ABSTRACT
Despite the serious public health problems caused by Chagas disease in several countries, the available therapy remains with only two drugs that are poorly active during the chronic phase of the disease in addition to having severe side effects. In search of new trypanocidal agents, herein we describe the synthesis and biological evaluation of eleven new 1,6-diphenyl-1H-pyrazolo[3,4-b]pyridine compounds containing the carbohydrazide or the 2,3-dihydro-1,3,4-oxadiazole moieties. Two of them showed promising in vitro activity against amastigote forms of T. cruzi and were evaluated in vivo in male BALB/c mice infected with T. cruzi Y strain. Our results suggest that the substitution at the C-2 position of the phenyl group connected to the carbohydrazide or to the 2,3-dihydro-1,3,4-oxadiazole moieties plays an important role in the trypanocidal activity of this class of compounds. Moreover, the compound containing the 2,3-dihydro-1,3,4-oxadiazole moiety has demonstrated more favorable structural requirements for in vivo activity than its carbohydrazide analog.
Subject(s)
Chagas Disease/drug therapy , Pyrazoles/pharmacology , Pyridines/pharmacology , Trypanocidal Agents/pharmacology , Trypanosoma cruzi/drug effects , Animals , Cell Line , Cell Survival/drug effects , Chagas Disease/pathology , Dose-Response Relationship, Drug , Male , Mice , Mice, Inbred BALB C , Molecular Structure , Parasitic Sensitivity Tests , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Pyridines/chemical synthesis , Pyridines/chemistry , Structure-Activity Relationship , Trypanocidal Agents/chemical synthesis , Trypanocidal Agents/chemistryABSTRACT
AIM: Novel 4-methoxy-naphthalene derivatives were synthesized based on hits structures in order to evaluate the antifungal activity against Paracoccidioides spp. METHODS: Antifungal activity of compounds was evaluated against P. brasiliensis and most promising compounds 2 and 3 were tested against eight clinically important fungal species. RESULTS: Compound 3 was the more active compound with MIC 8 to 32 µg.ml-1 for Paracoccidioides spp without toxicity monkey kidney and murine macrophagecells. Carbohydrazide 3 showed good synergistic antifungal activity with amphotericin B against P. brasiliensis specie. Titration assay of carbohydrazide 3 with PbHSD enzyme demonstrates the binding ligand-protein. Molecular dynamics simulations show that ligand 3 let the PbHSD protein more stable. CONCLUSION: New carbohydrazide 3 is an attractive lead for drug development to treat paracoccidioidomycoses.
Subject(s)
Antifungal Agents/pharmacology , Naphthalenes/pharmacology , Paracoccidioides/drug effects , Paracoccidioidomycosis/drug therapy , Amphotericin B/pharmacology , Animals , Antifungal Agents/therapeutic use , Chlorocebus aethiops , Drug Combinations , Drug Synergism , Homoserine Dehydrogenase/metabolism , Hydrazines/pharmacology , Macrophages/drug effects , Mice , Microbial Sensitivity Tests , Molecular Dynamics Simulation , Naphthalenes/chemical synthesis , Naphthalenes/therapeutic use , Paracoccidioides/pathogenicity , Protein Stability , Vero Cells/drug effectsABSTRACT
The crystal structures of three isomeric (E)-N'-(chloro-phenyl-methyl-idene)-N-methyl-2-(thio-phen-2-yl)acetohydrazides (C14H13ClN2OS) are described, with the Cl atom in ortho (I), meta (III) and para (IV) positions in the benzene ring. The ortho-bromo derivative (II) (C14H13BrN2OS), which is isostructural with its chloro congener (I), is also reported. Mol-ecules (I)-(III) have similar conformations, which approximate to l-shapes, as indicated by their N-C-C-Ct (t = thio-phene) torsion angles of -90.1â (3), -91.44â (18) and -90.7â (9)°, respectively. The conformation of (IV) is different, with an equivalent torsion angle of -170.75â (11)° corresponding to a more extended shape for the mol-ecule. The thio-phene ring in each structure features 'flip' rotational disorder. The packing for (I) and (II) features inversion dimers, linked by pairs of C-Hâ¯O inter-actions, which generate R22(14) loops. In the crystal of (III), [010] C(8) chains arise, with adjacent mol-ecules linked by pairs of C-Hâ¯O hydrogen bonds. The packing for (IV) features unusually short C-Hâ¯O inter-actions arising from an H atom attached to the benzene ring (Hâ¯O = 2.18â Å), which lead to C(9) [301] chains. Hirshfeld fingerprint percentage contact contributions are similar for the four title compounds.
ABSTRACT
The syntheses and crystal structures of (E)-N'-(3-cyano-benzyl-idene)-N-methyl-2-(thio-phen-2-yl)acetohydrazide, C15H13N3OS, (I), and (E)-N'-(4-meth-oxy-benzyl-idene)-N-methyl-2-(thio-phen-2-yl)acetohydrazide, C15H16N2O2S, (II), with different substituents in the meta and para position of the benzene ring are described. Compounds (I) and (II) both crystallize with two mol-ecules in the asymmetric unit, with generally similar conformations [r.m.s. overlay fits for (I) and (II) of 0.334 and 0.280â Å, respectively] that approximate to L-shapes. The thio-phene rings in (I) are well ordered, whereas those in (II) exhibit 'flip' rotational disorder [occupancies 0.662â (2) and 0.338â (2) for mol-ecule 1, and 0.549â (3) and 0.451â (3) for mol-ecule 2]. The packing for (I) features short C-Hâ¯O inter-actions arising from the C-H grouping adjacent to the cyanide group and C-Hâ¯Nc (c = cyanide) links arising from the methine groups to generate [110] double chains. Weak C-Hâ¯π inter-actions inter-link the chains into a three-dimensional network. The packing for (II) features numerous C-Hâ¯O and C-Hâ¯π inter-actions arising from different donor groups to generate a three-dimensional network. Hirshfeld fingerprint plots indicate significant differences in the percentage contact surfaces for (I) and (II).
ABSTRACT
The crystal structures of three isomeric (E)-N-methyl-N'-(nitro-benzyl-idene)-2-(thio-phen-2-yl)acetohydrazides (formula C14H13N3O3S) are described, with the nitro group in ortho, meta and para positions in the benzene ring. In each crystal structure, mol-ecules are linked by various weak inter-actions (C-Hâ¯O and C-Hâ¯π bonds, and π-π stacking), leading to three-dimensional networks in each case, but with little similarity between them.
ABSTRACT
In the title carbohydrazide, C10H7N3O4S, the dihedral angle between the terminal five-membered rings is 27.4â (2)°, with these lying to the same side of the plane through the central CN2C(=O) atoms (r.m.s. deviation = 0.0403â Å), leading to a curved mol-ecule. The conformation about the C=N imine bond [1.281â (5)â Å] is E, and the carbonyl O and amide H atoms are anti. In the crystal, N-Hâ¯O hydrogen bonds lead to supra-molecular chains, generated by a 41 screw-axis along the c direction. A three-dimensional architecture is consolidated by thienyl-C-Hâ¯O(nitro) and furanyl-C-Hâ¯O(nitro) inter-actions, as well as π-π inter-actions between the thienyl and furanyl rings [inter-centroid distance = 3.515â (2)â Å]. These, and other, weak inter-molecular inter-actions, e.g. nitro-N-Oâ¯π(thien-yl), have been investigated by Hirshfeld surface analysis, which confirms the dominance of the conventional N-Hâ¯O hydrogen bonding to the overall mol-ecular packing.
ABSTRACT
The crystal structures of three methyl-ated hydrazine carbamate derivatives prepared by multi-step syntheses from l-serine are presented, namely benzyl N-{(E)-1-[2-(4-cyanobenzylidene)-1-methylhydrazinyl]-3-hydroxy-1-oxopro-pan-2-yl}carbamate, C20H20N4O4, tert-butyl N-{(E)-1-[2-(4-cyanobenzylidene)-1-methylhydrazinyl]-3-hydroxy-1-oxopropan-2-yl}carbamate, C17H22N4O4, and tert-butyl N-[(E)-1-(2-benzylidene-1-methylhydrazinyl)-3-hydroxy-1-oxopro-pan-2-yl]carbamate, C16H23N3O4. One of them shows that an unexpected racemization has occurred during the mild-condition methyl-ation reaction. In each crystal structure, the mol-ecules are linked into chains by O-Hâ¯O hydrogen bonds, but with significant differences between them.
ABSTRACT
Oxazolidin-2-ones are widely used as protective groups for 1,2-amino alcohols and chiral derivatives are employed as chiral auxiliaries. The crystal structures of four differently substituted oxazolidinecarbohydrazides, namely N'-[(E)-benzylidene]-N-methyl-2-oxo-1,3-oxazolidine-4-carbohydrazide, C12H12N3O3, (I), N'-[(E)-2-chlorobenzylidene]-N-methyl-2-oxo-1,3-oxazolidine-4-carbohydrazide, C12H12ClN3O3, (II), (4S)-N'-[(E)-4-chlorobenzylidene]-N-methyl-2-oxo-1,3-oxazolidine-4-carbohydrazide, C12H12ClN3O3, (III), and (4S)-N'-[(E)-2,6-dichlorobenzylidene]-N,3-dimethyl-2-oxo-1,3-oxazolidine-4-carbohydrazide, C13H13Cl2N3O3, (IV), show that an unexpected mild-condition racemization from the chiral starting materials has occurred in (I) and (II). In the extended structures, the centrosymmetric phases, which each crystallize with two molecules (A and B) in the asymmetric unit, form A+B dimers linked by pairs of N-H···O hydrogen bonds, albeit with different O-atom acceptors. One dimer is composed of one molecule with an S configuration for its stereogenic centre and the other with an R configuration, and possesses approximate local inversion symmetry. The other dimer consists of either R,R or S,S pairs and possesses approximate local twofold symmetry. In the chiral structure, N-H···O hydrogen bonds link the molecules into C(5) chains, with adjacent molecules related by a 21 screw axis. A wide variety of weak interactions, including C-H···O, C-H···Cl, C-H···π and π-π stacking interactions, occur in these structures, but there is little conformity between them.
Subject(s)
Benzylidene Compounds/chemistry , Hydrazines/chemistry , Oxazoles/chemistry , Crystallography, X-Ray , Hydrogen Bonding , Molecular StructureABSTRACT
The neutral binuclear mol-ecule of the title complex, [V2(C15H12N2O2S)2(CH3O)2O2], exhibits inversion symmetry and consists of two oxidovanadium(V) (VO)(3+) fragments, each coordinated by a dianionic and O,N',O'-chelating N'-(1-benzoyl-prop-1-en-2-yl)thio-phene-2-carbohydrazidate ligand. The V(5+) cations are bridged by two asymmetrically bonding methano-late ligands [V-O = 1.8155â (12) and 2.3950â (13)â Å] originating from the deprotonation of the methanol solvent. The coordination sphere of the V(V) atom is distorted octa-hedral, with the equatorial plane defined by the three donor atoms of the thio-phene-2-carbohydrazidate ligand and the O atom of a methano-late unit. The axial positions are occupied by the oxide group and the remaining methano-late ligand. The axially bound methano-late ligand shows a longer V-O bond length due to the trans influence caused by the tightly bonded oxide group. The packing of the complex mol-ecules is dominated by dispersion forces.