Synthesis, In Vitro Screening and Docking Studies of New Thiosemicarbazide Derivatives as Antitubercular Agents

A series of thiosemicarbazide derivatives was designed and synthesized by reaction of carboxylic acid hydrazide with isothiocyanates. The molecular structures of the investigated thiosemicarbazides were confirmed and characterized by spectroscopic analysis. The conformational preference of carbonylthiosemicarbazide chain and intra- and intermolecular interactions in the crystalline state were characterized using X-ray analysis. The antituberculosis activity of the target compounds were tested in vitro against four Mycobacterium strains: M. H37Ra, M. phlei, M. smegmatis, M. timereck. The most active compounds were those with 2-pyridine ring. They exhibited lower minimal inhibitory concentration (MIC) values in the range 7.81–31.25 μg/mL in comparison to the other isomers. Compound 5 had activity against M. smegmatis at a concentration of 7.81 μg/mL whereas compound 2 had activity against all tested strains at a concentration of 15.625 μg/mL. The molecular docking studies were performed for investigated compounds using the Mycobacterium tuberculosis glutamine synthetase MtGS as their molecular target.


X-ray analysis: crystal structures of 4, 7, 11, 13 and 14
In the crystal structure of 4 the inversion related molecules form molecular dimers through the pair bifurcated intermolecular hydrogen bonds N1-H1…O5 and N3-H3…O5. Moreover, the benzene rings belonging to the inversion related molecules partially overlap each other with the π…π distance of 3.4567(7) Å characteristic for the overlapping π-aromatic ring systems.
In the crystal of 7 the molecules related by c glide planes are linked into molecular chains parallel to Z crystallographic axis via the pair of intermolecular hydrogen bonds N1-H1…O5 and N4-H4…S2. Additionally, the molecules related by translation a form molecular chains by N3-H3…N53 hydrogen bond. The combination of these two types of chains gives molecular planes parallel to (010) crystallographic plane.
In the crystal structure of 11 the net of intermolecular hydrogen bonds gives the molecular planes parallel to the (010) crystallographic plane as a combination of two molecular chains. The first one is formed by molecules related by translation a and connected via N1-H1…O5 and N4-H4…O5 bifurcated hydrogen bonds, while the second one is created by molecules related by c glide planes through N3 -H3…N53 hydrogen bond.
In the crystal of 13 the molecules A and B from asymmetric part of the unit cell form the molecular dimer using N1A-H1A…N54B and N1B-H1B…N54A hydrogen bonds. The π…π interaction between pyridine rings within this dimer is observed; the centroid-to-centroid separation and the angle between the overlapping planes of these rings are 3.4559(13) Å and 0.57(11) o , respectively. Moreover, the intermolecular hydrogen bonds N4A-H4A….O5A and N4B-H4B…O5B linking molecules A and B related by 21 axis (independently of each other) into molecular chains along b direction. Similar chains are formed by the A and 2-propanol molecules via O2-H1…S2A hydrogen bond.

Theoretical calculations
All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.   The symmetry employed for this shelxl refinement is uniquely defined by the following loop, which should always be used as a source of symmetry information in preference to the above space-group names. They are only intended as comments. ; loop_ _space_group_symop_operation_xyz 'x, y, z' '-x+1/2, y+1/2, -z+1/2' '-x, -y, -z' 'x-1/2, -y-1/2, z-1/2' _cell_length_a 13.4658(2) _cell_length_b 9.80280(10) _cell_length_c 23.9666 (3)