RESUMEN

The title compound, C(12)H(13)NO(2), represents a conformationally restricted 2-pyridone analogue of 1,4-dihydro-pyridine-type calcium antagonists and was selected for a crystal structure determination in order to explore some aspects of drug-receptor inter-action. In the mol-ecule, two stereogenic centres are of opposite chirality, whereas a racemate occurs in the crystal. It was found that the formally aminic N atom of the heterocycle is essentially sp(2)-hybridized with the lone-pair electrons partially delocalized through conjugation with the adjacent carbonyl bond. As a result, the central pyridone ring assumes an unsymmetrical half-chair conformation. The critical 4-phenyl ring is fixed in a pseudo-axial and perpendicular orientation [dihedral angle 85.8 (1)°] with respect to the pyridone ring via an oxygen bridge. In the crystal a pair of centrosymmetric N-H⋯O hydrogen bonds connect mol-ecules of opposite chirality into a dimer. The dimers are packed by hydrophobic van der Waals inter-actions.

RESUMEN

There are two crystallographically independent mol-ecules in the asymmetric unit of the title compound, C(21)H(18)N(4)O(4). The substituted benzopyran portion of one of the independent mol-ecules exhibits disorder [occupancy 0.5248 (18):0.4752 (18)], which was modelled by using two sets of atomic positions and restraints on the chemically equivalent bond lengths and angles. The central, partially saturated pyrimidine rings of both independent mol-ecules were found to assume unsymmetrical half-chair conformations. The hy-droxy-phenyl substituent occupies an equatorial position in both mol-ecules, and is rotated by 55.6 (1)° from the mean plane of the pyrimidine ring in one independent mol-ecule, and by 53.4 (1)° in the other. In the crystal, there are two types of inter-molecular hydrogen bond present: reciprocal N-H⋯N inter-actions join the two crystallographically independent mol-ecules into a dimer and O-H⋯N inter-actions link the dimers into sheets in the ab plane.

RESUMEN

The structure of the title compound, C(8)H(9)N(3), a potential anti-tumour drug, was determined in order to give more insight into its structure-function relationships. The benzimidazole core of the mol-ecule was found to be exactly planar, while the substituents are displaced slightly from the mol-ecular plane [C-C-N-C and C-C-C-N torsion angles of 0.8 (3) and 179.0 (1)° for the methyl and amino groups, respectively]. The bond lengths are analysed in detail and compared with those of the parent unsubstituted analogues. The results show that the lone-pair electrons on the amino N atom are involved in conjugation with the adjacent π system and hence affect the charge distribution in the heterocycle. Two inter-molecular N-H⋯N and C-H⋯N hydrogen bonds have been identified.

RESUMEN

In the title compound, C(11)H(10)N(2)O(2), a potential inhibitor of the cyclo-oxygenase-2 isoenzyme, the pyrazoline ring exists in a flat-envelope conformation while the puckering of the central oxazine ring is more severe. As a result, the mol-ecule as a whole is non-planar. The formal sp(3) pyrazoline N atom is sp(2) hybridized, with the lone-pair electrons delocalized through conjugation with the carbonyl group rather than the double bond of the pyrazoline ring.

RESUMEN

The title compound, C(13)H(14)N(2)OS, crystallizes as a racemate in a non-chiral space group. It represents a conformationally restricted analogue of so-called Biginelli compounds known to exhibit multiple pharmacological activities and was selected for a single-crystal X-ray analysis in order to probe the chemical and spatial requirements of some kinds of activity. It was found that the state of hybridization of the formally aminic nitro-gen of the heterocycle is between sp(2) and sp(3) with the lone-pair electrons partially delocalized through conjugation with the sulfur atom rather than the double bond of the pyrimidine nucleus. As a result, the thia-zolo ring adopts a flat-envelope conformation and the puckering of the central pyrimidine ring is close to a half-chair. The critical phenyl ring is fixed in a pseudo-axial and perpendicular [dihedral angle 84.6 (1)°] orientation with respect to the pyrimidine ring via an oxygen bridge.

RESUMEN

The title compound, C(15)H(16)N(2)O(5), belongs to the class of monastrol-type anti--cancer agents and was selected for crystal structure determination in order to determine the conformational details needed for subsequent structure-activity relationship studies. The central tetra-hydro-pyrimidine ring has a flat-envelope conformation. The 4-phenyl group occupies a pseudo-axial position and is inclined at an angle of ca 90° to the mean plane of the heterocyclic ring. Of the two methyl ester groups, one (in the 5-position) is in a coplanar and the other (in the 6-position) in a perpendicular orientation with respect to the heterocyclic plane. The coplanar 5-ester group has its carbonyl bond oriented cis with respect to the pyrimidine C=C double bond. By comparison of the structural results for the present compound with those determined previously for its diethyl analogue, we have identified the mol-ecular factors which control the dual course of the Biginelli reaction with salicylaldehyde. The crystal structure is dominated by two hydrogen bonds which link the mol-ecules into chains of dimers.

RESUMEN

In the title compound, C(18)H(16)N(2)O(3), a potential inhibitor of the cyclo-oxygenase-2 isoenzyme, the pyrazoline ring exists in a flattened envelope conformation with one C atom deviating by 0.463 Šfrom the mean plane of the remaining four atoms. The puckering of the central oxazine ring is more severe, with one N atom and one C atom displaced by 0.235 (6) and 0.370 (2) Å, respectively, on opposite sides of the mean plane defined by the other four atoms; the conformation is that of a half-chair. As a result, the mol-ecule as a whole is not planar. The carboxyl group is involved in an inter-molecular O-H⋯N hydrogen bond, which links the mol-ecules into centrosymmetric dimers.

RESUMEN

The title compound, C(8)H(7)N(3)O(2), a potential anti-tumour drug and an anti-oxidant agent, was studied in order to give more insight into structure-function relationships. The 1-methyl-benzimidazole unit of the mol-ecule was found to be exactly planar and the nitro group is inclined at an angle of 10.4 (2)° to the plane of the heterocycle. The bond lengths in the present derivative were analyzed in details and compared with those of the parent unsubstituted analogues in the Cambridge Structural Database. The results have shown that the additional nitro group is not involved in conjugation with the adjacent π-system and hence has no effect on the charge distribution of the heterocyclic ring.

RESUMEN

The title compound, C(17)H(20)N(2)O(6), belongs to the monastrol-type of anti-cancer agents and was selected for crystal structure determination in order to confirm its mol-ecular structure and explore some aspects of its structure-activity relationships. The central tetra-hydro-pyrimidine ring has a flat-envelope conformation. The 4-hydroxy-phenyl group occupies a pseudo-axial position and is inclined at an angle of 87.7 (2)° to the mean plane of the heterocyclic ring. Of the two ethyl ester groups, one (in the 5-position) is in a coplanar and the other (in the 6-position) is in a perpendicular orientation with respect to the heterocyclic plane. There is a three-dimensional hydrogen-bonding network in which all hydrogen-bond donors and acceptors are involved.

RESUMEN

Roots and stem-bark of Mahonia aquifolium (Oregon grape) (Berberidaceae) are effectively used in the treatment of skin inflammatory conditions.In the present study, the effect of Mahonia aquifolium crude extract and its two representative alkaloid fractions containing protoberberine and bisbenzylisoquinoline (BBIQ) alkaloids on activity of 12-lipoxygenase (12-LOX), was studied. The reactivity with 1,1-diphenyl-2-picryl-hydrazyl (DPPH), a free stable radical, was evaluated to elucidate the rate of possible lipid-derived radical scavenging in the mechanism of the enzyme inhibition.The results indicate that although the direct radical scavenging mechanism cannot be ruled out in the lipoxygenase inhibition by Mahonia aquifolium and its constituents, other mechanisms based on specific interaction between enzyme and alkaloids could play the critical role in the lipoxygenase inhibition rather than non-specific reactivity with free radicals.

RESUMEN

The crude extract of Mahonia aquifolium (Pursh) Nutt. stem bark and its two main protoberberine alkaloids, berberine and jatrorrhizine, were tested for their in vitro antimicrobial activity. Twenty strains of coagulase-negative staphylococci and 20 strains of Propionibacterium acnes isolated from skin lesions of patients with a severe form of acne, and 20 strains of Candida sp. isolated from chronic vulvovaginal candidoses were tested for their susceptibility to crude extract and two isolated alkaloids. The minimum inhibitory concentrations obtained in this study illustrate the varying degrees of antibacterial and antifungal activity of the tested agents. The results indicate a rational basis for the traditional use of Mahonia aquifolium for localized skin and mucosal infection therapy, as well as for the possible development of a preparation for supportive therapy of the diseases mentioned above.

Asunto(s)

RESUMEN

In the title compound, C(16)H(18)N(6)O, an N-carbonylimidazole derivative of pyrazoline-1-carboximidamide, the pi-electron density of the N atom in the 1-position on the pyrazoline ring is delocalized through the amidine moiety and the adjacent carbonyl group. The imidazole ring, though coplanar with the rest of the molecule, is deconjugated. The pyrazoline ring adopts a flat-envelope conformation, having the substituted phenyl ring oriented perpendicular to the mean plane of the heterocycle. Both of the two potential hydrogen-bond donors are involved in intramolecular hydrogen-bonding interactions.

RESUMEN

Both quantitative and qualitative chemical function based pharmacophore models of endothelin-A (ET(A)) selective receptor antagonists were generated by using the two algorithms HypoGen and HipHop, respectively, which are implemented in the Catalyst molecular modeling software. The input for HypoGen is a training set of 18 ET(A) antagonists exhibiting IC(50) values ranging between 0.19 nM and 67 microM. The best output hypothesis consists of five features: two hydrophobic (HY), one ring aromatic (RA), one hydrogen bond acceptor (HBA), and one negative ionizable (NI) function. The highest scoring Hip Hop model consists of six features: three hydrophobic (HY), one ring aromatic (RA), one hydrogen bond acceptor (HBA), and one negative ionizable (NI). It is the result of an input of three highly active, selective, and structurally diverse ET(A) antagonists. The predictive power of the quantitative model could be approved by using a test set of 30 compounds, whose activity values spread over 6 orders of magnitude. The two pharmacophores were tested according to their ability to extract known endothelin antagonists from the 3D molecular structure database of Derwent's World Drug Index. Thereby the main part of selective ET(A) antagonistic entries was detected by the two hypotheses. Furthermore, the pharmacophores were used to screen the Maybridge database. Six compounds were chosen from the output hit lists for in vitro testing of their ability to displace endothelin-1 from its receptor. Two of these are new potential lead compounds because they are structurally novel and exhibit satisfactory activity in the binding assay.

Asunto(s)

RESUMEN

In the title compound, C(13)H(13)NO(2), there is polarization of pi-electron density from the amine N atom to the acceptor carbonyl groups: as a result, the molecule exists predominantly in an azomethino-1,3-diketone tautomeric form. There is crystallographic evidence that the phenyl ring, although roughly coplanar with the rest of the molecule, is deconjugated with the adjacent pi system of the molecule. The cyclohexane ring adopts an unsymmetrical half-chair conformation and converts between two inversion-related conformers. The molecule is stabilized by an intramolecular hydrogen bond, while the intermolecular packing is dominated by a number of short C-H.O contacts.

Asunto(s)

RESUMEN

The molecule of the title compound, C(17)H(17)N(5)O(2)S, consists of three pi systems, viz. two aromatic rings and the triazene moiety, which are mutually deconjugated although coplanar. The n-butyl chain is roughly perpendicular to the molecular plane, with the terminal methylene and methyl groups disordered between two equally populated positions. The molecules in the crystal associate in an antiparallel fashion, forming dimers across the centre of symmetry, the principal intradimer interaction being stacking of the pi-electron portions of the molecules.

RESUMEN

Using the X-ray crystal structure of the human topoisomerase I (top1) - DNA cleavable complex and the Sybyl software package, we have developed a general model for the ternary cleavable complex formed with four protoberberine alkaloids differing in the substitution on the terminal phenyl rings and covering a broad range of the top1-poisoning activities. This model has the drug intercalated with its planar chromophore between the -1 and +1 base pairs flanking the cleavage site, with the nonplanar portion pointing into the minor groove. The ternary complexes were geometry-optimized and relative interaction energies, computed by using the Tripos force field, were found to rank in correct order the biological potency of the compounds; in addition, the model is also consistent with the top1-poisoning inactivity of berberine, a major prototype of the protoberberine alkaloids. The model might serve as a rational basis for elaboration of the most active compound as a lead structure, in order to develop more potent top1 poisons as next generation anti-cancer drugs.

Asunto(s)

RESUMEN

The crude extract of Mahonia aquifolium (Berberidaceae) stem bark and its components berberine, palmatine and jatrorrhizine were screened for their inhibitory activity against a variety of dermatophytes and two Candida species of human origin using the in vitro dilution agar plate method. Jatrorrhizine was found to be the most effective against all fungal species tested (MIC ranges from 62.5 to 125 micro g/mL), while the crude extract, berberine, and palmatine exhibited only marginal activity (MIC 500 to >/= 1000 micro g/mL). Dermatophytes were more susceptible to jatrorrhizine than yeasts, and Scopulariopsis brevicaulis appeared the least sensitive species to all the compounds tested. The effects of the alkaloids were compared with those of fluconazole and bifonazole for which the MIC ranges were 12.5 to >100 micro g/mL. Our results suggest that jatrorrhizine may serve as a leading compound for further studies to develop new antifungal agents with highly potent antifungal activity and low host toxicity.

Asunto(s)

RESUMEN

The reaction between 4-(4-methylphenyl)but-3-en-2-one and aminoguanidine produced an unexpected product of formula C(12)H(15)N(3)O, consisting of a carboxamide moiety joined to a substituted pyrazoline ring at one of the N atoms. The pyrazoline ring adopts a flat-envelope conformation and the substituted phenyl ring is oriented almost perpendicular to the heterocycle. The carbonyl O atom has partial anionic character as a result of the transfer of pi density from the two adjacent sp(2) N atoms and is involved in an intermolecular hydrogen bond with the amide group.

RESUMEN

The X-ray structure analysis of the unexpected product of the reaction between 4-(4-methylphenyl)but-3-en-2-one and aminoguanidine revealed the title compound, C(12)H(17)N(4)(+) x -C(2)H(3)O(2)(-) x 0.5C(3)H(6)O, consisting of a protonated amidine moiety joined to a substituted pyrazoline ring at the N1 atom. The amidine group is protonated and the positive charge is delocalized over the three C[bond]N bonds in a similar manner to that found in guanidinium salts. The amidinium moiety of the cation is linked to the acetate anions through four N[bond]H...O hydrogen bonds, with N...O distances of 2.749 (4), 2.848 (4), 2.904 (4) and 2.911 (4) A. The pyrazoline ring adopts a flattened envelope conformation and the substituted phenyl ring is oriented perpendicular to the attached heterocycle. The acetone solvate molecule lies across a twofold rotation axis.

RESUMEN

The title compound, C(11)H(10)N(3)(+) x Cl(-) x H(2)O, belongs to the N1-methyl-substituted imidazo[4,5-f]quinoline family, in which the heterocyclic ring is protonated at the pyridine rather than at the imidazole N atom. The molecule as a whole is almost exactly planar. The molecular structure has been compared with that of the 2-amino analogue described in the literature, and it was found that the extra amino group of the latter is involved in conjugation with the adjacent double bond, i.e. the conjugation does not extend over the entire heterocyclic system. The cation of the title compound forms a strong hydrogen bond with the Cl(-) anion and the anions are interconnected by the water solvent molecule.