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Quantum chemical analysis of alternative pathways for iron activation step for artemisinin, a new antimalarial drug
Journal of Infection (2006) 53, 148e151
www.elsevierhealth.com/journals/jinf
Quantum chemical analysis of alternative pathways for iron activation step for artemisinin, a new antimalarial drug Viroj Wiwanitkit* Department of Laboratory Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand Accepted 15 November 2005 Available online 28 December 2005
KEYWORDS Artemisinin; Quantum; Energy
Summary Malaria is a mosquito-borne parasitic infection. It can be said that malaria is a very important tropical mosquito-borne infectious disease. The selection of antimalarial drugs depends on the species and the reported resistance pattern in each setting. Artemisinins are a new group of antimalarial drugs against the drugresistant strains of malarial parasites. The mechanism of action of artemisinin compounds consists of two important steps: (a) activation and (b) alkylation. In the activation step by iron, there are two possible pathways for developing C-4 free radical: (a) 1.5 H-shift and (b) CeC cleavage. Here, the author performs a quantum chemical analysis of the activation reaction of artemisinin by the two alternative pathways. According to this study, the required energy for compound formation in CeC cleavage is more than that for CeO cleavage. It can be noted that the CeC cleavage pathway is less preferable, implying that the 1.5 H-shift should be the more common phenomenon. ª 2005 The British Infection Society. Published by Elsevier Ltd. All rights reserved.
Introduction Malaria is a mosquito-borne parasitic infection. It can be said that malaria is a very important tropical mosquito-borne infectious disease.
* Tel.: þ66 2 256 4136. E-mail addresses: [email protected], wviroj@pioneer. netserv.chula.ac.th
Malaria is caused by protozoan parasites of the genus Plasmodium. Four species of Plasmodium, P. falciparum, P. vivax, P. ovale and P. malaria, can produce the human disease in its various forms. In addition, there are other species that infect animals such as P. gallinaceum. In humans, malaria is a widespread and potentially deadly mosquito-borne disease in tropical countries characterized by cyclical bouts of fever with muscle stiffness, shaking and sweating.1,2
0163-4453/$30 ª 2005 The British Infection Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jinf.2005.11.011
Quantum chemical analysis of alternative pathways The concept of treatment is similar to other infections: getting rid of the pathogen or control of the infection and supportive or symptomatic treatment. Many antimalarial drugs have been available for a long time. The selection of antimalarial drugs depends on the species and the reported resistance pattern in each setting.3 Drug resistance is a very important problem in the use of antimalarial drugs. Historically, first case of chloroquine resistance was along the Thaie Cambodian border in the late 1950s, since when Southeast Asia has played an important role as a focus for the development of drug resistance in Plasmodium falciparum.4 In addition, the onset of chloroquine resistance marked the beginning of a new chapter in the history of malaria in Southeast Asia and by 1973, chloroquine finally had to be replaced by the combination of sulfadoxine and pyrimethamine (SP) as the first-line drug for the treatment of uncomplicated malaria in Thailand, and more than 10 African countries have also switched their first-line drug to other newly developed ones.4 Artemisinins are a new group of antimalarial drugs against the drug-resistant strains of malarial parasites. Artemisinins were discovered to be highly effective against malaria shortly after the isolation of the parent artemisinin in 1971 in China.5 These compounds combine potent, rapid antimalarial activity with a wide therapeutic index and an absence of clinically important resistance.5 Artemisinin-containing regimens meet H
CH3
O O O H O
149 the urgent need to find effective treatments for multidrug-resistant malaria and have recently been advocated for widespread deployment.5 The mechanism of action of artemisinin compounds consists of two important steps: (a) activation and (b) alkylation.5e7 In the activation step by iron, there are two possible pathways for the development of C-4 free radical: (a) 1.5 H-shift and (b) CeC cleavage.5e7 Here, the author performs a quantum chemical analysis of the activation reaction of artemisinin by the two alternative pathways.
Materials and methods Alternative pathways of the activation reaction of artemisinin This study focused on the activation reaction within one molecule of artemesinin. The two main alternative pathways to develop the C-4 free radical are 1.5 H-shift and CeC cleavage (Fig. 1).
Quantum chemical analysis for bonding energy The quantum chemical analysis for bonding energy of artemisinin was performed according to the classical bonding theory.8 Analyses were
CH3
H
CH3 O artemisinin molecule
A C
+
C
C
Fe3 O
O
O
C
.
Fe2+
H
C
O
C
O
O
B C
.
O
C
C
Fe2+ C
O O
+
C
O C
Fe3 O O
Figure 1 The alternative pathways for the iron activation step for development of C-4 free radical. In the artemisinin molecule (top), the changes in both alternative pathways occur within the rectangle. (A) 1.5 H-shift. (B) CeC cleavage.
150
V. Wiwanitkit
Table 1
Details and required energy for compound formation in 1.5 H-shift and CeC cleavage pathways
Items
1.5 H-shift
CeC cleavage
Bond breakinga Bond formingb Getting in energy
1 OeO, 1 CeH 1 OeH, 1 OeFe3þ 33 kcal/mol þ 100 kcal/mol
Giving out energy Required energyc
111 kcal/mol þ 1 eV 22 kcal/mol 1 eV
1 OeO, 1 CeH, 1 CeC, 1 CeO 1 C¼O, 1 OeFe3þ 33 kcal/mol þ 100 kcal/mol þ 82 kcal/mol þ 83 kcal/mol 177 kcal/mol þ 1 eV 121 kcal/mol 1eV
a b c
Getting in energy. Giving out energy. Required energy ¼ getting in energy giving out energy.
then carried out on the resulting compound, presenting C-4 free radical, and iron from each alternative reaction pathway. The required energy for compound formation in each pathway was compared.
Results The details and the required energy for compound formation in 1.5 H-shift and CeC cleavage pathways are presented in Table 1. The required energy for compound formation in 1.5 H-shift pathway is less than that required for the CeC cleavage pathway.
Discussion The recommended treatment for malaria has been changing in recent years due to the increasing malarial resistance. Of the new drugs, artemisinin derivatives have allowed considerable progress in the treatment of malaria.9 They have short halflives, allowing a fast parasitic clearance, and these derivatives do not provoke resistance.9 They are first-line drugs for the treatment of malaria in areas of drug resistance.9 It is suggested that the antimalarial activity of artemisinin may be mediated by a reaction with intraparasitic hemin.9,10 The mechanism of action of artemisinin appears to involve two steps. In the first step, activation, intra-parasitic iron catalyzes the cleavage of the endoperoxide bridge and the generation of free radicals.6 In the second step, alkylation, the artemisinin-derived free radical forms covalent bonds with parasite proteins.6 The reduction of the peroxide bond by Fe2þ in trioxane alcohol follows both the CeC cleavage and 1.5-H-shift pathways and produces a ring-contacted tetrahydrofuran acetal, which is converted to tetrahydrofuran aldehyde and C(4)-hydroxy deoxytrioxane alcohol, respectively.11 Biochemically, artemisinin, naturally occurring 1,2,4-trioxane originating from Artemisia annua L.,
and its derivatives are a potent class of antimalarial drugs.12 The clinical efficacy of these drugs is characterized by an almost immediate onset and rapid reduction of parasitemia, and is high in such areas where multidrug-resistance is rampant.12 Sriram et al. reviewed a broad range of medical and pharmaceutical disciplines in fighting malaria, including discovery, phytochemical aspects, antimalarial mechanism of action, pharmacokinetics, and major drawbacks and various structural modifications.13 They also noted that future antimalarial research would focus on the molecular mechanism of drugs and development of new effective choices.13 Evidence on the difference in the mode of action of antimalarial drugs and molecular structure/activity correlations is useful for future antimalarial studies. Hence, the study on the biochemical reaction of artemisinin can provide useful information for further malariology study. Here, the author studied the two possible mechanisms in the iron activation step for development of C-4 free radical by quantum chemical analysis based on basic thermodynamic principles, and found that the 1.5 H-shift pathway is more preferable. The required energy for the 1.5 H-shift pathway is much less than that required for CeC cleavage, implying that the 1.5 shift should be the more common phenomenon. This can confirm the previous report of Zhang et al. that the shift of the reduction potential to more positive values, a catalytic decomposition of artemisinin, played an important role in the antimalarial activity of artemisinin.10
References 1. Chareonviriyaphap T, Bangs MJ, Ratanatham S. Status of malaria in Thailand. Southeast Asian J Trop Med Public Health 2000;31:225e37. 2. Wernsdorfer G, Wernsdorfer WH. Malaria at the turn from the 2nd to the 3rd millennium. Wien Klin Wochenschr 2003;115(Suppl. 3):2e9. 3. Farooq U, Mahajan RC. Drug resistance in malaria. J Vector Borne Dis 2004;41:45e53.
Quantum chemical analysis of alternative pathways 4. Indonesian Society of Medicine. Consensus of malaria management 2003 (part 2). Acta Med Indones 2004;36:187e93. 5. Woodrow CJ, Haynes RK, Krishna S. Artemisinins. Postgrad Med J 2005;81:71e8. 6. Meshnick SR. The mode of action of antimalarial endoperoxides. Trans R Soc Trop Med Hyg 1994;88(Suppl. 1):S31e2. 7. Van der Meersch H. Review of the use of artemisinin and its derivatives in the treatment of malaria. J Pharm Belg 2005; 60:23e9. 8. Goldberg DL. Bonding. In: Goldberg DL, editor. Chemistry. Singapore: McGraw Hill; 1989. p. 95e118. 9. Dupouy-Camet J. New drugs for the treatment of human parasitic protozoa. Parasitologia 2004;46:81e4.
151 10. Zhang F, Gosser Jr DK, Meshnick SR. Hemin-catalyzed decomposition of artemisinin (qinghaosu). Biochem Pharmacol 1992;43:1805e9. 11. Kapetanaki S, Varotsis C. Fourier transform infrared investigation of non-heme Fe(III) and Fe(II) decomposition of artemisinin and of a simplified trioxane alcohol. J Med Chem 2001;44:3150e6. 12. Jung M, Lee K, Kim H, Park M. Recent advances in artemisinin and its derivatives as antimalarial and antitumor agents. Curr Med Chem 2004;11:1265e84. 13. Sriram D, Rao VS, Chandrasekhara KV, Yogeeswari P. Progress in the research of artemisinin and its analogues as antimalarials: an update. Nat Prod Res 2004;18:503e27.
www.elsevierhealth.com/journals/jinf
Quantum chemical analysis of alternative pathways for iron activation step for artemisinin, a new antimalarial drug Viroj Wiwanitkit* Department of Laboratory Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand Accepted 15 November 2005 Available online 28 December 2005
KEYWORDS Artemisinin; Quantum; Energy
Summary Malaria is a mosquito-borne parasitic infection. It can be said that malaria is a very important tropical mosquito-borne infectious disease. The selection of antimalarial drugs depends on the species and the reported resistance pattern in each setting. Artemisinins are a new group of antimalarial drugs against the drugresistant strains of malarial parasites. The mechanism of action of artemisinin compounds consists of two important steps: (a) activation and (b) alkylation. In the activation step by iron, there are two possible pathways for developing C-4 free radical: (a) 1.5 H-shift and (b) CeC cleavage. Here, the author performs a quantum chemical analysis of the activation reaction of artemisinin by the two alternative pathways. According to this study, the required energy for compound formation in CeC cleavage is more than that for CeO cleavage. It can be noted that the CeC cleavage pathway is less preferable, implying that the 1.5 H-shift should be the more common phenomenon. ª 2005 The British Infection Society. Published by Elsevier Ltd. All rights reserved.
Introduction Malaria is a mosquito-borne parasitic infection. It can be said that malaria is a very important tropical mosquito-borne infectious disease.
* Tel.: þ66 2 256 4136. E-mail addresses: [email protected], wviroj@pioneer. netserv.chula.ac.th
Malaria is caused by protozoan parasites of the genus Plasmodium. Four species of Plasmodium, P. falciparum, P. vivax, P. ovale and P. malaria, can produce the human disease in its various forms. In addition, there are other species that infect animals such as P. gallinaceum. In humans, malaria is a widespread and potentially deadly mosquito-borne disease in tropical countries characterized by cyclical bouts of fever with muscle stiffness, shaking and sweating.1,2
0163-4453/$30 ª 2005 The British Infection Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jinf.2005.11.011
Quantum chemical analysis of alternative pathways The concept of treatment is similar to other infections: getting rid of the pathogen or control of the infection and supportive or symptomatic treatment. Many antimalarial drugs have been available for a long time. The selection of antimalarial drugs depends on the species and the reported resistance pattern in each setting.3 Drug resistance is a very important problem in the use of antimalarial drugs. Historically, first case of chloroquine resistance was along the Thaie Cambodian border in the late 1950s, since when Southeast Asia has played an important role as a focus for the development of drug resistance in Plasmodium falciparum.4 In addition, the onset of chloroquine resistance marked the beginning of a new chapter in the history of malaria in Southeast Asia and by 1973, chloroquine finally had to be replaced by the combination of sulfadoxine and pyrimethamine (SP) as the first-line drug for the treatment of uncomplicated malaria in Thailand, and more than 10 African countries have also switched their first-line drug to other newly developed ones.4 Artemisinins are a new group of antimalarial drugs against the drug-resistant strains of malarial parasites. Artemisinins were discovered to be highly effective against malaria shortly after the isolation of the parent artemisinin in 1971 in China.5 These compounds combine potent, rapid antimalarial activity with a wide therapeutic index and an absence of clinically important resistance.5 Artemisinin-containing regimens meet H
CH3
O O O H O
149 the urgent need to find effective treatments for multidrug-resistant malaria and have recently been advocated for widespread deployment.5 The mechanism of action of artemisinin compounds consists of two important steps: (a) activation and (b) alkylation.5e7 In the activation step by iron, there are two possible pathways for the development of C-4 free radical: (a) 1.5 H-shift and (b) CeC cleavage.5e7 Here, the author performs a quantum chemical analysis of the activation reaction of artemisinin by the two alternative pathways.
Materials and methods Alternative pathways of the activation reaction of artemisinin This study focused on the activation reaction within one molecule of artemesinin. The two main alternative pathways to develop the C-4 free radical are 1.5 H-shift and CeC cleavage (Fig. 1).
Quantum chemical analysis for bonding energy The quantum chemical analysis for bonding energy of artemisinin was performed according to the classical bonding theory.8 Analyses were
CH3
H
CH3 O artemisinin molecule
A C
+
C
C
Fe3 O
O
O
C
.
Fe2+
H
C
O
C
O
O
B C
.
O
C
C
Fe2+ C
O O
+
C
O C
Fe3 O O
Figure 1 The alternative pathways for the iron activation step for development of C-4 free radical. In the artemisinin molecule (top), the changes in both alternative pathways occur within the rectangle. (A) 1.5 H-shift. (B) CeC cleavage.
150
V. Wiwanitkit
Table 1
Details and required energy for compound formation in 1.5 H-shift and CeC cleavage pathways
Items
1.5 H-shift
CeC cleavage
Bond breakinga Bond formingb Getting in energy
1 OeO, 1 CeH 1 OeH, 1 OeFe3þ 33 kcal/mol þ 100 kcal/mol
Giving out energy Required energyc
111 kcal/mol þ 1 eV 22 kcal/mol 1 eV
1 OeO, 1 CeH, 1 CeC, 1 CeO 1 C¼O, 1 OeFe3þ 33 kcal/mol þ 100 kcal/mol þ 82 kcal/mol þ 83 kcal/mol 177 kcal/mol þ 1 eV 121 kcal/mol 1eV
a b c
Getting in energy. Giving out energy. Required energy ¼ getting in energy giving out energy.
then carried out on the resulting compound, presenting C-4 free radical, and iron from each alternative reaction pathway. The required energy for compound formation in each pathway was compared.
Results The details and the required energy for compound formation in 1.5 H-shift and CeC cleavage pathways are presented in Table 1. The required energy for compound formation in 1.5 H-shift pathway is less than that required for the CeC cleavage pathway.
Discussion The recommended treatment for malaria has been changing in recent years due to the increasing malarial resistance. Of the new drugs, artemisinin derivatives have allowed considerable progress in the treatment of malaria.9 They have short halflives, allowing a fast parasitic clearance, and these derivatives do not provoke resistance.9 They are first-line drugs for the treatment of malaria in areas of drug resistance.9 It is suggested that the antimalarial activity of artemisinin may be mediated by a reaction with intraparasitic hemin.9,10 The mechanism of action of artemisinin appears to involve two steps. In the first step, activation, intra-parasitic iron catalyzes the cleavage of the endoperoxide bridge and the generation of free radicals.6 In the second step, alkylation, the artemisinin-derived free radical forms covalent bonds with parasite proteins.6 The reduction of the peroxide bond by Fe2þ in trioxane alcohol follows both the CeC cleavage and 1.5-H-shift pathways and produces a ring-contacted tetrahydrofuran acetal, which is converted to tetrahydrofuran aldehyde and C(4)-hydroxy deoxytrioxane alcohol, respectively.11 Biochemically, artemisinin, naturally occurring 1,2,4-trioxane originating from Artemisia annua L.,
and its derivatives are a potent class of antimalarial drugs.12 The clinical efficacy of these drugs is characterized by an almost immediate onset and rapid reduction of parasitemia, and is high in such areas where multidrug-resistance is rampant.12 Sriram et al. reviewed a broad range of medical and pharmaceutical disciplines in fighting malaria, including discovery, phytochemical aspects, antimalarial mechanism of action, pharmacokinetics, and major drawbacks and various structural modifications.13 They also noted that future antimalarial research would focus on the molecular mechanism of drugs and development of new effective choices.13 Evidence on the difference in the mode of action of antimalarial drugs and molecular structure/activity correlations is useful for future antimalarial studies. Hence, the study on the biochemical reaction of artemisinin can provide useful information for further malariology study. Here, the author studied the two possible mechanisms in the iron activation step for development of C-4 free radical by quantum chemical analysis based on basic thermodynamic principles, and found that the 1.5 H-shift pathway is more preferable. The required energy for the 1.5 H-shift pathway is much less than that required for CeC cleavage, implying that the 1.5 shift should be the more common phenomenon. This can confirm the previous report of Zhang et al. that the shift of the reduction potential to more positive values, a catalytic decomposition of artemisinin, played an important role in the antimalarial activity of artemisinin.10
References 1. Chareonviriyaphap T, Bangs MJ, Ratanatham S. Status of malaria in Thailand. Southeast Asian J Trop Med Public Health 2000;31:225e37. 2. Wernsdorfer G, Wernsdorfer WH. Malaria at the turn from the 2nd to the 3rd millennium. Wien Klin Wochenschr 2003;115(Suppl. 3):2e9. 3. Farooq U, Mahajan RC. Drug resistance in malaria. J Vector Borne Dis 2004;41:45e53.
Quantum chemical analysis of alternative pathways 4. Indonesian Society of Medicine. Consensus of malaria management 2003 (part 2). Acta Med Indones 2004;36:187e93. 5. Woodrow CJ, Haynes RK, Krishna S. Artemisinins. Postgrad Med J 2005;81:71e8. 6. Meshnick SR. The mode of action of antimalarial endoperoxides. Trans R Soc Trop Med Hyg 1994;88(Suppl. 1):S31e2. 7. Van der Meersch H. Review of the use of artemisinin and its derivatives in the treatment of malaria. J Pharm Belg 2005; 60:23e9. 8. Goldberg DL. Bonding. In: Goldberg DL, editor. Chemistry. Singapore: McGraw Hill; 1989. p. 95e118. 9. Dupouy-Camet J. New drugs for the treatment of human parasitic protozoa. Parasitologia 2004;46:81e4.
151 10. Zhang F, Gosser Jr DK, Meshnick SR. Hemin-catalyzed decomposition of artemisinin (qinghaosu). Biochem Pharmacol 1992;43:1805e9. 11. Kapetanaki S, Varotsis C. Fourier transform infrared investigation of non-heme Fe(III) and Fe(II) decomposition of artemisinin and of a simplified trioxane alcohol. J Med Chem 2001;44:3150e6. 12. Jung M, Lee K, Kim H, Park M. Recent advances in artemisinin and its derivatives as antimalarial and antitumor agents. Curr Med Chem 2004;11:1265e84. 13. Sriram D, Rao VS, Chandrasekhara KV, Yogeeswari P. Progress in the research of artemisinin and its analogues as antimalarials: an update. Nat Prod Res 2004;18:503e27.