Redetermination of skimmianine: a new inhibitor against the Leishmania APRT enzyme

The title compound (alternative names 7,8-di­methoxy­dictam­mine and 4,7,8-tri­methoxy­furo­[2,3-b]­quinoline), C₁₄H₁₃NO₄, is a natural product extracted from Adiscanthus fusciflorus (Ruta­ceae). Our biochemical tests show that it has inhibitory activity against the enzyme adenine phospho­ribosyl­transferase (APRT) from Leishmania, a tropical parasite causing endemic disease in poor countries. It crystallizes in the centrosymmetric space group P2₁/c, with one mol­ecule in the asymmetric unit, and has at least two C—H...O intermolecular interactions, leading to the formation of centrosymmetric dimers.

Key indicators

• Single-crystal X-ray study
• T = 120 K
• Mean [sigma](C-C) = 0.002 Å
• R factor = 0.038
• wR factor = 0.104
• Data-to-parameter ratio = 12.9

checkCIF/PLATON results

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Computing details

Data collection: COLLECT (Nonius, 1998); cell refinement: HKL SCALEPACK (Otwinowski & Minor, 1997); data reduction: HKL DENZO (Otwinowski & Minor, 1997) and SCALEPACK; program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: ORTEP-3 for Windows (Farrugia, 1997) and PLATON (Spek, 2002); software used to prepare material for publication: WinGX publication routines (Farrugia, 1999).

(I)

Crystal data

C14H13NO4	F(000) = 544
Mr = 259.25	Dx = 1.477 Mg m^−3
Monoclinic, P21/c	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2ybc	Cell parameters from 2808 reflections
a = 7.2429 (1) Å	θ = 3.4–27.5°
b = 10.4418 (2) Å	µ = 0.11 mm^−1
c = 15.4618 (3) Å	T = 120 K
β = 94.353 (1)°	Prism, light yellow
V = 1165.99 (4) Å^3	0.32 × 0.18 × 0.16 mm
Z = 4

Data collection

KappaCCD diffractometer	Rint = 0.013
φ and ω scans	θmax = 27.5°, θmin = 3.8°
5117 measured reflections	h = −9→9
2672 independent reflections	k = −13→13
2301 reflections with I > 2σ(I)	l = −20→20

Refinement

Refinement on F^2	0 restraints
Least-squares matrix: full	H atoms treated by a mixture of independent and constrained refinement
R[F^2 > 2σ(F^2)] = 0.038	w = 1/[σ^2(Fo^2) + (0.0633P)^2 + 0.2061P] where P = (Fo^2 + 2Fc^2)/3
wR(F^2) = 0.104	(Δ/σ)max < 0.001
S = 1.04	Δρmax = 0.29 e Å^−3
2672 reflections	Δρmin = −0.22 e Å^−3
207 parameters

Special details

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 (Ų)

	x	y	z	Uiso*/Ueq
N	0.33424 (12)	0.57374 (9)	0.13399 (5)	0.0194 (2)
O1	0.42550 (11)	0.43483 (8)	0.24532 (5)	0.0243 (2)
O2	0.28060 (11)	0.25320 (7)	−0.03212 (5)	0.0233 (2)
O3	0.27979 (10)	0.81129 (7)	0.06424 (5)	0.02058 (19)
O4	0.13823 (11)	0.84432 (7)	−0.09956 (5)	0.0245 (2)
C1	0.36749 (14)	0.45696 (11)	0.15976 (6)	0.0194 (2)
C2	0.35529 (13)	0.33930 (10)	0.11348 (7)	0.0192 (2)
C3	0.29818 (13)	0.34916 (10)	0.02597 (7)	0.0186 (2)
C4	0.25319 (13)	0.47355 (10)	−0.00799 (6)	0.0177 (2)
C5	0.27531 (13)	0.58198 (10)	0.04770 (6)	0.0175 (2)
C6	0.18805 (14)	0.49268 (11)	−0.09582 (7)	0.0200 (2)
C7	0.14623 (14)	0.61268 (11)	−0.12728 (7)	0.0208 (2)
C8	0.17206 (14)	0.72110 (10)	−0.07294 (6)	0.0186 (2)
C9	0.23761 (13)	0.70556 (10)	0.01291 (7)	0.0178 (2)
C10	0.45022 (15)	0.30320 (11)	0.25283 (8)	0.0253 (3)
C11	0.41129 (14)	0.24193 (11)	0.17749 (7)	0.0234 (2)
C12	0.32400 (16)	0.12536 (11)	−0.00303 (8)	0.0261 (3)
C13	0.13052 (15)	0.85758 (11)	0.11072 (7)	0.0249 (2)
H13A	0.0434	0.9021	0.0716	0.037*
H13B	0.1777	0.9151	0.1555	0.037*
H13C	0.07	0.7867	0.1363	0.037*
C14	0.09275 (16)	0.86442 (11)	−0.19021 (7)	0.0244 (2)
H6	0.1727 (18)	0.4202 (15)	−0.1341 (8)	0.027 (3)*
H7	0.0956 (19)	0.6262 (15)	−0.1894 (10)	0.035 (4)*
H11	0.4213 (18)	0.1499 (14)	0.1694 (9)	0.027 (3)*
H10	0.4961 (18)	0.2723 (14)	0.3098 (9)	0.027 (3)*
H12A	0.454 (2)	0.1187 (15)	0.0224 (10)	0.041*
H12B	0.307 (2)	0.0721 (16)	−0.0552 (10)	0.041*
H12C	0.241 (2)	0.0970 (16)	0.0400 (10)	0.041*
H14A	0.189 (2)	0.8265 (15)	−0.2252 (10)	0.041*
H14B	0.089 (2)	0.9608 (17)	−0.1963 (9)	0.041*
H14C	−0.032 (2)	0.8273 (15)	−0.2072 (10)	0.041*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
N	0.0198 (4)	0.0202 (4)	0.0179 (4)	0.0013 (3)	−0.0001 (3)	−0.0006 (3)
O1	0.0288 (4)	0.0239 (4)	0.0194 (4)	0.0034 (3)	−0.0040 (3)	0.0025 (3)
O2	0.0292 (4)	0.0149 (4)	0.0253 (4)	0.0008 (3)	−0.0002 (3)	−0.0024 (3)
O3	0.0217 (4)	0.0172 (4)	0.0228 (4)	−0.0003 (3)	0.0019 (3)	−0.0052 (3)
O4	0.0351 (4)	0.0183 (4)	0.0198 (4)	0.0040 (3)	−0.0003 (3)	0.0022 (3)
C1	0.0175 (5)	0.0227 (5)	0.0178 (5)	0.0017 (4)	−0.0002 (4)	0.0017 (4)
C2	0.0155 (5)	0.0196 (5)	0.0225 (5)	0.0002 (4)	0.0017 (4)	0.0013 (4)
C3	0.0161 (4)	0.0180 (5)	0.0219 (5)	−0.0007 (4)	0.0024 (4)	−0.0026 (4)
C4	0.0157 (5)	0.0182 (5)	0.0195 (5)	−0.0007 (4)	0.0026 (4)	−0.0012 (4)
C5	0.0150 (4)	0.0187 (5)	0.0188 (5)	−0.0002 (4)	0.0015 (4)	−0.0005 (4)
C6	0.0207 (5)	0.0205 (5)	0.0188 (5)	−0.0009 (4)	0.0012 (4)	−0.0031 (4)
C7	0.0220 (5)	0.0230 (5)	0.0172 (5)	0.0001 (4)	0.0006 (4)	−0.0010 (4)
C8	0.0191 (5)	0.0174 (5)	0.0193 (5)	0.0012 (4)	0.0024 (4)	0.0017 (4)
C9	0.0174 (5)	0.0171 (5)	0.0191 (5)	−0.0004 (4)	0.0016 (4)	−0.0022 (4)
C10	0.0248 (5)	0.0241 (6)	0.0265 (6)	0.0028 (4)	−0.0013 (4)	0.0063 (4)
C11	0.0214 (5)	0.0220 (5)	0.0267 (5)	0.0018 (4)	0.0002 (4)	0.0051 (4)
C12	0.0283 (6)	0.0155 (5)	0.0340 (6)	0.0004 (4)	0.0002 (5)	−0.0015 (4)
C13	0.0270 (5)	0.0240 (6)	0.0240 (5)	0.0017 (4)	0.0043 (4)	−0.0052 (4)
C14	0.0280 (6)	0.0250 (6)	0.0202 (5)	0.0045 (4)	0.0013 (4)	0.0050 (4)

Geometric parameters (Å, º)

N—C1	1.2996 (14)	C6—C7	1.3697 (15)
N—C5	1.3723 (13)	C6—H6	0.962 (15)
O1—C1	1.3769 (12)	C7—C8	1.4137 (15)
O1—C10	1.3898 (14)	C7—H7	1.012 (15)
O2—C3	1.3452 (12)	C8—C9	1.3848 (14)
O2—C12	1.4358 (13)	C10—C11	1.3401 (16)
O3—C9	1.3804 (12)	C10—H10	0.973 (14)
O3—C13	1.4272 (12)	C11—H11	0.973 (15)
O4—C8	1.3674 (13)	C12—H12A	0.992 (16)
O4—C14	1.4306 (13)	C12—H12B	0.980 (16)
C1—C2	1.4211 (15)	C12—H12C	0.976 (15)
C2—C3	1.3883 (15)	C13—H13A	0.96
C2—C11	1.4549 (14)	C13—H13B	0.96
C3—C4	1.4293 (14)	C13—H13C	0.96
C4—C6	1.4176 (14)	C14—H14A	0.999 (16)
C4—C5	1.4240 (14)	C14—H14B	1.011 (17)
C5—C9	1.4166 (14)	C14—H14C	0.998 (16)
C1—N—C5	113.18 (9)	C9—C8—C7	119.74 (10)
C1—O1—C10	105.92 (8)	O3—C9—C8	120.14 (9)
C3—O2—C12	118.42 (8)	O3—C9—C5	118.84 (9)
C9—O3—C13	114.67 (8)	C8—C9—C5	120.86 (10)
C8—O4—C14	117.11 (8)	C11—C10—O1	112.47 (10)
N—C1—O1	119.20 (10)	C11—C10—H10	131.6 (9)
N—C1—C2	130.83 (10)	O1—C10—H10	115.9 (9)
O1—C1—C2	109.97 (9)	C10—C11—C2	106.69 (10)
C3—C2—C1	115.41 (10)	C10—C11—H11	124.8 (8)
C3—C2—C11	139.63 (10)	C2—C11—H11	128.5 (8)
C1—C2—C11	104.96 (9)	O2—C12—H12A	111.6 (9)
O2—C3—C2	126.98 (10)	O2—C12—H12B	105.0 (9)
O2—C3—C4	115.10 (9)	H12A—C12—H12B	110.1 (12)
C2—C3—C4	117.91 (9)	O2—C12—H12C	111.3 (10)
C6—C4—C5	118.76 (9)	H12A—C12—H12C	108.8 (12)
C6—C4—C3	122.00 (9)	H12B—C12—H12C	110.1 (13)
C5—C4—C3	119.23 (9)	O3—C13—H13A	109.5
N—C5—C9	117.59 (9)	O3—C13—H13B	109.5
N—C5—C4	123.40 (10)	H13A—C13—H13B	109.5
C9—C5—C4	119.01 (9)	O3—C13—H13C	109.5
C7—C6—C4	121.18 (10)	H13A—C13—H13C	109.5
C7—C6—H6	119.3 (8)	H13B—C13—H13C	109.5
C4—C6—H6	119.5 (8)	O4—C14—H14A	110.7 (9)
C6—C7—C8	120.38 (9)	O4—C14—H14B	103.9 (8)
C6—C7—H7	121.3 (9)	H14A—C14—H14B	111.1 (12)
C8—C7—H7	118.3 (9)	O4—C14—H14C	109.7 (9)
O4—C8—C9	116.07 (9)	H14A—C14—H14C	111.1 (12)
O4—C8—C7	124.19 (9)	H14B—C14—H14C	110.1 (12)
C5—N—C1—O1	−179.22 (8)	C6—C7—C8—O4	178.33 (9)
C5—N—C1—C2	1.00 (16)	C6—C7—C8—C9	−0.90 (15)
C10—O1—C1—N	−179.69 (9)	C13—O3—C9—C8	91.14 (11)
C10—O1—C1—C2	0.13 (11)	C13—O3—C9—C5	−93.42 (11)
N—C1—C2—C3	−0.10 (17)	O4—C8—C9—O3	−5.38 (14)
O1—C1—C2—C3	−179.89 (8)	C7—C8—C9—O3	173.90 (8)
N—C1—C2—C11	179.60 (11)	O4—C8—C9—C5	179.27 (8)
O1—C1—C2—C11	−0.19 (11)	C7—C8—C9—C5	−1.45 (15)
C12—O2—C3—C2	0.09 (15)	N—C5—C9—O3	6.65 (14)
C12—O2—C3—C4	179.76 (8)	C4—C5—C9—O3	−172.47 (8)
C1—C2—C3—O2	178.01 (9)	N—C5—C9—C8	−177.94 (8)
C11—C2—C3—O2	−1.6 (2)	C4—C5—C9—C8	2.94 (15)
C1—C2—C3—C4	−1.65 (14)	C1—O1—C10—C11	−0.02 (12)
C11—C2—C3—C4	178.79 (11)	O1—C10—C11—C2	−0.10 (12)
O2—C3—C4—C6	2.33 (14)	C3—C2—C11—C10	179.76 (13)
C2—C3—C4—C6	−177.97 (9)	C1—C2—C11—C10	0.17 (11)
O2—C3—C4—C5	−177.27 (8)	N—O1—O2—O3	2.22 (3)
C2—C3—C4—C5	2.43 (14)	O1—O2—O3—O4	−173.67 (3)
C1—N—C5—C9	−179.19 (8)	O2—O3—O4—C1	4.96 (3)
C1—N—C5—C4	−0.11 (14)	O3—O4—C1—C2	−172.58 (8)
C6—C4—C5—N	178.82 (9)	O4—C1—C2—C3	0.54 (10)
C3—C4—C5—N	−1.57 (15)	C1—C2—C3—C4	−1.65 (14)
C6—C4—C5—C9	−2.11 (14)	C2—C3—C4—C5	2.43 (14)
C3—C4—C5—C9	177.50 (8)	C3—C4—C5—C6	179.61 (15)
C5—C4—C6—C7	−0.18 (15)	C4—C5—C6—C7	179.85 (13)
C3—C4—C6—C7	−179.77 (9)	C5—C6—C7—C8	1.61 (10)
C4—C6—C7—C8	1.70 (16)	C6—C7—C8—C9	−0.90 (15)
C14—O4—C8—C9	172.41 (9)	C7—C8—C9—C10	−1.95 (16)
C14—O4—C8—C7	−6.84 (14)	C8—C9—C10—C11	3.84 (12)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
C10—H10···O3^i	0.97 (1)	2.47 (1)	3.315 (1)	144.8 (11)
C12—H12A···O3^ii	0.99 (1)	2.54 (1)	3.159 (1)	120.3 (11)
C10—H10···N^i	0.97 (1)	2.53 (1)	3.290 (1)	134.9 (11)
C14—H14A···N^iii	0.99 (1)	2.69 (1)	3.403 (1)	128.0 (11)

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