-triazole 5 and pyridine 6, also were examined, indicating that the triazole - incorporated as part of the click assembly as a spacer - contributes to MDR-1 binding. Compounds were also assayed at the allosteric site of the mGluR5 receptor, as a GPCR 7TM control, indicating that the p-Br IDHPs 4d, 4e and 4f with tethers of from n=2 to 5 ethylenedioxy units, had sub-micromolar affinities with 4d being the most efficacious at 193nM at mGluR5. The results are interpreted using a docking study using a human ABC as our current working hypothesis, and suggest that the distinct SARs emerging for these three divergent classes of biomolecular targets may be tunable, and amenable to the development of further selectivity.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Dihydropyridines/chemistry , Dihydropyridines/pharmacology , Animals , Crystallography, X-Ray , Dimerization , Drug Resistance, Multiple/drug effects , Humans , Isoxazoles/chemistry , Isoxazoles/pharmacology , Mice , Molecular Docking Simulation , Protein Binding
6.
Acta Crystallogr C Struct Chem ; 70(Pt 8): 790-5, 2014 Aug.
Article in English | MEDLINE | ID: mdl-25093361

ABSTRACT

Three quinolone compounds were synthesized and crystallized in an effort to study the structure-activity relationship of these calcium-channel antagonists. In all three quinolones, viz. ethyl 4-(4-bromophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate, (I), ethyl 4-(3-bromophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate, (II), and ethyl 4-(2-bromophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate, (III), all C21H24BrNO3, common structural features such as a flat boat conformation of the 1,4-dihydropyridine (1,4-DHP) ring, an envelope conformation of the fused cyclohexanone ring and a bromophenyl ring at the pseudo-axial position and orthogonal to the 1,4-DHP ring are retained. However, due to the different packing interactions in each compound, halogen bonds are observed in (I) and (III). Compound (III) crystallizes with two molecules in the asymmetric unit. All of the prepared derivatives satisfy the basic structural requirements to possess moderate activity as calcium-channel antagonists.


Subject(s)
Bromine/chemistry , Quinolines/chemistry , Quinolones/chemistry , Crystallography, X-Ray , Hydrogen Bonding
7.
Acta Crystallogr Sect E Struct Rep Online ; 70(Pt 7): o791-2, 2014 Jul 01.
Article in English | MEDLINE | ID: mdl-25161575

ABSTRACT

The title compound, C25H27NO4, has a flattened di-hydro-pyridine ring. The benzene and phenyl rings are synclinal to one another, forming a dihedral angle of 49.82 (8)°; the axis of the biphenyl rings makes an 81.05 (9)° angle to the plane of the di-hydro-pyridine ring. In the crystal, N-H⋯O hydrogen bonds link the mol-ecules into chain motifs running along the a-axis direction. The chains are cross-linked by C-H⋯O inter-actions, forming sheet motifs running slightly off the (110) plane, together with an intermolecular interaction between head-to tail biphenyl groups, thus making the whole crystal packing a three-dimensional network. Intra-molecular C-H⋯O hydrogen bonds are also observed.

8.
Future Med Chem ; 6(8): 923-43, 2014 May.
Article in English | MEDLINE | ID: mdl-24962283

ABSTRACT

The association of the isoxazole and dihydropyridine (DHP) ring systems fused at the 4'-isoxazolyl- to the 4-position of the DHP has produced a combination scaffold, the isoxazolyl-DHPs (IDHPs) with unique conformational characteristics. The IDHPs are useful in probing biological activity, as exemplified by our efforts in the fields of voltage gated calcium channel (VGCC) antagonists and inhibitors of the multi-drug resistance (MDR) transporter. A strategically placed methyl group produced a signifcant change at the VGCC, with (R)-(+)-1-phenyl-prop-2-yl (3.7 nM) > phenethyl (22.9 nM) > (S)-(-)-1-phenyl-prop-2-yl (210 nM), a eudismic ratio of 56.7. Branching at the C-5 of the isoxazole produced a 25% increase in MDR binding, and replacing the DHP C-3 ester with a functionalized amide also gave a dramatic increase in binding affinity. Opportunities for combined scaffolds - including examples containing IDHPs - are waiting to be discovered: because new biology is driven by new chemistry.


Subject(s)
Calcium Channel Blockers/chemistry , Dihydropyridines/chemistry , Isoxazoles/chemistry , ATP Binding Cassette Transporter, Subfamily B/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily B/metabolism , Calcium Channel Blockers/metabolism , Calcium Channels/chemistry , Calcium Channels/metabolism , Dihydropyridines/chemical synthesis , Dihydropyridines/metabolism , Humans , Molecular Conformation , Structure-Activity Relationship
9.
Bioorg Med Chem Lett ; 24(1): 117-21, 2014 Jan 01.
Article in English | MEDLINE | ID: mdl-24342237

ABSTRACT

Isoxazole-1,4-dihydropyridines (IDHPs) were tethered to fluorescent moieties using double activation via a lanthanide assisted Weinreb amidation. IDHP-fluorophore conjugate 3c exhibits the highest binding to date for IDHPs at the multidrug-resistance transporter (MDR-1), and IDHP-fluorophore conjugates 3c and 7 distribute selectively in SH-SY5Y cells. A homology model for IDHP binding at MDR-1 is presented which represents our current working hypothesis.


Subject(s)
Fluorescent Dyes/pharmacology , Isoxazoles/pharmacology , Multidrug Resistance-Associated Proteins/antagonists & inhibitors , Pyridines/pharmacology , Binding Sites/drug effects , Cell Line, Tumor , Crystallography, X-Ray , Dose-Response Relationship, Drug , Fluorescent Dyes/chemical synthesis , Fluorescent Dyes/chemistry , Humans , Isoxazoles/chemical synthesis , Isoxazoles/chemistry , Microscopy, Confocal , Microscopy, Fluorescence , Models, Molecular , Molecular Structure , Multidrug Resistance-Associated Proteins/metabolism , Pyridines/chemical synthesis , Pyridines/chemistry , Structure-Activity Relationship
10.
Tetrahedron ; 68(50): 10360-10364, 2012 Dec 16.
Article in English | MEDLINE | ID: mdl-23526841

ABSTRACT

A critical comparison of methods to prepare sterically hindered 3-aryl isoxazoles containing fused aromatic rings using the nitrile oxide cycloaddition (NOC) reveal that modification of the method of Bode, Hachisu, Matsuura, and Suzuki (BHMS), utilizing either triethylamine as base or sodium enolates of the diketone, ketoester, and ketoamide dipolarophiles, respectively, was the method of choice for this transformation.

SELECTION OF CITATIONS
SEARCH DETAIL
...