A quantum chemistry study of Qinghaosu

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ELSEVIER

CHEMICAL PHYSICS L.~: :r.KS Chemical Physics Letters 277 (1997) 234-238

A quantum chemistry study of Qinghaosu Jian-De Gu 1, Kai-Xian Chert, Hua-Liang Jiang, Wei-Liang Zhu, Jian-Zhong Chen, Ru-Yun Ji State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Academia Sinica of Sciences, Shanghai200031, People's Republic of China Received 23 April 1997; in final form 19 June 1997

Abstract

The powerful anti-malarial drug, Qinghaosu (Artemisinin), has been studied using ab initio methods. The DF]" B3LYP method with the 6-31G * basis set gives an excellent geometry compared to experiments, especially for the O-O bond length and the 1,2,4-Trioxane ring subsystem. The R(O-O) bond length predicted at this level is 1.460/~, only 0.018 shorter than the experimental measurement. The vibrational analysis shows that the O-O stretching mode is combined with the O-C vibration mode, having the character of an O-O-C entity. The O-O vibrational band at 722 cm- ~ suggested in the experimental studies has been assigned as 1,2,4-trioxane ring breathing. © 1997 Published by Elsevier Science B.V.

The natural product Qinghaosu (also known as Artemisinin, Fig. 1), which has been used in Chinese medicine for centuries [1], is one of the most promising anti-malarial drugs. It is a powerful anti-malarial having significant activity against strains of the disease which are resistant to chloroquine. The structure of this compound, which contains a 1,2,4-trioxane ring system, has been determined experimentally by X-ray methods [2]. Quantum chemistry studies have been performed in order to reveal the structure and mechanism of action of the drug [3-5]. However, the theoretical levels have been limited to the semi-empirical methods such as AM1, PM3 [3-5] and ZINDO [3]. It is believed that the activity of Qinghaosu resides in the - O - O - linkage, since replacement of

I Present address: University of Georgia, Room 404, 1001 Cedar Street, Athens, GA 30602-2556, USA, E-mail: [email protected].

- O - O - by a single - O - group in its derivative destroys the activity completely. However, the geomelries optimized at semi-empirical level are far from satisfactory. The calculation of Qinghaosu at the AM1 and PM3 levels gives poor predictions for R(O-O), which is 0.19 ,~ too short at the AM1 level and 0.06 ,~ too long at the PM3 level compared to the experimental value of 1.478,~. The ZINDO result is even poorer - - too short by 0.24 ,~ [3]. Several model systems containing 1,2,4-trioxane ring have also been studied by using ab initio SCF methods using up to a 6-31G* basis set [3] to reveal the characters of - O - O - linkage. Even for the model system trioxane, the predicted R ( O - O ) are inconsistent with each other. The bond length of O - O is calculated to be 1.29 ,~, at the AM1 level, but considerably larger, 1.58 ,~, at the PM3 level. The ab initio SCF HF at 3-21G* and 6-31G* basic sets gave intermediate values 1.47 and 1.40 ,~ respectively [3]. Because of the poor predicted values of

0009-2614/97/$17.00 © 1997 Published by Elsevier Science B.V. All rights reserved. PII S 0 0 0 9 - 2 6 1 4 ( 9 7 ) 0 0 8 7 7 - 4

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J.-D. Gu et al. / Chemical Physics Letters 277 (1997) 234-238

Fig. I. The geometry of Qinghaosu, where H atoms has been omitted and the unlabeled circles are C. O - O b o n d length, the calculated vibrational frequencies for O - O vibration are not reliable. A reliable calculation is certainly in need to predict the vibration spectra in view o f the disagreement between the different observations [6-8]. In this research, the structure o f the Qinghaosu molecule has been optimized with the analytic gradient techniques using the restricted H a r t r e e - F o c k ( R H F ) self-consistent-field ( S C F ) method at 6-31G and 6-31G* basis set levels, and the hybrid H a r t r e e - F o c k / D F T methods with B e c k e ' s three pa-

rameter (B3) exchange functional along with L e e Y a n g - P a r r nonlocal correlation functional (B3LYP) [9,10] at 6-31G *. The harmonic vibrational frequencies and their infrared intensities have also been predicted at the R H F / 6 - 3 1 G * level. All computations were carried out on a S G I P O W E R C H A L L E N G E R10000 workstation using the Gaussian 94 program package [I 1]. The 1,2,4-trioxane ring o f the optimized geometries o f Qinghaosu obtained in this work are given in Table 1. As a comparison, the semi-empirical results and the experimental results are also listed in this Table. O f particular interest axe the value o f the bond length o f O - O , which is predicted to be 1.447 ~ a t the S C F H F / 6 - 3 1 G level (0.031 A shorter than that o f experimental result o f 1.478 A ) and 1.39 ~, at the S C F H F / 6 - 3 1 G * level (0.088 A shorter than experiment). A s for the result obtained at the D F T B 3 L Y P / 6 - 3 1 G * level, the bond length o f O - O is very close to the experimental result. The predicted R ( O - O ) is 1.460 A, only 0.018 ,~ shorter than the experimental measurement. Considering the S C F calculations have difficulty in giving the correct struc-

Table 1 The geometries of the 1,2,4-1rioxane ring in Qinghaosu optimized at different theoretical level and the comparison of the experimental results. R (bond length) in A, A (angle) and D (dihedral) in degrees GeomeUT Semi-empirical SCF I-IF DFF Experiment Parameter

AM1 a

PM3 a

ZINDO a

6-31G

6-31G *

6-31G *

Ref. [2]

1.289 1.427 1.427 1.416 1.537

1.544 1.402 1.428 1.403 1.555

1.240 1.404 1.402 1.394 1.499

1.4467 1.4352 1.4347 1.4027 1.5325 1.4686

1.3901 1.3962 1.4084 1.3761 1.5318 1.4295

1.4598 1.4140 1.4410 1.3961 1.5390 1.4553

1.478 1.403 1.437 1.390 1.529 1.456

112.5 103.6 115.5 113.5

110.3 104.8 116.0 115.2

112.4 106.7 111.8 114.1

108.8 106.8 117.3 112.3 110.9 113.2

109.5 107.8 115.3 112.3 110.5 112.7

108.3 108.5 114.1 113.3 111.3 111.6

107.5 107.3 114.1 113.3 111.0 111.1

- 77.7 41.9 11.5

-- 73.3 52.7 2.8

- 76.9 34.6 21.1

- 71.9 33.4 25.3

- 73.4 31.0 27.5

- 74.0 32.9 27.3

R

O102 O2C3 C304 O4C5 C5C6 C601 A O102C3 O2C304 C304C5 O4C5C6 C5C601 C6OIO2 D 0102C3C4 O2C304C5 C304C5C6 a See ref. [3]

J.-D. Gu et al. / Chemical Physics Letters 277 (1997) 234-238

236

ture for H202 (producing too short a bond length), the R ( O - O ) predicted in this research is excellent. The overall structure of the 1,2,4-trioxane in Qinghaosu predicted in this study is quite good compared with the experimental results. The SCF HF at 6-31G * basis set gives a fair structural prediction for the 1,2,4-trioxane subsystem. However, the polarization function in the basis set seems to have a tendency to reduce all the bond lengths, not only the O - O bond length. The calculated results of the structure of Qinghaosu at 6-31G level are better than that of 6-31G *. The largest difference in the trioxane ring compared to the experimental result is 0.032 ,~ longer for R(O2-C3). Of the three methods used in the calculation, the DFT B3LYP/6-31G* gives the best prediction. The largest difference among the bond lengths of the 1,2,4-trioxane subsystem in Qinghaosu between the calculated and the experimental results is only 0.011 ,~ for R(O2-C3) (excluding the O - O bond), and the angle differences are less than 1.2 °. Based on these results, the DFT B3LYP at 6-31G * level seems to be efficient for the theoretical study of Qinghaosu and its derivatives. Although the previous studies showed the semiempirical method PM3 predicted acceptable bond lengths for the 1,2,4-trioxane ring in Qinghaosu, the dihedral of C304C5C6 in the ring is too small - only 2.8 °, 25 ° smaller than the ab initio predictions. This suggests the PM3 method might be not reliable for the structural study of the 1,2,4-trioxane ringcontaining system. As the polarization functions are mandatory for

40

reliable IR intensity predictions [12], we report here the results of vibrational analysis at the SCF H F / 6 31G* level. The predicted SCF H F / 6 - 3 1 G * infrared spectrum of Qinghaosu is given in Fig. 2, in which the frequencies have been multiplied by a factor of 0.875 to give an overall consistency with the experimental result. In this case, the three strongly absorbing bands located around 500 ~ 600 cm -1, 1000 ~ 1300 cm - I and 1400 cm - I , as well as the strongest absorption of C = O stretching at 1770 cm - j , in the experimental IR spectrum can be reproduced qualitatively in our calculated spectrum. It should be noted that although the IR intensities and the frequencies predicted at the SCF H F / 6 - 3 1 G * level cannot be expected to reproduce the experimental results precisely, they are good for the qualitative interpretation. The experimental studies on Qinghaosu have assigned the O - O vibration to be the bands at 722, 831,881, and 1115 cm - t , respectively [6,8]. The O - O stretching band had been predicted to be at ~ 750 cm -1 at the AM1 level and -- 760 c m - l at the PM3 level by Thomson et al. [3]. However, calculation at the SCF H F / 6 - 3 1 G * level shows that there is no vibrational mode that can be simply assigned to the O - O stretching alone. This result is consistent with the conclusion of Monhaupt et al. based on their experimental studies on some 1,2,4-trioxanes [7]. The vibrational mode at v = 1101 cm-1 with an IR intensity 48 k m / m o l in Fig. 3a shows clearly that the O - O stretching mode is actually combined with the O - C vibrational mode, having the character of an O - O - C entity, as described

I

1

0

2000

1000

3000

O C~ l

Fig. 2. Predicted infrared intensities (in km/mol) at SCF HF/6-31G *, in which the frequencies have been multipliedby a factor of 0.875 to fit the experimentalspectrum.

Z-D. Gu et al. / Chemical Physics Letters 277 (1997) 234-238

l i s t e d in F i g . 3b. T h i s m o d e at 8 8 5 c m - L w i t h a n I R i n t e n s i t y o f 17 k m / m o i is c l e a r l y a t w i s t i n g v i b r a t i o n o f t h e 1 , 2 , 4 - t r i o x a n e r i n g in Q i n g h a o s u . A n o t h e r

in R e t [ 7 ] . T h i s m o d e c a n b e a s s i g n e d to t h e e x p e r i m e n t a l b a n d at 1115 c m - j . T h e m o d e w h i c h c a n b e a s s i g n e d t o t h e e x p e r i m e n t a l b a n d at 881 c m -1

(a)

237

is

(b)

X

"',.

d

",,

"°s#

,,=-

""-i~.

(d)

h

",. ",,,,,

(c)

"

°4

\ (e)

Fig. 3. T h e vibrational normal m o d e s which can be assigaed to the O - O

vibration at II15 ¢ m -l , 881 ¢ m -t , 831 c m -l and 722 c m -i .

Only those vectors related to the Trioxane ring are shown. The hydrogen atoms and the unimportant vectors have been omitted for clarity. (a) v = 1101 c m - t with IR intensity 48 km/mol, O - O stretching mode is actually combined with the O - C vibration mode, having the character of O - O - C entity. (b) v = 885 cm -I with IR intensity of 17 k m / m o l is clearly a twisting vibration of the 1,2,4-Trioxane ring in Qinghaosu. (c) v = 826 cm - t with IR intensity of 19 km/mol. This mode can be expected to be assigned to the band at 833 cm-= in experiments, and also shows a twisting vibration. (d) u = 701 cm - t , IR intensity 3.5. (e) v = 748 cm - t , IR intensity 5.5. Both (d) and (e) may be assigned to the experimental band at 722 cm - t , and show the breathing vibration of 1,2,4-Trioxane in Qinghaosu.

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J.-D. Gu et al. / Chemical Physics Letters 277 (1997) 234-238

twisting vibrational mode of the 1,2,4-1rioxane ring is at 826 cm -1 with an IR intensity of 19 km/mol. This mode can be expected to be assigned to the band at 833 c m - i in experiments and is depicted in Fig. 3c. In Fig. 3, two vibrational modes possibly related to the experimental band at 722 cm -l are also displayed. Both of the modes contain the breathing vibrational motion of the 1,2,4-trioxane ring. The mode at 701 cm -I (Fig. 3d) shows a higher breathing vibration percentage than that of the mode at 748 c m - l (Fig. 3e), and as expected the IR intensity of the former is lower (3.5 k m / m o l ) than the later (5.5 km/mol). These two vibrational modes invalidate the conclusion from the study of Monhaupt et al. [7]. Based on the comparison of the structure of Qinghaosu and the cis-fused trioxane, they believed that the 722 cm-~ band should be of non-trioxane ring origin. However, our vibrational analysis result for the band at 722 cm -I suggests that although this band can not be assigned to the O - O stretching, it has the characteristic motion of the 1,2,4-trioxane ring in Qinghaosu. In summary, the geometric structure of the promising anti-malarial drug Qinghaosu studied using the ab initio SCF HF and the DFT methods in conjunction with the 6-31G and 6-31G * basis sets has shown to be very consistent with the experimental result. The harmonic vibrational frequency analysis at the SCF HF/6-31G * level shows clearly that the O - O stretching mode is actually combined with the O - C vibrational mode, having the character of an O - O - C entity, as suggested by Jefford's group. The O - O vibrational bands at 722, 831, 881 and 1115 c m - i suggested by experimental studies have been assigned as Qinghaosu's 1 , 2 , 4 - trioxane ring breathing (722 c m - l ), twisting (831 and 881 cm- i ) and coupled C - O and O - O stretching modes of O - O - C entity (1115 c m - [ ), respectively. The calculation using the hybrid HartreeF o c k / D F T B3LYP method with the 6-31G* basis set gives excellent geometric prediction compared with the experimental results, especially for the O - O

bond length and the 1,2,4-trioxane ring structure in Qinghaosu. The harmonic vibrational frequencies predicted at this level should be more reliable in interpreting the characters of experimental spectra. An ab initio calculation of frequencies at the B3LYP/6-31G * theoretical level is in progress.

Acknowledgements This research was supported by the National Science Foundation of China and the Post-Doctoral Foundation of China. A generous grant of computer time provided by the Network Information Center, Chinese Academy of Sciences, is gratefully acknowledged. We thank Steve Wesolowski at CCQC, the University of Georgia for helpful discussions.

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