Synthesis, crystal structure, and in silico mol­ecular docking studies of 4-hy­droxy-3,5-di­meth­oxy­benzaldehyde (6-chloro­pyridazin-3-yl)hydrazone monohydrate

Ummer, M.R.; NizamMohideen, M.; Noorulla, M.N.; Moolan Khaja, A.S.

doi:10.1107/S205698902500252X

research communications

CRYSTALLOGRAPHIC
COMMUNICATIONS

ISSN: 2056-9890

Volume 81| Part 4| April 2025| Pages 336-340

https://doi.org/10.1107/S205698902500252X

Open

access

Synthesis, crystal structure, and in silico molecular docking studies of 4-hydroxy-3,5-dimethoxybenzaldehyde (6-chloropyridazin-3-yl)hydrazone monohydrate

Muhammed Rafi Ummer,^a ^* M. NizamMohideen,^b Mohammed Nazrudeen Noorulla ^a and Abubacker Sidhik Moolan Khaja ^a

^aPost-Graduate and Research Department of Chemistry, The New College, University of Madras, Chennai 600 014, Tamilnadu, India, and ^bDepartment of Physics, The New College, Chennai 600 014, University of Madras, Tamil Nadu, India
^*Correspondence e-mail: muhammedrafi@thenewcollege.edu.in

Edited by C. Schulzke, Universität Greifswald, Germany (Received 10 February 2025; accepted 19 March 2025; online 25 March 2025)

In the title compound, C₁₃H₁₃ClN₄O₃·H₂O, the organic molecule has an E configuration with regard to the C=N bond of the hydrazone bridge. The phenyl and pyridazine rings subtend a dihedral angle of 2.1 (1)° between their mean planes, while the hydrazone moiety makes dihedral angles of 1.6 (2) and 3.0 (2)°, respectively, with these aromatic rings. This renders the entire molecule comparably flat. A C—H⋯N hydrogen bond generates an inversion dimer with a large R₂²(14) ring motif. Within this ring, a further C—H⋯N hydrogen bond establishes a smaller R₂²(8) ring. The molecules of a dimer are thereby firmly linked by four hydrogen bonds. A bifurcated O—H⋯(O,O) hydrogen bond is formed between a water hydrogen atom and the hydroxyl and methoxy oxygen atoms of an adjacent molecule, leading to the formation of an R₂¹(5) membered ring. C—H⋯π and face-to-face π–π stacking interactions are also present in the two-dimensional framework, which may be of relevance for the packing. In a complementary analysis, the compound was docked in silico to EGFR and HER2 receptors and the results imply that the compound targets EGFR preferentially over HER2.

Keywords: crystal structure; hydrazone; pyridazine; syringaldehyde; molecular docking; EGFR kinase; hydrogen bonding.

CCDC reference: 2342583

1. Chemical context

Hydrazone compounds are known to be associated with a wide spectrum of biological and medicinal applications, such as antimicrobial, anticonvulsant, analgesic and anti-inflammatory activities (NizamMohideen et al., 2019 ). Compounds that target the epidermal growth factor receptor (EGFR) and the human epidermal growth factor receptor 2 (HER2) are known as tyrosine kinase inhibitors (TKIs) include gefitinib, erlotinib, neratinib, and afatinib, which act as anticancer agents (Uribe et al., 2021 ; Weinberg et al., 2020 ). However, these inhibitors show side effects and have adverse negative impacts on the patient's health (Riecke & Witzel, 2020 ). As a result, new EGFR inhibitors need to be developed that would be more effective with less toxicity. Pyridazine derivatives have been the subject of extensive study in recent years, and the results have demonstrated a broad spectrum of pharmacological actions, including antidepressant (Komkov et al., 2015 ), COX-2 inhibitor (Harris et al., 2004 ) and anticancer properties (Rafi et al., 2019 ; Ahmad et al., 2010 ). Commercially available physiologically active compounds with pyridazine as a structural component are hydralazine (vasodilator), minaprine (antidepressant), and azelastine (bronchodilator) (Contreras et al., 1999 ; del Olmo et al., 2006 ). Our current research is focused on the synthesis of a new compound containing a pyridazine unit and a syringaldehyde derived moiety linked by a hydrazone motif, which may potentially act as a better TKI.

2. Structural commentary

The molecular structure of the title compound is illustrated in Fig. 1. The organic molecule features a central, essentially planar region flanked on either side by a chlorine-substituted pyridazine, and a trisubstituted phenyl ring and it crystallized together with a water molecule. The phenyl and pyridazine rings (C6–C11 and N1/N2/C1–C4, respectively) are each planar with a dihedral angle of 2.1 (1)° between their mean planes. The mean plane through the hydrazone unit (N3/N4/C5) forms angles of 1.6 (2) and 3.0 (2)° with the phenyl and pyridazine rings, respectively. In the title compound, the hydrazone molecule adopts an E configuration with regard to the hydrazone bridge N4=C5, with torsion angles N3—N4—C5—C6 of −178.3 (2)° and C4—N3—N4—C5 of 178.5 (2)°, which are consistent with the trans relationship in the central moiety (Table 1). The bond lengths and angles in the hydrazone functional group of the title compound are comparable with the values reported for related structures (NizamMohideen et al., 2019; Prabhu et al., 2011 ). The chlorine and hydroxy oxygen atoms deviate by −0.05 and 0.15 Å, respectively, from their pyridazine and phenyl ring mean planes. The C4—N3 and C5=N4 bond lengths differ by 0.075 Å, whereby these two bonds may be assigned as localized single and double bonds, respectively, while some resonance effects cannot be firmly excluded. One of the two methoxy groups is more coplanar with the C5–C11 phenyl ring than the other one, which deviates somewhat from the benzene ring plane, with torsion angles C12—O3—C10—C11 of 5.9 (3) Å and C13—O1—C8—C7 of 8.3 (3) Å.

Table 1
Selected geometric parameters (Å, °)

C4—N3	1.353 (2)	N1—N2	1.350 (2)
C5—N4	1.278 (2)	N3—N4	1.3769 (17)

C4—N3—N4	121.38 (15)	C5—N4—N3	113.84 (14)

N4—C5—C6—C11	1.3 (2)	C4—N3—N4—C5	−178.52 (15)
C3—C4—N3—N4	−2.2 (3)	C7—C8—O1—C13	8.3 (3)
C6—C5—N4—N3	−178.31 (14)	C11—C10—O3—C12	5.9 (3)

Figure 1
The molecular structure of the title compound, with atom labelling. Displacement ellipsoids are drawn at the 50% probability level.

3. Supramolecular features

Extensive hydrogen bonding plus some van der Waals contacts are the dominant interactions in the crystal packing (Table 2). The C5—H5⋯N1 hydrogen bond generates an inversion dimer with an R₂² (14) ring motif (Bernstein et al., 1995 ); within this larger ring the C3—H3N⋯N2 hydrogen bond links the molecules into an R₂²(8) ring motif. The two molecules of one dimer are therefore firmly connected by four hydrogen bonds. In addition, a bifurcated O4—H4W⋯(O2, O1)(−x + 1, −y + 1, −z + 2) hydrogen bond is formed between the water hydrogen atom and the hydroxyl and methoxy oxygen atoms of an adjacent organic molecule, leading to the formation of an R₂¹(5) ring. The same water molecule forms another hydrogen bond to the hydroxyl oxygen atom [O4—H5W⋯O2(x, y + 1, z)] of a different adjacent molecule. As acceptor, the water forms a hydrogen bond within the asymmetric unit: O2—H2O⋯O4. All in all, the water molecules link the hydrogen-bonded dimers throughout the crystal structure into a 3D network, one dimension of which is shown in Fig. 2. Potentially C—H⋯π interactions (Table 2) and/or off-centre face-to-face π–π stacking interaction [Cg1⋯Cg1( $[{1\over 2}]$ − x, − $[{1\over 2}]$ − y, 1 − z) = 4.374 (2) with slippage of 2.929 Å, where Cg1 is the centroid of the N1/N2/C1–C4 ring] may contribute to a two-dimensional substructure. As a result of the presence of a twofold screw axis ( $[{1\over 2}]$ − x, − $[{1\over 2}]$ + y, $[{3\over 2}]$ − z), which does not lie in the plane of the organic molecule, the latter appears in two orientations relative to the cell dimensions, resulting in a folded sheet arrangement with an inter-planar angle of 88.45°, when all atoms of the two aromatic rings and the hydrazone moiety are used to calculate the planes.

Table 2
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
C5—H5⋯N1ⁱ	0.93	2.60	3.519 (2)	172
C12—H12A⋯N4ⁱⁱ	0.96	2.66	3.369 (2)	132
O2—H2O⋯O4	0.85 (2)	1.84 (2)	2.668 (2)	164 (2)
N3—H3N⋯N2ⁱ	0.87 (2)	2.12 (2)	2.993 (2)	178.3 (18)
O4—H4W⋯O1ⁱⁱⁱ	0.79 (3)	2.23 (3)	2.9254 (19)	146 (3)
O4—H4W⋯O2ⁱⁱⁱ	0.79 (3)	2.55 (3)	3.239 (2)	147 (3)
O4—H5W⋯O2^iv	0.85 (3)	2.08 (3)	2.914 (2)	169 (3)
C12—H12B⋯Cg(C6–C11)^v	0.96	2.87	3.671 (1)	142
C13—H13B⋯Cg(C6–C11)^iv	0.96	2.90	3.666 (1)	138
Symmetry codes: (i) $[-x+{\script{1\over 2}}, -y+{\script{1\over 2}}, -z+1]$ ; (ii) $[-x+{\script{1\over 2}}, y+{\script{1\over 2}}, -z+{\script{3\over 2}}]$ ; (iii) ; (iv) ; (v) .

Figure 2
A view along the a axis of the crystal packing of title compound. Hydrogen bonds (Table 2

) are shown as dashed lines, and H atoms not involved in hydrogen bonding were omitted for clarity.

4. Database survey

A survey of the Cambridge Structural Database (CSD, Version 5.38; Groom et al., 2016 ) for the presence of 3-(2-benzylidenehydrazinyl)pyridazine as the main skeleton revealed three structures as closely related to the title compound. The molecule of DUTQUF (Ather et al., 2010 ) is much less planar than the title compound. However, the bidirectional N—H⋯N hydrogen bonding is present here as well, albeit twisted because of the non-planarity. Chlorine acts as a hydrogen-bonding acceptor. In GUTYEB01 (Bakale et al., 2018 ), the molecule is also less planar due to the torsion of the nitro group, and the aromatic systems are not as coplanar as in the title compound. It is the only one of the three related compounds that has co-crystallized water. Hydrogen bonding involving water forms dimers of molecules. The three-dimensional hydrogen-bonding network is facilitated by including chloride as hydrogen-bonding acceptor from water O—H, phenyl C—H and hydrazine N—H. Lastly, the KUZSOP (Rafi et al., 2016 ) molecule is less planar than the title compound in its general scaffold but more planar than the other two. It is the only one of the three related derivatives that has the exact same hydrogen-bonding pattern for the N—H⋯N contacts as found in the tittle compound. Additional C—H⋯O interactions lead to band structures, which protrude indefinitely through the crystal structure and are not connected to any adjacent bands. This means that the hydrogen-bonding network is two-dimensional considering the molecular dimensions and one-dimensional considering the band dimension, which is a unique feature among the four structures. All compounds have N—H⋯N bonds except GUTYEB01, while KUZSOP has overall similar types of hydrogen bonds (C—H⋯N and O—H⋯N) as the title compound. The N—C—N—N torsion angle between the pyridazine ring and hydrazine moiety of the title compound are comparable with those in DUTQUF and GUTYEB01 but differs slightly more from that in KUZSOP. The C—C—N—N torsion angles between the phenyl ring and hydrazine moiety of the title compound are comparable with all three compounds. Most of the bond angles of the title compound have close similarities with all three compounds, except for N—N—H and N—C—N, which may be attributed to the formation of hydrogen bonding involving these atoms.

5. Molecular docking studies

The main factors in determining the binding affinity and the efficacy of a new drug molecule are hydrogen bonding and hydrophobic interactions. Hydrogen bonds play an important role in drug-receptor interactions, which improve many biological functions (Chen et al., 2016 ), while the hydrophobic interactions affect a wide range of biological processes. Hence, molecular docking studies were utilized to predict the in silico molecular interactions between the compound and the targets, namely, EGFR and HER2 protein receptors. The binding energies of the title compound with these receptors are summarized in Table S2 in the Supporting Information.

4-Hydroxy-3,5-dimethoxybenzaldehyde (6-chloropyridazin-3-yl)hydrazone exhibits hydrophobic interactions and hydrogen bonding with both the EGFR and HER2 kinases (Figs. 3 and 4). The compound interacts with the EGFR receptor through two hydrogen-bonding interactions, one between the oxygen atoms of the methoxy group with Lys721, and the second between the oxygen atoms of the hydroxyl and methoxy groups with Asp831. The compound shows π–sulfur interactions with residue Cys751, alkyl interactions with residues Leu694, Val702, Lys721 and Met742, as well as van der Waals interactions with residues Glu738, Gln767, Met769, Pro770, Gyl772, The830 and Phe832. The compound interacts with the HER2 receptor through two hydrogen-bonding interactions, the first being the one between the nitrogen atom of the pyridazine ring with Lys753, and the second between the oxygen atom in the hydroxyl group and Met801. Additionally, the compound has π–sigma interactions with residues Ala751, Thr798 and Leu852, alkyl interactions with residues Leu785, Leu796, Leu800, Cyc805 and Phe1004, and van der Waals interactions with residues Leu726, Val734, Val797 and Thr862.

Figure 3
(a) Three-dimensional visualization of the binding pose of the compound within the EGFR kinase receptor. (b) Two-dimensional ligand–protein interaction plot of the title compound with the EGFR kinase receptor. Figure prepared using Discovery Studio Visualizer (v2021; BIOVIA, 2021

Figure 4
(a) Three-dimensional visualization of the binding pose of the compound within the HER2 kinase receptor. (b) Two-dimensional ligand–protein interaction plot of the title compound with the HER2 kinase receptor. Figure prepared using Discovery Studio Visualizer (v2021; BIOVIA, 2021

Though the title compound interacts through hydrogen bonds and hydrophobic interactions with both the receptors, it has different binding energy values. The compound has a higher binding energy for the EGFR receptor (−8.43 kJ mol⁻¹) than the HER2 receptor (−6.88 kJ mol⁻¹). Hence, the compound is tightly bound in the EGFR binding pocket, indicating that it can in principle act as a potent EGFR inhibitor.

6. Synthesis and crystallization

An ethanolic solution (25 mL) of syringaldehyde (0.3642g, 1 mmol) was slowly added to an ethanolic solution (25 mL) of 3-chloro-6-hydrazinopyridazine (0.289 g, 1 mmol) with constant stirring for 1 h and refluxed for 2 h. The obtained clear solution was allowed to stand and the compound crystallized under slow evaporation. Single crystals of the compound suitable for X-ray analysis were recrystallized by slow evaporation from ethanol/water at room temperature·Yellow solid. Yield: 0.4631 g (70.89%), m.p. 528 K. Selected IR data (KBr, cm⁻¹): 3452 ν (OH), 3381 ν (NH), 1695 ν (C=N), 1502 ν (N=N), 1314 ν (Ar—O).

7. Refinement

Crystal data, data collection and structure refinement details, are summarized in Table 3. The water, hydroxyl and NH hydrogen atoms were located in difference-Fourier maps and freely refined. The C-bound H atoms were positioned geometrically and constrained to ride on their parent atoms, with C—H =0.95–0.98 Â, and with U_iso = 1.5U_eq(C) for methyl H atoms and 1.2U_eq(C) for other H atoms.

Table 3
Experimental details

Crystal data
Chemical formula	C₁₃H₁₃ClN₄O₃·H₂O
M_r	326.74
Crystal system, space group	Monoclinic, C2/c
Temperature (K)	298
a, b, c (Å)	32.1977 (19), 4.6431 (3), 26.400 (2)
β (°)	127.495 (2)
V (Å³)	3131.4 (4)
Z	8
Radiation type	Mo Kα
μ (mm⁻¹)	0.27
Crystal size (mm)	0.45 × 0.25 × 0.10

Data collection
Diffractometer	Bruker D8 VENTURE with PHOTON II detector
Absorption correction	Multi-scan (SADABS; Krause et al., 2015 )
T_min, T_max	0.580, 0.746
No. of measured, independent and observed [I > 2σ(I)] reflections	32222, 3867, 3259
R_int	0.052
(sin θ/λ)_max (Å⁻¹)	0.666

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.049, 0.132, 1.07
No. of reflections	3867
No. of parameters	215
H-atom treatment	H atoms treated by a mixture of independent and constrained refinement
Δρ_max, Δρ_min (e Å⁻³)	0.32, −0.27
Computer programs: APEX3, SAINT and XPREP (Bruker, 2016 ), SHELXT2018/2 (Sheldrick, 2015a ), SHELXL2019/3 (Sheldrick, 2015b ), ORTEP-3 for Windows and WinGX (Farrugia, 2012 ), PLATON (Spek, 2009 ) and publCIF (Westrip, 2010 ).

Supporting information

CCDC reference: 2342583

Crystal structure: contains datablocks global, I. DOI: https://doi.org/10.1107/S205698902500252X/yz2065sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S205698902500252X/yz2065Isup2.hkl

The supporting information contains the experimental section, molecular docking procedure, IR spectral characterization, additional tables and figure. DOI: https://doi.org/10.1107/S205698902500252X/yz2065sup3.docx

Supporting information file. DOI: https://doi.org/10.1107/S205698902500252X/yz2065Isup4.cml

checkCIF report

Computing details top

4-Hydroxy-3,5-dimethoxybenzaldehyde (6-chloropyridazin-3-yl)hydrazone monohydrate top

Crystal data top

C₁₃H₁₃ClN₄O₃·H₂O	F(000) = 1360
M_r = 326.74	D_x = 1.386 Mg m⁻³
Monoclinic, C2/c	Mo Kα radiation, λ = 0.71073 Å
a = 32.1977 (19) Å	Cell parameters from 9970 reflections
b = 4.6431 (3) Å	θ = 2.5–28.2°
c = 26.400 (2) Å	µ = 0.27 mm⁻¹
β = 127.495 (2)°	T = 298 K
V = 3131.4 (4) Å³	Block, brown
Z = 8	0.45 × 0.25 × 0.10 mm

Data collection top

Bruker D8 VENTURE diffractometer equipped with PHOTON II detector	3259 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	R_int = 0.052
ω and φ scan	θ_max = 28.3°, θ_min = 3.2°
Absorption correction: multi-scan (SADABS; Krause et al., 2015)	h = −42→42
T_min = 0.580, T_max = 0.746	k = −6→4
32222 measured reflections	l = −35→35
3867 independent reflections

Refinement top

Refinement on F²	Primary atom site location: dual
Least-squares matrix: full	Hydrogen site location: mixed
R[F² > 2σ(F²)] = 0.049	H atoms treated by a mixture of independent and constrained refinement
wR(F²) = 0.132	w = 1/[σ²(F_o²) + (0.0564P)² + 2.0701P] where P = (F_o² + 2F_c²)/3
S = 1.07	(Δ/σ)_max = 0.001
3867 reflections	Δρ_max = 0.32 e Å⁻³
215 parameters	Δρ_min = −0.27 e Å⁻³
0 restraints

Special details top

Geometry. 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.s. planes.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq
C1	0.12978 (7)	0.8456 (4)	0.41979 (9)	0.0544 (4)
C2	0.14422 (8)	0.9256 (4)	0.47956 (10)	0.0612 (5)
H2	0.125598	1.064179	0.483681	0.073*
C3	0.18687 (8)	0.7917 (4)	0.53169 (9)	0.0570 (4)
H3	0.198656	0.837253	0.572787	0.068*
C4	0.21223 (6)	0.5831 (4)	0.52099 (7)	0.0452 (4)
C5	0.31793 (6)	0.3204 (4)	0.66896 (7)	0.0473 (4)
H5	0.328952	0.194971	0.651841	0.057*
C6	0.34738 (6)	0.3305 (4)	0.73833 (7)	0.0424 (3)
C7	0.39076 (6)	0.1498 (4)	0.77521 (7)	0.0469 (4)
H7	0.400366	0.030334	0.755628	0.056*
C8	0.41951 (6)	0.1486 (4)	0.84109 (7)	0.0448 (3)
C9	0.40516 (5)	0.3252 (3)	0.87054 (6)	0.0411 (3)
C10	0.36127 (6)	0.5033 (3)	0.83331 (7)	0.0397 (3)
C11	0.33270 (6)	0.5085 (3)	0.76741 (7)	0.0411 (3)
H11	0.303949	0.630052	0.742856	0.049*
C12	0.30407 (7)	0.8281 (5)	0.83303 (9)	0.0615 (5)
H12A	0.301109	0.929493	0.862401	0.092*
H12B	0.305110	0.964118	0.806431	0.092*
H12C	0.274442	0.703171	0.806886	0.092*
C13	0.48434 (8)	−0.1772 (5)	0.85738 (12)	0.0732 (6)
H13A	0.514242	−0.283563	0.891218	0.110*
H13B	0.458548	−0.308440	0.825325	0.110*
H13C	0.494847	−0.047217	0.838793	0.110*
N1	0.15369 (6)	0.6503 (4)	0.41076 (7)	0.0542 (4)
N2	0.19538 (6)	0.5134 (3)	0.46188 (6)	0.0509 (3)
N3	0.25458 (6)	0.4304 (4)	0.56743 (6)	0.0515 (4)
N4	0.27767 (5)	0.4770 (3)	0.63098 (6)	0.0470 (3)
O1	0.46277 (5)	−0.0183 (3)	0.88222 (6)	0.0642 (4)
O2	0.43409 (5)	0.3129 (3)	0.93550 (5)	0.0548 (3)
O3	0.35056 (4)	0.6626 (3)	0.86749 (5)	0.0550 (3)
O4	0.44334 (6)	0.7811 (3)	1.00029 (6)	0.0619 (4)
Cl1	0.07736 (2)	1.01427 (14)	0.35124 (3)	0.0811 (2)
H2O	0.4312 (9)	0.472 (5)	0.9495 (11)	0.072 (7)*
H3N	0.2689 (8)	0.304 (4)	0.5582 (9)	0.054 (5)*
H4W	0.4738 (12)	0.791 (6)	1.0283 (15)	0.100 (10)*
H5W	0.4362 (10)	0.937 (6)	0.9796 (13)	0.084 (8)*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
C1	0.0465 (8)	0.0610 (10)	0.0545 (9)	−0.0077 (8)	0.0300 (8)	0.0089 (8)
C2	0.0656 (11)	0.0575 (10)	0.0721 (12)	−0.0019 (9)	0.0478 (10)	0.0019 (9)
C3	0.0697 (11)	0.0578 (10)	0.0532 (9)	−0.0107 (9)	0.0425 (9)	−0.0058 (8)
C4	0.0478 (8)	0.0523 (9)	0.0386 (7)	−0.0127 (7)	0.0279 (7)	−0.0030 (6)
C5	0.0485 (8)	0.0610 (10)	0.0361 (7)	−0.0106 (7)	0.0277 (7)	−0.0088 (7)
C6	0.0409 (7)	0.0515 (9)	0.0347 (7)	−0.0104 (6)	0.0230 (6)	−0.0068 (6)
C7	0.0444 (8)	0.0545 (9)	0.0436 (8)	−0.0056 (7)	0.0278 (7)	−0.0133 (7)
C8	0.0360 (7)	0.0463 (8)	0.0431 (8)	0.0007 (6)	0.0194 (6)	−0.0060 (6)
C9	0.0371 (7)	0.0455 (8)	0.0311 (7)	−0.0007 (6)	0.0158 (6)	−0.0040 (6)
C10	0.0356 (7)	0.0461 (8)	0.0331 (7)	−0.0010 (6)	0.0187 (6)	−0.0054 (6)
C11	0.0350 (7)	0.0492 (8)	0.0320 (7)	−0.0006 (6)	0.0168 (6)	−0.0008 (6)
C12	0.0467 (9)	0.0736 (13)	0.0581 (10)	0.0132 (9)	0.0288 (8)	−0.0081 (9)
C13	0.0618 (11)	0.0681 (13)	0.0876 (15)	0.0153 (10)	0.0444 (11)	−0.0102 (11)
N1	0.0475 (7)	0.0687 (10)	0.0404 (7)	−0.0070 (7)	0.0237 (6)	0.0036 (7)
N2	0.0504 (7)	0.0645 (9)	0.0357 (6)	−0.0045 (6)	0.0251 (6)	−0.0007 (6)
N3	0.0536 (8)	0.0668 (9)	0.0330 (6)	−0.0029 (7)	0.0257 (6)	−0.0052 (6)
N4	0.0499 (7)	0.0603 (8)	0.0323 (6)	−0.0128 (6)	0.0258 (6)	−0.0063 (6)
O1	0.0499 (7)	0.0685 (8)	0.0518 (7)	0.0191 (6)	0.0193 (6)	−0.0089 (6)
O2	0.0540 (7)	0.0569 (7)	0.0317 (5)	0.0128 (6)	0.0148 (5)	−0.0027 (5)
O3	0.0473 (6)	0.0731 (8)	0.0345 (5)	0.0169 (6)	0.0197 (5)	−0.0053 (5)
O4	0.0582 (8)	0.0642 (9)	0.0379 (6)	−0.0048 (7)	0.0161 (6)	−0.0042 (6)
Cl1	0.0572 (3)	0.0952 (4)	0.0770 (4)	0.0074 (3)	0.0337 (3)	0.0300 (3)

Geometric parameters (Å, º) top

C1—N1	1.302 (2)	C9—C10	1.399 (2)
C1—C2	1.397 (3)	C10—O3	1.3636 (18)
C1—Cl1	1.7374 (19)	C10—C11	1.3874 (19)
C2—C3	1.366 (3)	C11—H11	0.9300
C2—H2	0.9300	C12—O3	1.415 (2)
C3—C4	1.402 (3)	C12—H12A	0.9600
C3—H3	0.9300	C12—H12B	0.9600
C4—N2	1.343 (2)	C12—H12C	0.9600
C4—N3	1.353 (2)	C13—O1	1.418 (2)
C5—N4	1.278 (2)	C13—H13A	0.9600
C5—C6	1.463 (2)	C13—H13B	0.9600
C5—H5	0.9300	C13—H13C	0.9600
C6—C11	1.392 (2)	N1—N2	1.350 (2)
C6—C7	1.396 (2)	N3—N4	1.3769 (17)
C7—C8	1.386 (2)	N3—H3N	0.87 (2)
C7—H7	0.9300	O2—H2O	0.85 (2)
C8—O1	1.3706 (19)	O4—H4W	0.79 (3)
C8—C9	1.388 (2)	O4—H5W	0.85 (3)
C9—O2	1.3664 (17)

N1—C1—C2	124.38 (17)	O3—C10—C9	114.20 (12)
N1—C1—Cl1	115.54 (14)	C11—C10—C9	120.45 (13)
C2—C1—Cl1	120.07 (16)	C10—C11—C6	119.51 (14)
C3—C2—C1	117.16 (18)	C10—C11—H11	120.2
C3—C2—H2	121.4	C6—C11—H11	120.2
C1—C2—H2	121.4	O3—C12—H12A	109.5
C2—C3—C4	117.59 (17)	O3—C12—H12B	109.5
C2—C3—H3	121.2	H12A—C12—H12B	109.5
C4—C3—H3	121.2	O3—C12—H12C	109.5
N2—C4—N3	113.48 (16)	H12A—C12—H12C	109.5
N2—C4—C3	121.83 (16)	H12B—C12—H12C	109.5
N3—C4—C3	124.68 (15)	O1—C13—H13A	109.5
N4—C5—C6	122.62 (15)	O1—C13—H13B	109.5
N4—C5—H5	118.7	H13A—C13—H13B	109.5
C6—C5—H5	118.7	O1—C13—H13C	109.5
C11—C6—C7	120.26 (13)	H13A—C13—H13C	109.5
C11—C6—C5	122.03 (15)	H13B—C13—H13C	109.5
C7—C6—C5	117.69 (14)	C1—N1—N2	118.93 (15)
C8—C7—C6	119.86 (14)	C4—N2—N1	120.08 (15)
C8—C7—H7	120.1	C4—N3—N4	121.38 (15)
C6—C7—H7	120.1	C4—N3—H3N	121.0 (13)
O1—C8—C7	125.21 (14)	N4—N3—H3N	117.6 (13)
O1—C8—C9	114.48 (13)	C5—N4—N3	113.84 (14)
C7—C8—C9	120.32 (14)	C8—O1—C13	118.39 (15)
O2—C9—C8	118.24 (13)	C9—O2—H2O	109.7 (16)
O2—C9—C10	122.15 (13)	C10—O3—C12	117.64 (12)
C8—C9—C10	119.59 (13)	H4W—O4—H5W	104 (3)
O3—C10—C11	125.35 (13)

N1—C1—C2—C3	1.1 (3)	C8—C9—C10—C11	−1.3 (2)
Cl1—C1—C2—C3	−177.81 (14)	O3—C10—C11—C6	−178.86 (15)
C1—C2—C3—C4	−0.7 (3)	C9—C10—C11—C6	1.3 (2)
C2—C3—C4—N2	−0.6 (3)	C7—C6—C11—C10	−0.5 (2)
C2—C3—C4—N3	−179.46 (17)	C5—C6—C11—C10	178.22 (14)
N4—C5—C6—C11	1.3 (2)	C2—C1—N1—N2	−0.1 (3)
N4—C5—C6—C7	−179.98 (15)	Cl1—C1—N1—N2	178.86 (12)
C11—C6—C7—C8	−0.3 (2)	N3—C4—N2—N1	−179.38 (14)
C5—C6—C7—C8	−179.12 (15)	C3—C4—N2—N1	1.6 (2)
C6—C7—C8—O1	−179.85 (15)	C1—N1—N2—C4	−1.3 (2)
C6—C7—C8—C9	0.4 (2)	N2—C4—N3—N4	178.88 (14)
O1—C8—C9—O2	−1.0 (2)	C3—C4—N3—N4	−2.2 (3)
C7—C8—C9—O2	178.82 (15)	C6—C5—N4—N3	−178.31 (14)
O1—C8—C9—C10	−179.37 (15)	C4—N3—N4—C5	−178.52 (15)
C7—C8—C9—C10	0.4 (2)	C7—C8—O1—C13	8.3 (3)
O2—C9—C10—O3	0.5 (2)	C9—C8—O1—C13	−171.94 (17)
C8—C9—C10—O3	178.88 (15)	C11—C10—O3—C12	5.9 (3)
O2—C9—C10—C11	−179.61 (14)	C9—C10—O3—C12	−174.30 (16)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
C5—H5···N1ⁱ	0.93	2.60	3.519 (2)	172
C12—H12A···N4ⁱⁱ	0.96	2.66	3.369 (2)	132
O2—H2O···O4	0.85 (2)	1.84 (2)	2.668 (2)	164 (2)
N3—H3N···N2ⁱ	0.87 (2)	2.12 (2)	2.993 (2)	178.3 (18)
O4—H4W···O1ⁱⁱⁱ	0.79 (3)	2.23 (3)	2.9254 (19)	146 (3)
O4—H4W···O2ⁱⁱⁱ	0.79 (3)	2.55 (3)	3.239 (2)	147 (3)
O4—H5W···O2^iv	0.85 (3)	2.08 (3)	2.914 (2)	169 (3)
C12—H12B···Cg(C6–C11)^v	0.96	2.87	3.671 (1)	142
C13—H13B···Cg(C6–C11)^iv	0.96	2.90	3.666 (1)	138

Symmetry codes: (i) −x+1/2, −y+1/2, −z+1; (ii) −x+1/2, y+1/2, −z+3/2; (iii) −x+1, −y+1, −z+2; (iv) x, y+1, z; (v) x, y−1, z.

Acknowledgements

The authors thank DST and SC-XRD LAB, Sophisticated Analytical Instruments Facility (SAIF), Indian Institute Technology Madras (IIT-M), Chennai, for the X-ray data collection and the Department of Chemistry, The New College, Chennai, for recording the IR spectroscopic data.

References

Ahmad, S., Rathish, I. G., Bano, S., Alam, M. S. & Javed, K. K. (2010). J. Enzyme Inhib. Med. Chem. 25, 266–271. CAS PubMed Google Scholar
Ather, A. Q., Tahir, M. N., Khan, M. A. & Athar, M. M. (2010). Acta Cryst. E66, o2107. Web of Science CSD CrossRef IUCr Journals Google Scholar
Bakale, R. P., Naik, G. N., Machakanur, S. S., Mangannavar, C. V., Muchchandi, I. S. & Gudasi, K. B. (2018). J. Mol. Struct. 1154, 92–99. Web of Science CSD CrossRef CAS Google Scholar
Bernstein, J., Davis, R. E., Shimoni, L. & Chang, N.-L. (1995). Angew. Chem. Int. Ed. Engl. 34, 1555–1573. CrossRef CAS Web of Science Google Scholar
BIOVIA (2021). Discovery Studio Visualizer. Dassault Systèmes, San Diego, USA. Google Scholar
Bruker (2016). APEX2 and SAINT. Bruker AXS Inc., Madison, Wisconsin, USA. Google Scholar
Chen, D., Oezguen, N., Urvil, P., Ferguson, C., Dann, S. M. & Savidge, T. C. (2016). Sci. Adv. 2, e1501240. Web of Science CrossRef PubMed Google Scholar
Contreras, J. M., Rival, Y. M., Chayer, S., Bourguignon, J. J. & Wermuth, C. G. (1999). J. Med. Chem. 42, 730–741. Web of Science CrossRef PubMed CAS Google Scholar
Farrugia, L. J. (2012). J. Appl. Cryst. 45, 849–854. Web of Science CrossRef CAS IUCr Journals Google Scholar
Groom, C. R., Bruno, I. J., Lightfoot, M. P. & Ward, S. C. (2016). Acta Cryst. B72, 171–179. Web of Science CrossRef IUCr Journals Google Scholar
Harris, R. R., Black, L., Surapaneni, S., Kolasa, T., Majest, S., Namovic, M. T., Grayson, G., Komater, V., Wilcox, D., King, L., Marsh, K., Jarvis, M. F., Nuss, N., Nellans, H., Pruesser, L., Reinhart, G. A., Cox, B., Jacobson, P., Stewart, A., Coghlan, M., Carter, G. & Bell, R. L. (2004). J. Pharmacol. Exp. Ther. 311, 904–912. PubMed CAS Google Scholar
Komkov, A. V., Komendantova, A. S., Menchikov, L. G., Chernoburova, E. I., Volkova, Y. A. & Zavarzin, I. V. (2015). Org. Lett. 17, 3734–3737. CAS PubMed Google Scholar
Krause, L., Herbst-Irmer, R., Sheldrick, G. M. & Stalke, D. (2015). J. Appl. Cryst. 48, 3–10. Web of Science CSD CrossRef ICSD CAS IUCr Journals Google Scholar
Olmo, E. del, Barboza, B., Ybarra, M. I., López-Pérez, J. L., Carrón, R., Sevilla, M. A., Boselli, C. & San Feliciano, A. (2006). Bioorg. Med. Chem. Lett. 16, 2786–2790. PubMed Google Scholar
Prabhu, M., Parthipan, K., Ramu, A., Chakkaravarthi, G. & Rajagopal, G. (2011). Acta Cryst. E67, o2716. Web of Science CSD CrossRef IUCr Journals Google Scholar
Rafi, U. M., Mahendiran, D., Haleel, A. K., Nankar, R. P., Doble, M. & Rahiman, A. K. (2016). New J. Chem. 40, 2451–2465. CAS Google Scholar
Rafi, U. M., Mahendiran, D., Kumar, R. S. & Rahiman, A. K. (2019). Appl. Organom Chem. 33, e4946. Google Scholar
Riecke, K. & Witzel, I. (2020). Breast Care 15, 579–585. PubMed Google Scholar
Sheldrick, G. M. (2015a). Acta Cryst. A71, 3–8. Web of Science CrossRef IUCr Journals Google Scholar
Sheldrick, G. M. (2015b). Acta Cryst. C71, 3–8. Web of Science CrossRef IUCr Journals Google Scholar
Spek, A. L. (2009). Acta Cryst. D65, 148–155. Web of Science CrossRef CAS IUCr Journals Google Scholar
Syed Abuthahir, S., NizamMohideen, M., Viswanathan, V., Abiraman, T. & Balasubramanian, S. (2019). Acta Cryst. E75, 655–661. CSD CrossRef IUCr Journals Google Scholar
Uribe, M. L., Marrocco, I. & Yarden, Y. (2021). Cancers, 13, 2748. PubMed Google Scholar
Weinberg, F., Peckys, D. B. & de Jonge, N. (2020). Int. J. Mol. Sci. 21, 9008. PubMed Google Scholar
Westrip, S. P. (2010). J. Appl. Cryst. 43, 920–925. Web of Science CrossRef CAS IUCr Journals Google Scholar

This is an open-access article distributed under the terms of the Creative Commons Attribution (CC-BY) Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited.