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Pyridyl thiosemicarbazide: synthesis, crystal structure, DFT/B3LYP, molecular docking studies and its biological investigations


N-(pyridin-2-yl)hydrazinecarbothioamide has been synthesized and characterized by single-crystal X-ray and spectroscopic techniques. Furthermore, its geometry optimization, calculated vibrational frequencies, non-linear optical properties, electrostatic potential and average local ionization energy properties of molecular surface were being evaluated using Jaguar program in the Schrödinger’s set on the basis of the density functional concept to pretend the molecular geometry and predict properties of molecule performed by the hybrid density functional routine B3LYP. Furthermore, the docking study of N-(pyridin-2-yl)hydrazinecarbothioamide were applied against negative Escherichia coli bacterial and gram positive Staphylococcus aureus bacterial strains by Schrödinger suite program using XP glide protocol.


Compounds containing sulfur and nitrogen atoms appear to display antimicrobial activity; antiviral [1, 2], antifungal [3], antibacterial [4, 5], antitumor [6, 7], anticarcinogenic [8,9,10] and insulin mimetic properties [11]. The antitumor action could be credited to the hindrance of DNA production by the alteration in the reductive transformation of ribonucleotide to deoxyribonucleotide [8]. Thiosemicarbazides have also been utilized for spectrophotometric detection of metals [12,13,14], gadget applications with respect to media communications and optical storage [15, 16]. Thiosemicarbazides are well-known source in heterocyclic synthesis. They also exist in tautomeric C=S (thione) and (C–S) thiol forms [17]. The presence of tautomeric forms as an equilibrium combination in solution is basic for their adaptable chelating behavior. From these application, we reported the isolation, X-ray crystal characterization, DFT computational studies using B3LYP, molecular interaction docking studies and biological applications of N-(pyridin-2-yl)hydrazinecarbothioamide. This study aims to investigate the stability of different isomers either in solid state or solution and show the synergy between the experimental and theoretical data.


Equipment and materials

All the substances were bought from different high quality sources and used as it is without any additional refining. The infra-red spectrum (4000–400 cm−1) by means of KBr discs was measured utilizing a Mattson 5000 FTIR spectrophotometer.

1H NMR spectra was measured utilizing a JEOL 500 MHz NMR spectrometer, in (DMSO-d6) at 25 °C using TMS as an internal standard. D2O solvent is applied to approve the assignment of the NH– and SH– protons. On the other hand, the theoretical calculation of the 1H NMR for the different isomers of N-(pyridin-2-yl)hydrazinecarbothioamide was done using ACD/SpecManager.

An appropriate crystal for single-crystal X-ray study of the thiosemicarbazide has been selected and mounted onto thin glass fibers. An Enraf–Nonius 590 diffractometer having a Kappa CCD sensor utilizing graphite monochromated Mo-Kα (λ = 0.71073 Å) was utilized for collection of the diffraction data of the colorless X-ray single-crystal at normal temperature (25 °C) at the “National Research Center”, Egypt. Reflection data have been recorded in the rotation mode using the φ and ω scan technique with 2θmax = 27.49 and 27.45. Without any critical peculiar dissipation, Friedel pairs have been combined. Changes in lit up volume were kept to a base and were considered by the multiscan interframe scaling [18, 19]. The parameters of the unit cell were determined from least-squares refinement with θ in the range 0 ≤ θ ≤ 30.11 and 3.05 ≤ θ ≤ 30.11. The refinement was completed by full-framework slightest squares strategy on the positional and anisotropic temperature parameters of all non-hydrogen atoms on the basis of F2 by means of CRYSTALS package [20]. The hydrogen atoms were set in figured positions and refined utilizing riding atoms with a typical settled isotropic thermal parameter [21].

Synthesis of N-(pyridin-2-yl)hydrazinecarbothioamide

N-(pyridin-2-yl)hydrazinecarbothioamide is synthesized utilizing Scheme 1. The obtained white precipitate filtered off, splashed using ethanol and desiccated over anhydrous CaCl2. (Yield 85%, m.p. 193–195 °C). Crystal suitable for X-ray measurements has been separated by recrystallization from acetonitrile.

Scheme 1

Scheme for synthesis of N-(pyridin-2-yl)hydrazinecarbothioamide

Molecular modeling

Jaguar package [22] in the Schrödinger’s complement [22] was utilized for structural geometry optimization. The density functional principle (DFT) to pretend chemical manners and predict properties of materials performed by the hybrid density functional technique B3LYP [23] implanted with a 6-311G**++basis set.

Molecular docking

Protein preparation

The three-dimensional complex structure of Escherichia coli (PDB ID: 1C14) and Staphylococcus aureus (PDB ID: 3BL6) were taken from the protein information store [24, 25]. The protein structures were readied utilizing the protein arrangement wizard software in the Schrödinger set [22] in which water molecules (radius > 5Å) and trivial molecules found were expelled from the structure part, disulphide bonds were made and hydrogens were put onto the PDB constructions. Controlled impref minimization having the ordinary inputs was achieved on the structure with improved potentials for fluid reenactments (OPLS-2005) force field. The subsequent structures were utilized for receptor matrix age for docking.

Ligand preparation

The investigated compound were equipped utilizing the default procedure of the Ligprep program [22] in the Schrödinger’s set. Glide program [22] in the Schrödinger’s complement was utilized for molecular docking educations. It was docked to the marked protein by means of the glide dock XP practice without any utilization of implement post-docking minimization.

Result and discussion

1H NMR of N-(pyridin-2-yl)hydrazinecarbothioamide

Experimental 1H NMR (500 MHz, DMSO-d6) ppm 5.23 (br. s., 2 H, [H18 and H19]) 7.00–7.04 (m, 1 H, H14) 7.13 (d, J = 8.41 Hz, 1 H, H12) 7.76 (t, J = 6.88 Hz, 1 H, H13) 8.22 (d, J = 5.36 Hz, 1 H, H15) 10.57 (s, 1 H, H16) 12.59 (br. s., 1 H, H17) (Fig. 1). The disappearance of the signals of H16, H17, H18 and H19 on addition of D2O (Fig. 2), which suggests that they are easily exchangeable The presence of a signal at 12.59 ppm attributable to SH proton confirming the presence of the N-(pyridin-2-yl)hydrazinecarbothioamide in the thiol form. Additional proof comes from the association of the experimental and theoretical data of the 1H NMR for the different isomers of N-(pyridin-2-yl)hydrazinecarbothioamide confirmed the presence of the thiosemicarbazide in the thiol form (isomer A) (Scheme 2) in DMSO solution as illustrated in Tables 1 and 2 in addition to Figs. 3, 4 and 5.

Fig. 1

1H NMR of N-(pyridin-2-yl)hydrazinecarbothioamide in d6-DMSO

Fig. 2

1H NMR of N-(pyridin-2-yl)hydrazinecarbothioamide in d6-DMSO with addition of D2O

Scheme 2

The possible isomers of N-(pyridin-2-yl)hydrazinecarbothioamide

Table 1 Match factor, RMS of assignment, structure purity, reliability, R2 of possible isomers related to experimental 1H NMR data
Table 2 Comparing of experimental shift (ppm) and calculated shift (ppm) possible isomers
Fig. 3

1H NMR of (1) Experimental (2) form (A) (3) form (B) (4) form (C) of N-(pyridin-2-yl)hydrazinecarbothioamide

Fig. 4

The assignment of linear regression between experimental and calculated shift (ppm) of possible isomers

Fig. 5

Residual graphs of calculated shift (ppm) of possible isomers related to experimental shift (ppm)

Description of the crystal structure

The processing data and crystallographic properties of N-(pyridin-2-yl)hydrazinecarbothioamide are summarized in Table 3 and Fig. 6 reveals the numbering pattern of N-(pyridin-2-yl)hydrazinecarbothioamide thiosemicarbazide. Table 4 illustrate the nominated bond lengths and angles. The ligand crystallizes in the C2/c monoclinic space group with one molecule per asymmetric unit. It comprises of only one independent N-(pyridin-2-yl)hydrazinecarbothioamide molecule with no solvent molecules.

Table 3 Crystallographic data for N-(pyridin-2-yl)hydrazinecarbothioamide
Fig. 6

Numbering scheme and atomic displacement ellipsoids drawn at 30% probability level for N-(pyridin-2-yl)hydrazinecarbothioamide

Table 4 Calculated and experimental bond lengths and angles of N-(pyridin-2-yl)hydrazinecarbothioamide

The least-squares planes as defined by the carbon atoms of the phenyl group besides the nitrogen atom of the pyridine ring and the atom directly bonded to it on the one hand and the carbon and nitrogen atoms of the chain-type substituent on the other hand enclose an angle of 9.51°. The C=S bond length is found at 1.694 Å which is intermediate between the usual values for a S(?)-C(sp2) single (1.75–1.78 Å) and a double (1.59 Å) bond and in good agreement with other reported thioketones [26]. The two C(=S)–N bonds differ slightly in length with values of 1.322 Å and 1.373 Å with the longer bond established towards the nitrogenous atom bonded to the aromatic system. The N–N bond is measured at 1.417 Å corresponds to a single bond. The most striking evidence for the single bond character of the N(11)–N(9) bond is that the hydrogen atoms, placed in the positions calculated on the assumption that N(7) is trigonally hybridized in the mean molecular plane, lead to H… H contact, with an adjacent molecule, which are greatly smaller (1.22 Å) than the value of the van der Waals radii (2.40 Å). In the crystal, intra- and intermolecular classical hydrogen bonds of the N–H–N type are apparent next to C–H–S contacts whose range falls below the sum of van-der-Waals radii (2.40 Å) of the atoms participating in the construction stability [27]. The two molecules can be assumed to be practically coplanar and to be joined together in a dimer by the hydrogen bonds with the neighboring molecule.

As an issue of guideline, the packing figure of N-(pyridin-2-yl)hydrazinecarbothioamide construction (Fig. 7) is very straightforward. It consists of layers of ligand molecules with the same orientation (all the molecule pointing in the same direction), which are held together via hydrogen bonds as appeared in Fig. 8. There are ππ stacking interactions with distances about 3.348–3.46 Å between the molecules of each row, prompting heaps of stacked ligand molecules. The pyridine rings of the adjacent ligand molecule are not coplanar in the solid state, which is probably due to stacking effects. In the crystal packing, offset ππ stacking interactions have been observed between neighboring pyridine rings of two molecules in the head-to-tail arrangement forming similar dimeric packing structures, as displayed in Fig. 8. The centroid–centroid separations between the dimeric pairs are 3.586 Å.

Fig. 7

Packing diagram of N-(pyridin-2-yl)hydrazinecarbothioamide showing molecular stacking along the ac-plane

Fig. 8

Hydrogen bridges (green lines) along the ac plane of the unit cell

Molecular computational calculation

Geometry optimization using DFT

Structure 1 illustrates the optimized structure and numbering scheme of N-(pyridin-2-yl)hydrazinecarbothioamide. From the analysis of the estimated and measured data for the bond lengths and angles Table 4 one can observe the similarity between the estimated and measured data.

Structure 1

Geometry optimization using DFT method of ligands a N-(pyridin-2-yl)hydrazinecarbothioamide, b HOMO and c LUMO

The calculated energy components and energies of both HOMO (π donor) and LUMO (π acceptor) Table 5 are main parameters in quantum chemical studies. Where, HOMO is the orbital that behaves as an electron giver, LUMO is the orbital that behave as the electron acceptor and these molecular orbitals are known as the frontier molecular orbitals (FMOs) Structure 1.

Table 5 Calculated energy components, EHOMO, ELUMO, energy band gap (EH EL), chemical potential (μ), electronegativity (χ), global hardness (η), global softness (S) and global electrophilicity index (ω) for N-(pyridin-2-yl)hydrazinecarbothioamide

DFT technique illustrates the discernment of the molecular arrangements and expects the chemical reactivity. The energies of gas stage, FMOs (EHOMO, ELUMO), electronegativity (χ), energy band gap that clarifies the inevitable charge exchange communication inside the particle inside the molecule, global hardness (η), chemical potential (µ), global electrophilicity index (ω) and global softness (S) [28, 29] are recorded in Table 5.

In numerous responses, the overlap amongst HOMO and LUMO orbitals assumed as an administering reason, where in compounds under examination; the orbitals with the higher molecular orbital coefficients can be considered as the fundamental destinations of the complexation. The energy gap (EHOMO − ELUMO) is a noteworthy stability index simplify the description of both kinetic stability and chemical reactivity of the investigated moieties [30]. The energy gap of ligand is small showing that charge transfers easily in it and this influences the biological activity of the molecule, which agree with experimental data of antibacterial, and antifungal activities. Furthermore, the small quantity of energy difference can be assigned to the groups that enter into conjugation [31].

Experimental IR and vibrational calculation

In order to get the spectroscopic signature of ligands compounds, a frequency calculation analysis were carried out. The calculations were completed for free molecule in vacuum, while experiments were performed for solid sample (Table 6), so there are small differences between hypothetical and measured vibrational frequencies as illustrated in Fig. 9. The modes of vibrations are very complex because of the low symmetry of ligands. Particularly, in plane, out of plane and torsion vibrations have the greatest difficultly to allocate because of the involvement with the ring vibrations and with the substituent vibrations. However, there are some strong frequencies useful to characterize in the IR graph. The relationship that showed the similarities among the calculated and measured data is illustrated in Fig. 10 which confirm the existence of the N-(pyridin-2-yl)hydrazinecarbothioamide in the thione form (isomer C). The relations between the calculated and experimental wavenumbers are linear for ligand and described by νcal = 1.1111 νExp− 115.87 with R2 = 0.9963.

Table 6 Expermintal and theoretical wavenumber (cm−1) of N-(pyridin-2-yl)hydrazinecarbothioamide
Fig. 9

Comparison of experimental and theoretical IR spectra of N-(pyridin-2-yl)hydrazinecarbothioamide

Fig. 10

The linear regression between the experimental and theoretical frequencies of N-(pyridin-2-yl)hydrazinecarbothioamide

As a glance of table and figures, one can conclude the following remarks:

  1. i.

    The linear regression between the experimental and theoretical frequencies confirms the existence of the N-(pyridin-2-yl)hydrazinecarbothioamide in the thione form (isomer C).

  2. ii.

    The relations between the hypothetical and measured data is linear and described by equation νcal = 1.1111 νExp − 115.87 with R2 = 0.9963.

  3. iii.

    The two bands at 3240 and 3160 cm−1 were attributed to the stretching (NH)7 and (NH)9 groups, respectively [32].

  4. iv.

    The bands observed at 1606, 1544 and 1243 cm−1 assigned to ν(C=N), (C=C) and (C–N) stretching of pyridine rings, respectively [33]. Also the out of plane and in plane binding frequencies of (C=N)py appeared at 632 [34].

  5. v.

    The thiosemicarbazide exhibited ν(–NH2 → =NH) at 3025 and 3046 cm−1. While ν(–NH2) wagging appeared at 761 cm−1.

  6. vi.

    A band at 1006 cm−1 corresponding to ν(N–N) [35].

  7. vii.

    The thioamide group (HN–C=S) displayed four thioamide bands (I–IV) at 1474 cm−1 (I), 1337 cm−1 (II), 1143 cm−1 (III) and 893 cm−1 (IV) [36,37,38,39].

Non-linear optical (NLO) properties

The quantum chemistry based prediction of NLO possessions of N-(pyridin-2-yl)hydrazinecarbothioamide has an essential part for the design of materials in communication technology, signal processing and optical interconnections [40]. The total static dipole moment μ, the average linear polarizability \(\overline{\alpha }\), the anisotropy of the polarizability ∆α, and the first hyper-polarizability β can be calculated as reported by Sajan et al. [40]. Table 7 illustrates the ingredients of dipole moment, polarizability and the average first hyper-polarizability of N-(pyridin-2-yl)hydrazinecarbothioamide framework.

Table 7 Calculated dipole moments (D), polarizability and the first hyperpolarizability components (a.u.) for ligand compounds

The estimated data were changed into Debye Å3 and electrostatic units (e.s.u.) utilizing the well-known conversion relations (for μ: 1 a.u. = 2.5416 Debye; for α: 1 a.u. = 0.14818 Å3; for β: 1 a.u. = 8.641 × 10−33 e.s.u.) [41]. Urea is utilizes as an acute parameter for comparison studies because it has a decent NLO activity (μ = 1.3732 Debye, \(\overline{\alpha }\) = 3.8312 Å3 and β = 3.7289 × 10−31 cm5/e.s.u.). Furthermore N-(pyridin-2-yl)hydrazinecarbothioamide have parameters μ = 4.4481 Debye, \(\overline{\alpha }\) = 18.9817 Å3, ∆α = 44.3551 Å3, and β = 2.1727 × 10−30 cm5/e.s.u.

The first hyper-polarizability of N-(pyridin-2-yl)hydrazinecarbothioamide is greater than that of urea 5.82 times, respectively. According to the magnitude of β, the N-(pyridin-2-yl)hydrazinecarbothioamide under study may be have a potential applicant in the improvement of NLO materials due to they have a worthy non-linear property.

Electrostatic potential (ESP) and average local ionization energy (ALIE) properties on molecular surface

Electrostatic potential V(r) and average local ionization energy \(\overline{I}\)(r) of molecule have confirmed to be active guides to its reactive behavior [42].

Electrostatic potential V(r) and average local ionization energy \(\overline{\text{I}}\)(r) of all frameworks were shown in Structures 2 and 3, respectively. Also, estimated molecular surface data showed in Table 8. This table include the following parameters:

Structure 2

Surface structure of ESP using DFT method for N-(pyridin-2-yl)hydrazinecarbothioamide

Structure 3

Surface structure of ALIE using DFT method for N-(pyridin-2-yl)hydrazinecarbothioamide

Table 8 Computed molecular surface properties (ESP) and (ALIE) of compound
  1. i.

    The data of the most positive and most negative VS,max and VS,min.

  2. ii.

    Overall surface potential value \(\overline{V}\)S, its positive and negative averages \(\overline{V}_{s}^{ + }\) and \(\overline{V}_{s}^{ - }\).

  3. iii.

    The internal charge transfer (local polarity) Π, which is deduced as a meter for the internal charge separation and it is present even in molecules with zero dipole moment because of the symmetry.

  4. iv.

    The variances, \(\sigma_{ + }^{2}\), \(\sigma_{ - }^{2}\) and \(\sigma_{tot}^{2}\) which reflect the strengths and variabilities of the positive, negative and overall surface potentials [43].

  5. v.

    An electrostatic balance parameter ν = 0.25, that illustrate the extent of the equilibrium amongst the positive and negative potentials; when \(\sigma_{ + }^{2} = \sigma_{ - }^{2}\)

  6. vi.

    The most positive and most negative \(\overline{I}\)S,max and \(\overline{I}\)S,min and the average over the surface of the local ionization energy \(\overline{I}\)S,ave.

From Table 8 we notice that N-(pyridin-2-yl)hydrazinecarbothioamide has the internal charge separation, Π = 15.37 kcal mol−1, may be due to it was structurally quite symmetric.

In Structures 2 and 3 is displayed the VS(r) and \(\overline{I}\)S(r) on surfaces of N-(pyridin-2-yl)hydrazinecarbothioamide. These structures show the locations of the various most positive and most negative VS(r), VS,max and VS,min, and the highest and lowest \(\overline{I}\)S(r), \(\overline{I}\)S,max and \(\overline{I}\)S,min. There are often several local maxima and minima of each property on a studied molecular surface. The most negative electrostatic potential on N-(pyridin-2-yl)hydrazinecarbothioamide surface is related to the nitrogen (N1) of pyridine ring, VS,min = − 41.62 kcal mol−1, followed by weaker value − 38.6 kcal mol−1 on the sulfur (S10). Thus, VS(r) would wrongly predict electrophilic attack to occur preferentially at the nitrogen. In contrast, the lowest values of \(\overline{I}\)S(r) placed on the (S10), with \(\overline{I}\)S,min = 159.79 kcal mol−1; also, there is an \(\overline{I}\)S,min by the hydrogen (H18), but it is much higher, 165.39 kcal mol−1. Thus, \(\overline{I}\)S(r) shows the most reactive, least-tightly-bound electrons to be at the (S10), properly indicating these sites to be most susceptible to electrophiles. On the other hand, the very strongly positive electrostatic potential of the hydrogen (H16), VS,max = 48.98 kcal mol−1, and the VS,min = − 41.62 kcal mol−1 of the nitrogen (N1) indicate their tendencies for noncovalent hydrogen bonding, as a donor and an acceptor, respectively.

Molecular docking

The molecular interaction of N-(pyridin-2-yl)hydrazinecarbothioamide for inhibition against E. coli and S. aureus are represented in Structures 4, 5, 6 and 7 shows exchanges with the active site residues with dock score − 4.523 and − 5.265 kcal/mol for both E. coli and S. aureus, respectively. The affinity of N-(pyridin-2-yl)hydrazinecarbothioamide against E. coli is resulting from two hydrogen bonds interaction (NH2 → TYR156 and (NH)7 → ALA196). While, the interaction with S. aureus resulting from the molecular hydrogen bonds interaction (NH2 → SER75 and (NH)9 → H2O → GLU11).

Structure 4

2D molecular interaction of N-(pyridin-2-yl)hydrazinecarbothioamide for inhibitor to E. coli

Structure 5

3D molecular interaction of N-(pyridin-2-yl)hydrazinecarbothioamide for inhibitor to E. coli

Structure 6

2D molecular interaction of N-(pyridin-2-yl)hydrazinecarbothioamide for inhibitor to S. aureus

Structure 7

3D molecular interaction of N-(pyridin-2-yl)hydrazinecarbothioamide for inhibitor to S. aureus


Novel thiosemicarbazide; N-(pyridin-2-yl)hydrazinecarbothioamide has been isolated and described utilizing single-crystal X-ray and 1HNMR. Additionally, its geometry optimization, calculated vibrational frequencies, non-linear optical properties, electrostatic potential and average local ionization energy properties of molecular surface were being assessed by means of Jaguar program in the Schrödinger’s set on the basis of the density functional concept (DFT) to pretend the molecular geometry and predict properties of molecule performed by the hybrid density functional routine B3LYP. Finally, the docking study of N-(pyridin-2-yl)hydrazinecarbothioamide were applied against negative E. coli bacterial and gram positive S. aureus bacterial strains by Schrödinger suite program using XP glide protocol.


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Abu-Melha, S. Pyridyl thiosemicarbazide: synthesis, crystal structure, DFT/B3LYP, molecular docking studies and its biological investigations. Chemistry Central Journal 12, 101 (2018).

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  • N-(pyridin-2-yl)hydrazinecarbothioamide
  • Single-crystal X-ray
  • Spectral characterization
  • Molecular docking