Design, synthesis and spectroscopic and structural characterization of novel N-(2-hy­droxy-5-methyl­phen­yl)-2,3-di­meth­oxy­benz­amide: DFT, Hirshfeld surface analysis, antimicrobial activity, mol­ecular docking and toxicology

Çakmak, Ş.; Aycan, T.; Öztürk, F.; Veyisoğlu, A.

doi:10.1107/S2053229622008257

Design, synthesis and spectroscopic and structural characterization of novel N-(2-hydroxy-5-methylphenyl)-2,3-dimethoxybenzamide: DFT, Hirshfeld surface analysis, antimicrobial activity, molecular docking and toxicology

Ş. Çakmak, T. Aycan, F. Öztürk and A. Veyisoğlu

The novel compound N-(2-hydroxy-5-methylphenyl)-2,3-dimethoxybenzamide, C₁₆H₁₇NO₄, I, was prepared by a two-step reaction and then characterized by elemental analysis and X-ray diffraction (XRD) methods. Moreover, its spectroscopic properties were investigated by FT–IR and ¹H and ¹³C NMR. Compound I crystallized in the monoclinic space group P2₁/c and the molecular geometry is not planar, being divided into three planar regions. Supramolecular structures are formed by connecting units via hydrogen bonds. The ground-state molecular structure of I was optimized by the DFT-B3LYP/6-31G(d,p) method and the theoretical structure was compared with that obtained by X-ray diffraction. Intermolecular interactions in the crystal network were studied by two-dimensional (2D) and three-dimensional (3D) Hirshfeld analyses. The calculated electronic transition results were examined and the molecular electrostatic potentials (MEPs) were also determined. The in vitro antimicrobial activities of I against three Gram-positive bacteria, three Gram-negative bacteria and two fungi were determined. The compound was compared with several control drugs and showed better activity than the amoxicillin standard against Gram-positive bacteria B. subtilis, S. aureus and E. faecalis, and Gram-negative bacteria E. coli, K. pneumoniae and P. aeruginosa. The density functional theory (DFT)-optimized structure of the small molecule was used to perform molecular docking studies with proteins from experimentally studied bacterial and fungal organisms using AutoDock to determine the most preferred binding mode of the ligand within the protein cavity. A druglikeness assay and ADME (absorption, distribution, metabolism and excretion) and toxicology studies were carried out and predict a good drug-like character.

Keywords: crystal structure; benzamide; X-ray diffraction; antimicrobial activity; spectroscopic studies; molecular docking; Hirshfeld analysis.

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Supporting information

	Crystallographic Information File (CIF) https://doi.org/10.1107/S2053229622008257/zo3025sup1.cif Contains datablocks I, global
	Structure factor file (CIF format) https://doi.org/10.1107/S2053229622008257/zo3025Isup2.hkl Contains datablock I
	Chemical Markup Language (CML) file https://doi.org/10.1107/S2053229622008257/zo3025Isup3.cml Supplementary material

CCDC reference: 2174193

Computing details top

Data collection: APEX2 (Bruker, 2006); cell refinement: SAINT (Bruker, 1998); data reduction: SAINT (Bruker, 1998); program(s) used to solve structure: SHELXT2018 (Sheldrick, 2015a); program(s) used to refine structure: SHELXL2018 (Sheldrick, 2015b); molecular graphics: WinGX (Farrugia, 2012), ORTEP-3 (Farrugia, 2012) and Mercury (Macrae et al., 2020); software used to prepare material for publication: SHELXTL (Bruker, 2006).

N-(2-Hydroxy-5-methylphenyl)-2,3-dimethoxybenzamide top

Crystal data top

C₁₆H₁₇NO₄	F(000) = 608
M_r = 287.30	D_x = 1.333 Mg m⁻³
Monoclinic, P2₁/c	Mo Kα radiation, λ = 0.71073 Å
a = 6.7134 (5) Å	Cell parameters from 9654 reflections
b = 15.9685 (11) Å	θ = 3.0–25.9°
c = 13.3879 (8) Å	µ = 0.10 mm⁻¹
β = 93.999 (2)°	T = 293 K
V = 1431.73 (17) Å³	Block, colourless
Z = 4	0.19 × 0.16 × 0.12 mm

Data collection top

Bruker D8 QUEST diffractometer	R_int = 0.052
Radiation source: fine-focus sealed tube	θ_max = 28.3°, θ_min = 2.0°
φ and ω scans	h = −8→8
29028 measured reflections	k = −21→21
3533 independent reflections	l = −17→17
2474 reflections with I > 2σ(I)

Refinement top

Refinement on F²	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F² > 2σ(F²)] = 0.053	Hydrogen site location: mixed
wR(F²) = 0.157	H atoms treated by a mixture of independent and constrained refinement
S = 1.08	w = 1/[σ²(F_o²) + (0.0737P)² + 0.3634P] where P = (F_o² + 2F_c²)/3
3533 reflections	(Δ/σ)_max < 0.001
222 parameters	Δρ_max = 0.24 e Å⁻³
0 restraints	Δρ_min = −0.18 e Å⁻³

Special details top

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.

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

	x	y	z	U_iso*/U_eq
O4	0.54603 (18)	0.43051 (8)	0.39099 (8)	0.0401 (3)
O2	0.8022 (2)	0.34966 (9)	0.13115 (9)	0.0512 (4)
O1	0.8127 (2)	0.25647 (10)	0.46937 (10)	0.0565 (4)
O3	0.2097 (2)	0.52048 (10)	0.37656 (10)	0.0600 (4)
N1	0.8156 (2)	0.34236 (9)	0.30058 (10)	0.0379 (4)
C10	0.5479 (3)	0.42134 (10)	0.21206 (11)	0.0335 (4)
C1	0.9662 (3)	0.23909 (11)	0.41068 (12)	0.0389 (4)
C9	0.7333 (3)	0.36847 (10)	0.21119 (11)	0.0336 (4)
C2	1.1142 (3)	0.18170 (12)	0.43645 (14)	0.0468 (5)
H2	1.113523	0.152916	0.496814	0.056*
C6	1.1226 (3)	0.26844 (11)	0.25812 (13)	0.0378 (4)
H6	1.126253	0.298387	0.198692	0.045*
C7	0.9699 (3)	0.28335 (10)	0.32024 (12)	0.0341 (4)
C3	1.2636 (3)	0.16683 (12)	0.37283 (15)	0.0481 (5)
H3	1.361682	0.127373	0.390549	0.058*
C17	0.4560 (3)	0.44714 (10)	0.29723 (12)	0.0337 (4)
C4	1.2702 (3)	0.20979 (11)	0.28274 (14)	0.0415 (4)
C14	0.2799 (3)	0.49493 (11)	0.28836 (14)	0.0416 (4)
C11	0.4577 (3)	0.44351 (12)	0.11808 (13)	0.0449 (5)
H11	0.516710	0.427138	0.060366	0.054*
C16	0.4293 (4)	0.38700 (15)	0.46134 (16)	0.0499 (5)
C12	0.2843 (3)	0.48886 (13)	0.11000 (15)	0.0530 (5)
H12	0.226723	0.502602	0.046932	0.064*
C13	0.1936 (3)	0.51448 (12)	0.19444 (16)	0.0510 (5)
H13	0.075069	0.544742	0.188104	0.061*
C5	1.4322 (4)	0.19196 (17)	0.2134 (2)	0.0582 (6)
C15	0.0319 (4)	0.56845 (17)	0.3735 (2)	0.0759 (7)
H15A	0.000546	0.581886	0.440568	0.114*
H15B	0.050199	0.619218	0.336892	0.114*
H15C	−0.075649	0.536759	0.341149	0.114*
H1A	0.749 (3)	0.3585 (13)	0.3510 (15)	0.046 (6)*
H16A	0.330 (5)	0.354 (2)	0.431 (3)	0.121 (12)*
H16B	0.364 (4)	0.426 (2)	0.504 (2)	0.098 (9)*
H16C	0.523 (5)	0.357 (2)	0.503 (2)	0.104 (10)*
H5A	1.424 (4)	0.230 (2)	0.156 (2)	0.094 (9)*
H5B	1.427 (4)	0.1382 (19)	0.1910 (19)	0.085 (9)*
H5C	1.564 (5)	0.194 (2)	0.247 (2)	0.104 (10)*
H1	0.815 (4)	0.2212 (17)	0.5191 (19)	0.072 (7)*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
O4	0.0399 (7)	0.0530 (7)	0.0272 (6)	0.0070 (5)	0.0016 (5)	−0.0028 (5)
O2	0.0563 (9)	0.0698 (9)	0.0284 (6)	0.0072 (7)	0.0096 (6)	−0.0054 (6)
O1	0.0630 (10)	0.0679 (10)	0.0409 (7)	0.0222 (7)	0.0212 (7)	0.0189 (7)
O3	0.0531 (9)	0.0692 (10)	0.0578 (9)	0.0266 (7)	0.0041 (7)	−0.0082 (7)
N1	0.0428 (9)	0.0452 (8)	0.0265 (7)	0.0093 (7)	0.0088 (6)	0.0008 (6)
C10	0.0387 (10)	0.0322 (8)	0.0294 (8)	−0.0055 (7)	−0.0003 (7)	0.0023 (6)
C1	0.0433 (10)	0.0399 (9)	0.0340 (9)	0.0042 (8)	0.0060 (7)	−0.0002 (7)
C9	0.0383 (10)	0.0356 (9)	0.0273 (8)	−0.0063 (7)	0.0042 (7)	−0.0013 (6)
C2	0.0535 (12)	0.0457 (10)	0.0408 (10)	0.0083 (9)	0.0006 (9)	0.0060 (8)
C6	0.0415 (10)	0.0381 (9)	0.0343 (9)	−0.0021 (8)	0.0068 (7)	−0.0035 (7)
C7	0.0363 (9)	0.0350 (8)	0.0311 (8)	0.0022 (7)	0.0025 (7)	−0.0026 (7)
C3	0.0471 (12)	0.0418 (10)	0.0548 (12)	0.0108 (8)	−0.0010 (9)	−0.0018 (8)
C17	0.0373 (9)	0.0321 (8)	0.0311 (8)	−0.0026 (7)	−0.0023 (7)	0.0006 (6)
C4	0.0385 (10)	0.0397 (9)	0.0468 (10)	−0.0006 (8)	0.0059 (8)	−0.0110 (8)
C14	0.0398 (10)	0.0372 (9)	0.0473 (10)	0.0023 (8)	−0.0005 (8)	0.0007 (7)
C11	0.0519 (12)	0.0497 (11)	0.0325 (9)	−0.0050 (9)	−0.0020 (8)	0.0059 (7)
C16	0.0567 (14)	0.0587 (13)	0.0353 (10)	0.0060 (11)	0.0108 (9)	0.0051 (9)
C12	0.0560 (13)	0.0571 (12)	0.0434 (11)	−0.0013 (10)	−0.0148 (9)	0.0139 (9)
C13	0.0439 (11)	0.0452 (11)	0.0621 (12)	0.0064 (9)	−0.0093 (9)	0.0081 (9)
C5	0.0506 (14)	0.0562 (14)	0.0700 (16)	0.0047 (11)	0.0196 (12)	−0.0106 (12)
C15	0.0580 (15)	0.0777 (16)	0.0920 (18)	0.0322 (13)	0.0055 (13)	−0.0112 (14)

Geometric parameters (Å, º) top

O4—C17	1.3804 (19)	C3—C4	1.391 (3)
O4—C16	1.445 (2)	C3—H3	0.9300
O2—C9	1.2336 (19)	C17—C14	1.405 (2)
O1—C1	1.367 (2)	C4—C5	1.505 (3)
O1—H1	0.87 (3)	C14—C13	1.383 (3)
O3—C14	1.364 (2)	C11—C12	1.369 (3)
O3—C15	1.417 (2)	C11—H11	0.9300
N1—C9	1.349 (2)	C16—H16A	0.92 (4)
N1—C7	1.411 (2)	C16—H16B	0.97 (3)
N1—H1A	0.87 (2)	C16—H16C	0.95 (3)
C10—C17	1.396 (2)	C12—C13	1.383 (3)
C10—C11	1.403 (2)	C12—H12	0.9300
C10—C9	1.505 (2)	C13—H13	0.9300
C1—C2	1.378 (3)	C5—H5A	0.97 (3)
C1—C7	1.404 (2)	C5—H5B	0.91 (3)
C2—C3	1.381 (3)	C5—H5C	0.97 (3)
C2—H2	0.9300	C15—H15A	0.9600
C6—C7	1.385 (2)	C15—H15B	0.9600
C6—C4	1.386 (3)	C15—H15C	0.9600
C6—H6	0.9300

C17—O4—C16	117.55 (15)	C3—C4—C5	120.61 (19)
C1—O1—H1	109.6 (16)	O3—C14—C13	124.85 (17)
C14—O3—C15	118.59 (17)	O3—C14—C17	115.39 (15)
C9—N1—C7	128.45 (14)	C13—C14—C17	119.74 (17)
C9—N1—H1A	113.3 (13)	C12—C11—C10	121.04 (18)
C7—N1—H1A	117.4 (13)	C12—C11—H11	119.5
C17—C10—C11	118.08 (16)	C10—C11—H11	119.5
C17—C10—C9	125.78 (14)	O4—C16—H16A	113 (2)
C11—C10—C9	116.09 (15)	O4—C16—H16B	110.9 (17)
O1—C1—C2	123.39 (16)	H16A—C16—H16B	107 (3)
O1—C1—C7	116.95 (16)	O4—C16—H16C	105.4 (19)
C2—C1—C7	119.67 (17)	H16A—C16—H16C	114 (3)
O2—C9—N1	122.70 (16)	H16B—C16—H16C	107 (2)
O2—C9—C10	120.26 (15)	C11—C12—C13	120.82 (17)
N1—C9—C10	117.03 (14)	C11—C12—H12	119.6
C1—C2—C3	120.14 (17)	C13—C12—H12	119.6
C1—C2—H2	119.9	C12—C13—C14	119.75 (18)
C3—C2—H2	119.9	C12—C13—H13	120.1
C7—C6—C4	121.34 (16)	C14—C13—H13	120.1
C7—C6—H6	119.3	C4—C5—H5A	111.1 (16)
C4—C6—H6	119.3	C4—C5—H5B	111.6 (17)
C6—C7—C1	119.32 (16)	H5A—C5—H5B	109 (2)
C6—C7—N1	124.55 (15)	C4—C5—H5C	112.7 (18)
C1—C7—N1	116.11 (15)	H5A—C5—H5C	111 (2)
C2—C3—C4	121.23 (17)	H5B—C5—H5C	101 (2)
C2—C3—H3	119.4	O3—C15—H15A	109.5
C4—C3—H3	119.4	O3—C15—H15B	109.5
O4—C17—C10	119.73 (15)	H15A—C15—H15B	109.5
O4—C17—C14	119.57 (15)	O3—C15—H15C	109.5
C10—C17—C14	120.55 (15)	H15A—C15—H15C	109.5
C6—C4—C3	118.30 (16)	H15B—C15—H15C	109.5
C6—C4—C5	121.09 (19)

C7—N1—C9—O2	−8.8 (3)	C9—C10—C17—O4	6.0 (2)
C7—N1—C9—C10	170.08 (16)	C11—C10—C17—C14	−0.9 (2)
C17—C10—C9—O2	−179.66 (16)	C9—C10—C17—C14	−178.47 (15)
C11—C10—C9—O2	2.7 (2)	C7—C6—C4—C3	−1.1 (3)
C17—C10—C9—N1	1.4 (2)	C7—C6—C4—C5	178.10 (18)
C11—C10—C9—N1	−176.22 (15)	C2—C3—C4—C6	0.2 (3)
O1—C1—C2—C3	179.38 (18)	C2—C3—C4—C5	−179.1 (2)
C7—C1—C2—C3	−1.1 (3)	C15—O3—C14—C13	2.1 (3)
C4—C6—C7—C1	1.0 (3)	C15—O3—C14—C17	−179.56 (19)
C4—C6—C7—N1	179.51 (17)	O4—C17—C14—O3	−1.0 (2)
O1—C1—C7—C6	179.71 (16)	C10—C17—C14—O3	−176.52 (15)
C2—C1—C7—C6	0.1 (3)	O4—C17—C14—C13	177.48 (16)
O1—C1—C7—N1	1.1 (2)	C10—C17—C14—C13	1.9 (3)
C2—C1—C7—N1	−178.53 (17)	C17—C10—C11—C12	−0.2 (3)
C9—N1—C7—C6	30.2 (3)	C9—C10—C11—C12	177.57 (17)
C9—N1—C7—C1	−151.24 (18)	C10—C11—C12—C13	0.3 (3)
C1—C2—C3—C4	0.9 (3)	C11—C12—C13—C14	0.7 (3)
C16—O4—C17—C10	−125.94 (18)	O3—C14—C13—C12	176.47 (18)
C16—O4—C17—C14	58.5 (2)	C17—C14—C13—C12	−1.8 (3)
C11—C10—C17—O4	−176.44 (15)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
O1—H1···O2ⁱ	0.87 (3)	1.89 (3)	2.7548 (19)	175 (2)
N1—H1A···O1	0.87 (2)	2.29 (2)	2.6447 (19)	104.1 (15)
N1—H1A···O4	0.87 (2)	1.89 (2)	2.6510 (19)	144.7 (18)
C6—H6···O2	0.93	2.44	2.948 (2)	115
C11—H11···O2	0.93	2.42	2.751 (2)	101
C16—H16B···O3	0.97 (3)	2.45 (3)	2.788 (3)	100.2 (19)

Symmetry code: (i) x, −y+1/2, z+1/2.

Dihedral angles (°) between planes top

Planes	Dihedral angle (XRD)	Dihedral angle (DFT)
P1–P2	5.87°	6.18°
P2–P3	23.24°	3.08°
P1–P3	27.12°	3.12°

Bond lengths (Å) and bond angles (°) related to X-ray diffraction (XRD) and theoretical calculations (DFT) top

Bond length	XRD	DFT	Bond angles	XRD	DFT
O4—C17	1.380 (2)	1.398	C17—O4—C16	117.55 (15)	119.60
O4—C16	1.445 (2)	1.472	C14—O3—C15	118.59 (17)	118.57
O2—C9	1.234 (2)	1.259	C9—N1—C7	128.45 (14)	127.69
O1—C1	1.367 (2)	1.403	C17—C10—C11	118.08 (16)	118.66
O3—C14	1.364 (2)	1.393	C17—C10—C9	125.78 (14)	125.85
O3—C15	1.417 (2)	1.452	C11—C10—C9	116.09 (15)	115.47
N1—C9	1.349 (2)	1.370	O1—C1—C2	123.39 (16)	123.11
N1—C7	1.411 (2)	1.407	O1—C1—C7	116.95 (16)	116.00
C10—C17	1.396 (2)	1.408	C2—C1—C7	119.67 (17)	120.94
C10—C11	1.403 (2)	1.409	O2—C9—N1	122.70 (16)	123.29
C10—C9	1.505 (2)	1.509	O2—C9—C10	120.26 (17)	119.47
C1—C2	1.378 (3)	1.389	N1—C9—C10	117.03 (14)	117.24
C1—C7	1.404 (2)	1.413	C1—C2—C3	120.14 (17)	119.85
C2—C3	1.381 (3)	1.402	C7—C6—C4	121.34 (16)	121.05
C6—C7	1.385 (2)	1.402	C6—C7—C1	119.32 (16)	118.51
C6—C4	1.386 (3)	1.407	C6—C7—N1	124.55 (15)	125.35
C3—C4	1.391 (3)	1.400	C1—C7—N1	116.11 (15)	116.13
C17—C14	1.405 (2)	1.412	C2—C3—C4	121.23 (17)	120.48
C4—C5	1.505 (3)	1.514	O4—C17—C10	119.73 (15)	119.28
C14—C13	1.383 (3)	1.396	O4—C17—C14	119.57 (15)	120.43
C11—C12	1.369 (3)	1.389	C10—C17—C14	120.55 (15)	120.16
C12—C13	1.383 (3)	1.401	C3—C4—C6	118.53 (19)	119.16
			C3—C4—C5	120.61 (19)	121.09
			C6—C4—C5	120.09 (19)	119.74
			O3—C14—C13	124.85 (17)	123.98
			O3—C14—C17	115.39 (15)	115.82
			C13—C14—C17	119.74 (17)	120.19
			C12—C11—C10	121.04 (18)	120.97

The geometric data of noncovalent interactions top

Cg1 is the centroid of the C1–C3/C5–C7 ring.

D—H···A	D—H	H···A	D···A	D—H···A
O1—H1···O2ⁱ	0.87	1.89	2.7548 (19)	175.0 (2)
N1—H1A···O1	0.87 (2)	2.29 (3)	2.6447 (19)	104.1 (15)
N1—H1A···O4	0.87 (2)	1.89 (3)	2.6510 (19)	144.7 (18)
C6—H6···O2	0.93	2.44	2.948 (3)	115
C11—H11···O2	0.93	2.42	2.751 (3)	101
C16—H16B···O3	0.97	2.45 (3)	2.788 (3)	100.2 (19)

X—H···Cg	X—H	H···Cg	X···Cg	X—H···Cg
C16—H16A···Cg1ⁱⁱ	0.92 (4)	2.71 (3)	3.603	164

Symmetry codes: (i) x, -y+1/2, z+1/2; (ii) x-1, y, z.

MPA of title compound top

Atom	MPA	Atom	MPA	Atom	MPA	Atom	MPA
O1	-0.6480	C3	-0.1569	C9	0.5055	C15	-0.1692
H1	0.3768	H3	0.1170	C10	0.0360	H15A	0.1706
O2	-0.4809	C4	0.0935	C11	-0.1561	H15B	0.1515
O3	-0.5673	C5	-0.4781	H11	0.1729	H15C	0.1559
O4	-0.5919	H5A	0.1348	C12	-0.1344	C16	-0.1709
N1	-0.8147	H5B	0.1538	H12	0.1318	H16B	0.1698
H1A	0.4190	H5C	0.1541	C13	-0.1333	H16A	0.1454
C1	0.1938	C6	-0.1422	H13	0.1347	H16C	0.1809
C2	-0.1336	H6	0.1853	C14	0.2966	C17	0.2417
H2	0.1130	C7	0.3427

Comparison of quantum chemical descriptors of I with the literature top

HOMO is the highest occupied molecular orbital, LUMO is the lowest unoccupied molecular orbital, E_gap is the energy band gap, I is ionization potantial, A is electron affinity, η is chemical hardness, σ is the hemical softness, χ is lectronegativity, µ is chemical potential, ω is the electrophilic index, N is the ucleophilic index; ΔN_max is maximum charge transfer and S is global softness.

	Title compound DFT-B3LYP/631-G	Demir et al. (2015)
E_HOMO (eV)	-5.39	-5.44
E_LUMO (eV)	-1.03	-0.98
E_gap (eV) (E_HOMO – E_LUMO)	4.36	4.46
I (eV) (–E_HOMO)	5.39	5.44
A (eV) (–E_LUMO)	1.03	0.98
η (eV) ((I-A)/2)	2.18	2.23
σ (eV^-1) (1/η)	0.46	0.45
χ (eV) ((I+A)/2)	3.21	3.21
µ (eV) –((I+A)/2)	-3.21	-3.21
ω (eV) (µ²/2η)	2.36	2.31
N (eV^-1) (1/ω)	0.42	0.43
ΣN_max (-µ/η)	1.47	1.44
S (eV^-1) (1/2η)	0.23	0.22

Experimental and theoretical ¹H and ¹³C NMR chemical shifts of the title compound top

Atom	Experimental	Calculated	Atom	Experimental	Calculated
C1	147.69	132.98	H1	7.16	6.00
C2	152.61	139.40	H2	7.26-7.22	6.34
C3	119.83	100.44	H3	7.82	7.25
C4	124.98	108.14	H (NH)	10.40	10.30
C5	123.14	108.92	H4	6.99	5.57
C6	122.91	112.18	H5	6.87	5.84
C7	169.32	150.76	H6	7.83	8.13
C8	125.49	113.56	H (OH)	9.10	3.16
C9	149.97	126.31	H7a	2.31	1.66
C10	116.54	97.67	H7b		1.66
C11	127.76	107.65	H7c		0.90
C12	129.7602	117.31	H8a	3.96	3.81
C13	124.80	104.61	H8b		2.76
C14	20.40	9.97	H8c		4.45
C15	61.73	49.24	H9a	4.06	3.55
C16	56.21	43.12	H9b		3.13
			H9c		3.03

Intermolecular interactions in the complex according to XRD and Hirshfeld results top

Interaction	H···O (XRD) (Å)	H···O (Hirshfeld) (Å)
O1—H1···O2	1.89	1.97

The physicochemical properties, druglikeness and pharmacological properties with SwissADME prediction of I top

MW is tmolecular weight (g/mol), H-A is the number of hydrogen-bond acceptors, H-D is the number of hydrogen-bond donors, LogS is solubility, TPSA is the total polar surface area, MR is molar refractivity N_atoms is the number of atoms, WLogP is lipophilicity, SA is synthetic accessibility, GI is gastrointestinal, BBB is blood–brain barrier, P-gp is P-glycoprotein, CYP1A2 is cytochrome P450 family 1 subfamily A member 2 (PDB entry 2hi4), CYP2D6 is cytochrome P450 family 2 subfamily D member 6 (PDB entry 5tft) and Log K_p is skin permeation (cm s^-1)

Physicochemical properties		Druglikeness		Pharmacokinetic properties
MW	299.41	WLogP	1.48	GI	High
H-A	4	SA	4.09	BBB	Yes
TPSA	67.79	LogS	-2.84	CYP1A2 inhibitor	No
Rotatable bonds	5			CYP2C6 inhibitor	No
MR	81.13			LogK_p	-7.22
N_atoms	21

Toxicity prediction values and results of compound and its intermediates calculated by T.E.S.T and Pro-TOX II top

Acute toxicity		Developmental toxicity		Mutagenicity
Oral rat LD₅₀ (mg kg^-1)	Fat-head minnow LC₅₀ (96 h) (mg l^-1)	Predicted value	Predicted result	Predicted value	Predicted result
118.19	39.55	10.04	Developmental toxicant	0.75	Negative

Organ toxicity	Toxicity End points
Hepatotoxicity	Carcinogenicity	Immunotoxicity	Mutagenicity	Cytotoxicity	LD₅₀ (mg kg^-1)
Inactive	Inactive	Inactive	Inactive	Inactive	5000

Molecular docking energy values for the ligand–protein interaction top

Protein ID	Affinity (kcal mol^-1)	Est. free energy of binding (kcal mol^-1)	Est. inhibition constant, K_i (mM)	vdW + Hbond + desolve energy (kcal mol^-1)	Electrostatic energy (kcal mol^-1)	Final total internal energy (kcal mol^-1)	Torsional free energy (kcal mol^-1)	Unbound system's energy (kcal mol^-1)	Total internal energy (kcal mol^-1)
1zuw	-6.8	-4.36	0.64	-5.8	-0.04	-2.08	+1.49	-2.08	-5.85
5j9b	-6.9	-4.44	0.55	-5.79	-0.14	-2.34	+1.49	-2.34	-5.94
4ph6	-6.1	-4.02	1.13	5.51	+0.00	-2.32	+1.49	-2.32	-5.51
5bmm	-6.6	-3.96	1.24	-5.12	-0.34	-1.99	+1.49	-1.99	-5.46
7bye	-6.2	-5.05	0.20	-6.27	-0.27	-1.34	+1.49	-1.34	-6.54
4f0v	-6.0	-3.67	2.04	-5.19	+0.03	-1.99	+1.49	-1.99	-5.16
1zap	-6.0	-3.60	2.28	-4.97	-0.13	-1.33	+1.49	-1.33	-5.10
3k4p	-7.1	-4.40	0.60	-5.86	-0.03	-1.91	+1.49	-1.91	-5.89

The minimum inhibition concentrations (MICs) of the compound and standard drugs top

	MIC (µg ml^-1)
	Gram-staining positive			Gram-staining negative			Fungi
Sample	B. subtilis	S. aureus	E. faecalis	E. coli	K. pneumoniae	P. aeruginosa	A. niger	C. albicans
Title compound	128	256	512	512	512	256	-	-
Amoxicillin	>1024	>1024	>1024	>1024	>1024	>1024	-	-
Tetracycline	4	64	64	64	64	64	-	-
Ketoconazole	-	-	-	-	-	-	1	2

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Design, synthesis and spectroscopic and structural characterization of novel N-(2-hy­droxy-5-methyl­phen­yl)-2,3-di­meth­oxy­benz­amide: DFT, Hirshfeld surface analysis, antimicrobial activity, mol­ecular docking and toxicology

Supporting information

Design, synthesis and spectroscopic and structural characterization of novel N-(2-hydroxy-5-methylphenyl)-2,3-dimethoxybenzamide: DFT, Hirshfeld surface analysis, antimicrobial activity, molecular docking and toxicology