Camilo H. da Silva Lima

(Pyrazinecarbonyl)hydrazone halobenzaldehydes: supramolecular arrays generated by face to face stacking of ribbons, formed from C–H–O interactions

Abstract The crystal structures of seven (pyrazinecarbonyl)hydrazone mono-halo-benzaldehyde derivatives, N2C4H3CONHN=CHC6H4X (X = F, Cl or Br) are reported. In all cases, hydrogen-bonds link the planar molecules edge to edge to form ribbons which are themselves essentially planar. These ribbons are then packed face to face in a variety of ways dependent upon the position and nature of the halogen substituent. In all of the structures the molecules are found in layers one molecule thick. For the chloro- and bromo-substituted compounds three distinct forms of two-dimensional connectivity in the layers is achieved by combination of π · · · π interactions with the ribbon hydrogen-bonds. For the fluoro- derivatives the ribbon hydrogen-bonds connect layers in which the two-dimensional connectivity is provided by the π · · · π interactions, in one case augmented by C–H · · · F and C–H · · · π bonds, resulting in complete three-dimensional connectivity.

Structures of (pyrazinecarbonyl)hydrazones of substituted benzaldehydes: supramolecular arrangements generated by various intermolecular contacts

Abstract The crystal structures of seven (pyrazinecarbonyl)hydrazone mono-substituted benzaldehyde derivatives, N2C4H3CONHN=CHC6H4X (1: X = CN, OMe, OEt or NO2) are reported. In all cases extensive intermolecular C–H · · · X (X = O, N or π-ring) hydrogen-bonding is present in which the nitrogen atom of p-CN and one oxygen atom of o-NO2 substitutents act as hydrogen-bond acceptors and C–H bonds of the methyl groups of the p-OME and m-OEt substituents act as hydrogen-bond donors. While the m-OMe substituted compound exhibits only one-dimensional connectivity in the form of face to face ribbons of molecules two-dimensional layer connectivity is observed in all other cases. If, however, π · · · π interactions and, in the case of (1: X = m-OEt) C–H · · · N and C–H · · · π-ring contacts, which arise between the layers as they are stacked, are taken into account three-dimensional connectivity is the norm for the layer structures except for that of (1: X = o-Et).

Structures of (pyrazinecarbonyl)hydrazones of substituted benzaldehydes: different supramolecular arrangements from C—H···X (X = O, N, π) hydrogen bonds

Abstract The crystal structures of six (pyrazinecarbonyl)hydrazone di-substituted benzaldehyde derivatives [N2C4H3CONHN = CHC6H3XY: X,Y = 2,3-Cl2; 2,3-(MeO)2; 2,4-F2; 2,4-Me2; 3-HO—4-MeO; 3-MeO—4-HO] and one tri-substituted benzaldehyde derivative, [N2C4H3CONHN = CHC6H2X3: X3 = 3,4,5-(MeO)3] are reported. In all cases extensive intermolecular C—H···X (X = O, N or π-ring) hydrogen-bonding is present in which the the oxygen atoms of OH and OMe substituents act as hydrogen-bond acceptors and C—H bonds of methyl groups act as hydrogen-bond donors. The connectivity attained is one-dimensional in chains or ribbons in the 2,3-(OMe)2 and 2,4-Me2 derivatives, three dimensional only in the case of the 3-MeO—4-HO derivative and two dimensional in layers of molecules otherwise. It is concluded, therefore, that the bulky nature of the substituents limits the connectivity attainable in this series of compounds.

Hydrated (pyrazinecarbonyl)hydrazones of hydroxy and methoxy substituted benzaldehydes

Abstract The crystal structures of hydrates of five substituted benzaldehyde (pyrazinecarbonyl)hydrazone derivatives [N2C4H3CONHN=CHC6H5-nXn · m H2O: m = 1, n = 1, X = 3-HO; m = 1, n = 2, X2 = 2,5-(HO)2; m = 1, n = 2, X2 = 2,4-(MeO)2; m = 2.5, n = 2, X2 = 3,4-(MeO)2; m = 3, n = 1, X = 4-HO] are reported. In all cases the water molecules participate in strong hydrogen-bonds extending and partially replacing the weak intermolecular C–HX (X = O, N or π-ring) hydrogen-bonding and π · · · π interactions normally present in anhydrous structures of compounds of this type.

In vitro anti-mycobacterial activity of (E)-N´-(monosubstituted-benzylidene) isonicotinohydrazide derivatives against isoniazid-resistant strains

A series of twenty-three N-acylhydrazones derived from isoniazid (INH 1-23) have been evaluated for their in vitro antibacterial activity against INH- susceptible strain of M. tuberculosis (RG500) and three INH-resistant clinical isolates (RG102, RG103 and RG113). In general, derivatives 4, 14, 15 and 16 (MIC=1.92, 1.96, 1.96 and 1.86 µM, respectively) showed relevant activities against RG500 strain, while the derivative 13 (MIC=0.98 µM) was more active than INH (MIC=1.14 µM). However, these derivatives were inactive against RGH102, which displays a mutation in the coding region of inhA. These results suggest that the activities of these compounds depend on the inhibition of this enzyme. However, the possibility of other mechanisms of action cannot be excluded, since compounds 2, 4, 6, 7, 12–17, 19, 21 and 23 showed good activities against katG-resistant strain RGH103, being more than 10-fold more active than INH.

Aqueous Molecular Dynamics Simulations of the M. tuberculosis Enoyl-ACP Reductase-NADH System and Its Complex with a Substrate Mimic or Diphenyl Ethers Inhibitors

Molecular dynamics (MD) simulations of 12 aqueous systems of the NADH-dependent enoyl-ACP reductase from Mycobacterium tuberculosis (InhA) were carried out for up to 20–40 ns using the GROMACS 4.5 package. Simulations of the holoenzyme, holoenzyme-substrate, and 10 holoenzyme-inhibitor complexes were conducted in order to gain more insight about the secondary structure motifs of the InhA substrate-binding pocket. We monitored the lifetime of the main intermolecular interactions: hydrogen bonds and hydrophobic contacts. Our MD simulations demonstrate the importance of evaluating the conformational changes that occur close to the active site of the enzyme-cofactor complex before and after binding of the ligand and the influence of the water molecules. Moreover, the protein-inhibitor total steric (ELJ) and electrostatic (EC) interaction energies, related to Gly96 and Tyr158, are able to explain 80% of the biological response variance according to the best linear equation, pKi = 7.772 − 0.1885 × Gly96 + 0.0517 × Tyr158 (R2 = 0.80; n = 10), where interactions with Gly96, mainly electrostatic, increase the biological response, while those with Tyr158 decrease. These results will help to understand the structure-activity relationships and to design new and more potent anti-TB drugs.

Synthesis and Biological Evaluation of N,N′-di(thiopheneacetyl)diamines Series as Antitubercular Agents

The series of new N,N′-di(thiopheneacetyl)diamines derivatives, 8–17, were synthesized and evaluated for their in vitro antibacterial activity against Mycobacterium tuberculosis(TB), and the activity expressed as the minimum inhibitory concentration (MIC) in μ g/mL. Compound 13 was the only one determined to be active and exhibited a MIC 50 μg/mL, indicating that the alkyl chain-length of the diamines is critical for biological activity. This class of compound has not been evaluated before, and it could be a good starting point to find new lead compounds in the fight against multi-drug resistant TB.

(Pyrazinecarbonyl)hydrazones of heteroarenealdehydes: crystal structures formed from N—H···O, N—HN, C—H···O hydrogen-bonds, C—H···π and π···π interactions

Abstract The molecules of the (pyrazinecarbonyl)hydrazones of the heterocyclic aldehydes RCHO with R = pyrrol-2-yl, furan-2-yl, thien-2-yl and pyridin-2-yl corresponding to compounds (2: X = NH), (2: X = O), (2: X = S)and 3, respectively, are formally rather similar. Despite this the molecular packing and intermolecular interactions show unexpectedly wide variation throughout the series. In 2 hydrogen-bonds link the planar molecules edge to edge to form chains or, in one case, planar ribbons while 3 exhibits zig-zag chain connectivity. Three-dimensional connectivity is attained by intermolecular hydrogen-bonds alone in ortho-(2: X = S), the orthorhombic polymorph of (2: X = S)and by intermolecular hydrogen-bonds combined with π···π interactions in (2: X = O) and 3. No more than two-dimensional layer connectivity is found in (2: X = NH) and the monoclinic polymorph, mono-(2: X = S) of (2: X = S).

N'-[(E)-2-Meth-oxy-benzyl-idene]pyrazine-2-carbohydrazide.

In the title compound, C13H12N4O2, all the non-H atoms lie on a crystallographic mirror plane and an intramolecular N—H⋯N hydrogen bond generates an S(5) ring; the conformation about the imine bond [1.280 (3) Å] is E. In the crystal, molecules assemble into a two-dimensional array via C—H⋯O(carbonyl) and C—H⋯N(pyrazine) contacts. Layers stack along the b-axis direction via weak π–π interactions between pyrazine rings [ring centroid distance = 3.8028 (8) Å].

N-(2-Chloro-eth-yl)pyrazine-2-carboxamide.

In the title molecule, C7H8ClN3O, the pyrazine and amide groups are almost co-planar [N—C—C—N torsion angle = −2.4 (2) °], a conformation stabilized by an intramolecular N—H⋯N hydrogen bond. The chloroethyl group lies out of the plane [N—C—C—Cl = −65.06 (17) °]. In the crystal, the presence of N—H⋯N hydrogen bonds leads to the formation of a C(6) supramolecular chain along the b axis. The carbonyl-O atom accepts two C—H⋯O interactions. These, plus Cl⋯Cl short contacts [3.3653 (6) Å], consolidate the packing of the chains in the crystal.