Synthesis, XRD structural analysis and theoretical studies of a potential inhibitor against rheumatoid arthritis (RA)

This work focused on analyzing the properties of N-(5-nitro­thia­zol-2-yl)furan-2-carboxamide (C₈H₅N₃O₄S, NTFC) as a possible inhibitor of the rheumatoid arthritis process. The synthesis of NTFC was carried out and good-quality crystals were obtained and studied by NMR (¹H and ¹³C), DEPT 135, UV–Vis, IR, MS and single-crystal X-ray diffraction. The structure of NTFC consists of two rings, thia­zole and furan, and a central C—N—C(=O)—C segment, which appears to be planar. This central amide segment forms angles of 2.61 (10) and 7.97 (11)° with the planes of the thia­zole and furan rings, respectively. The crystal structure of NTFC exhibits N—H...N, N—H...O and C—H...O hy­dro­gen bonds, and C—H...π and π–π inter­actions that facilitate self-assembly and the formation of hy­dro­gen-bonded dimers, which implies the appearance of R₂²(8) graph-set motifs in this inter­action. The stability of the dimeric unit is com­plemented by the formation of strong intra­molecular C—S...O inter­actions of chalcogen character, with an S...O distance of 2.6040 (18) Å. Hirshfeld surface (HS) analysis revealed that O...H/H...O inter­actions were dominant, accounting for 36.8% of the total HS, and that N—H...N inter­actions were fundamental to the formation of the dimeric structure. The mol­ecular electrostatic potential (MEP) map showed a maximum energy of 46.73 kcal mol⁻¹ and a minimum of −36.06 kcal mol⁻¹. The inter­action energies of mol­ecular pairs around NTFC are highest for those inter­actions linked by N—H hy­dro­gen bonds. The properties of the NTFC ligand as a potential inhibitor of the DHODH (di­hydro­orotate de­hy­dro­genase) enzyme were evaluated by mol­ecular docking, showing coupling energies very close to those obtained with the control drug for rheumatoid arthritis, i.e. leflunomide.

Computing details

N-(5-Nitrothiazol-2-yl)furan-2-carboxamide

Crystal data

C8H5N3O4S	F(000) = 488
Mr = 239.21	Dx = 1.707 Mg m^−3
Monoclinic, P21/c	Mo Kα radiation, λ = 0.71073 Å
a = 12.8126 (4) Å	Cell parameters from 3557 reflections
b = 13.0399 (5) Å	θ = 3.1–26.4°
c = 5.6276 (1) Å	µ = 0.35 mm^−1
β = 98.022 (2)°	T = 293 K
V = 931.03 (5) Å^3	Plate, light brown
Z = 4	0.2 × 0.16 × 0.12 mm

Data collection

Nonius KappaCCD diffractometer	1885 independent reflections
Radiation source: fine-focus sealed tube	1479 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.019
CCD rotation images, thick slices scans	θmax = 26.4°, θmin = 3.1°
Absorption correction: multi-scan (SADABS; Sheldrick, 2010)	h = −16→16
Tmin = 0.657, Tmax = 1.000	k = −16→16
3557 measured reflections	l = −7→7

Refinement

Refinement on F^2	0 restraints
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F^2 > 2σ(F^2)] = 0.047	H-atom parameters constrained
wR(F^2) = 0.135	w = 1/[σ^2(Fo^2) + (0.0764P)^2 + 0.2947P] where P = (Fo^2 + 2Fc^2)/3
S = 1.10	(Δ/σ)max = 0.001
1885 reflections	Δρmax = 0.51 e Å^−3
145 parameters	Δρmin = −0.31 e Å^−3

Special details

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 (Ų)

	x	y	z	Uiso*/Ueq
S1	−0.15130 (5)	0.84939 (5)	0.94086 (10)	0.0393 (2)
O1	−0.43474 (14)	0.89035 (17)	0.6183 (3)	0.0623 (6)
O2	−0.37576 (16)	0.82965 (18)	0.9699 (4)	0.0684 (6)
O3	0.04067 (14)	0.83049 (14)	1.1596 (3)	0.0481 (5)
O4	0.25060 (13)	0.89923 (14)	0.8413 (3)	0.0471 (5)
N1	−0.36269 (16)	0.86402 (16)	0.7739 (4)	0.0464 (5)
N2	−0.12255 (15)	0.93957 (15)	0.5415 (3)	0.0401 (5)
N3	0.03422 (15)	0.90763 (15)	0.7970 (3)	0.0374 (5)
H3	0.069569	0.937276	0.697411	0.045*
C1	−0.25706 (18)	0.87973 (18)	0.7282 (4)	0.0385 (5)
C2	−0.22802 (18)	0.92421 (19)	0.5330 (4)	0.0418 (6)
H2	−0.276387	0.943169	0.401531	0.050*
C3	−0.07319 (17)	0.90261 (17)	0.7436 (4)	0.0345 (5)
C4	0.08772 (19)	0.86670 (17)	1.0054 (4)	0.0375 (5)
C5	0.20189 (19)	0.87023 (17)	1.0337 (4)	0.0385 (5)
C6	0.3561 (2)	0.8927 (2)	0.9183 (5)	0.0532 (7)
H6	0.408318	0.907834	0.824385	0.064*
C7	0.3746 (2)	0.8616 (2)	1.1473 (5)	0.0529 (7)
H7	0.440072	0.851329	1.238637	0.063*
C8	0.2750 (2)	0.84753 (19)	1.2221 (4)	0.0456 (6)
H8	0.262251	0.826499	1.373280	0.055*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
S1	0.0358 (4)	0.0466 (4)	0.0363 (4)	−0.0020 (2)	0.0082 (2)	0.0060 (2)
O1	0.0343 (10)	0.0865 (15)	0.0644 (12)	0.0003 (10)	0.0014 (9)	0.0064 (11)
O2	0.0492 (11)	0.0917 (16)	0.0683 (13)	−0.0019 (11)	0.0224 (10)	0.0245 (11)
O3	0.0434 (10)	0.0597 (11)	0.0423 (9)	0.0000 (8)	0.0097 (8)	0.0115 (8)
O4	0.0352 (9)	0.0618 (12)	0.0454 (10)	0.0025 (8)	0.0094 (7)	0.0122 (8)
N1	0.0345 (11)	0.0525 (13)	0.0533 (13)	−0.0033 (9)	0.0102 (10)	0.0030 (10)
N2	0.0348 (11)	0.0489 (12)	0.0371 (10)	−0.0005 (9)	0.0067 (8)	0.0046 (9)
N3	0.0329 (10)	0.0457 (11)	0.0342 (10)	−0.0012 (8)	0.0068 (7)	0.0075 (8)
C1	0.0310 (12)	0.0435 (13)	0.0417 (12)	−0.0021 (10)	0.0073 (9)	0.0003 (10)
C2	0.0352 (13)	0.0491 (14)	0.0405 (13)	−0.0001 (10)	0.0037 (10)	0.0031 (10)
C3	0.0355 (12)	0.0358 (12)	0.0331 (11)	−0.0009 (9)	0.0077 (9)	0.0011 (9)
C4	0.0389 (13)	0.0372 (12)	0.0371 (12)	0.0022 (10)	0.0073 (10)	0.0013 (9)
C5	0.0398 (13)	0.0403 (12)	0.0367 (12)	0.0024 (10)	0.0091 (10)	0.0010 (10)
C6	0.0327 (13)	0.0632 (17)	0.0644 (17)	0.0013 (11)	0.0089 (12)	0.0093 (13)
C7	0.0340 (14)	0.0632 (17)	0.0584 (16)	0.0020 (12)	−0.0046 (12)	−0.0027 (13)
C8	0.0496 (15)	0.0484 (15)	0.0376 (13)	0.0029 (11)	0.0019 (11)	0.0007 (10)

Geometric parameters (Å, º)

S1—C1	1.724 (2)	N3—C3	1.369 (3)
S1—C3	1.740 (2)	N3—C4	1.381 (3)
O1—N1	1.229 (3)	C1—C2	1.340 (3)
O2—N1	1.224 (3)	C2—H2	0.9300
O3—C4	1.219 (3)	C4—C5	1.450 (3)
O4—C5	1.376 (3)	C5—C8	1.346 (3)
O4—C6	1.363 (3)	C6—H6	0.9300
N1—C1	1.427 (3)	C6—C7	1.340 (4)
N2—C2	1.360 (3)	C7—H7	0.9300
N2—C3	1.313 (3)	C7—C8	1.410 (4)
N3—H3	0.8600	C8—H8	0.9300
C1—S1—C3	86.10 (10)	N3—C3—S1	121.96 (17)
C6—O4—C5	105.72 (19)	O3—C4—N3	121.2 (2)
O1—N1—C1	117.9 (2)	O3—C4—C5	121.7 (2)
O2—N1—O1	124.1 (2)	N3—C4—C5	117.0 (2)
O2—N1—C1	117.9 (2)	O4—C5—C4	118.9 (2)
C3—N2—C2	109.41 (19)	C8—C5—O4	109.7 (2)
C3—N3—H3	118.9	C8—C5—C4	131.3 (2)
C3—N3—C4	122.21 (19)	O4—C6—H6	124.5
C4—N3—H3	118.9	C7—C6—O4	111.1 (2)
N1—C1—S1	121.02 (18)	C7—C6—H6	124.5
C2—C1—S1	112.77 (18)	C6—C7—H7	126.9
C2—C1—N1	126.1 (2)	C6—C7—C8	106.3 (2)
N2—C2—H2	122.5	C8—C7—H7	126.9
C1—C2—N2	115.0 (2)	C5—C8—C7	107.2 (2)
C1—C2—H2	122.5	C5—C8—H8	126.4
N2—C3—S1	116.65 (17)	C7—C8—H8	126.4
N2—C3—N3	121.38 (19)
S1—C1—C2—N2	−1.8 (3)	C2—N2—C3—S1	−1.5 (3)
O1—N1—C1—S1	177.61 (19)	C2—N2—C3—N3	179.6 (2)
O1—N1—C1—C2	2.4 (4)	C3—S1—C1—N1	−175.0 (2)
O2—N1—C1—S1	1.0 (3)	C3—S1—C1—C2	0.71 (19)
O2—N1—C1—C2	−174.2 (3)	C3—N2—C2—C1	2.1 (3)
O3—C4—C5—O4	171.4 (2)	C3—N3—C4—O3	−5.3 (4)
O3—C4—C5—C8	−7.1 (4)	C3—N3—C4—C5	175.6 (2)
O4—C5—C8—C7	−0.5 (3)	C4—N3—C3—S1	3.0 (3)
O4—C6—C7—C8	−0.1 (3)	C4—N3—C3—N2	−178.2 (2)
N1—C1—C2—N2	173.7 (2)	C4—C5—C8—C7	178.1 (2)
N3—C4—C5—O4	−9.5 (3)	C5—O4—C6—C7	−0.2 (3)
N3—C4—C5—C8	171.9 (2)	C6—O4—C5—C4	−178.4 (2)
C1—S1—C3—N2	0.49 (19)	C6—O4—C5—C8	0.4 (3)
C1—S1—C3—N3	179.3 (2)	C6—C7—C8—C5	0.4 (3)