Stereoelectronic Properties of Antimalarial Artemisinin Analogues in

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Chem. Res. Toxicol. 1999, 12, 422-428

Stereoelectronic Properties of Antimalarial Artemisinin Analogues in Relation to Neurotoxicity Apurba K. Bhattacharjee and Jean M. Karle* Department of Pharmacology, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Washington, D.C. 20307-5100 Received September 9, 1998

Quantum chemical calculations on the molecular electronic structure of artemisinin (qinghaosu) and eight of its derivatives have resulted in stereoelectronic discriminators that differentiate between analogues with higher and lower neurotoxicities. Detailed ab initio quantum chemical calculations leading to complete optimization of geometry of each of the molecules were followed by calculation of their stereoelectronic properties using the 3-21G* split valence basis sets and comparison of the stereoelectronic properties to in vitro neurotoxicity. The least neurotoxic compounds are more polar with an electric field pointing away from the endoperoxide bond and have a higher positive potential on the van der Waals surface of the all carbon-containing ring C, a more stable peroxide bond to cleavage, a less negative electrostatic potential by the endoperoxide, and a single negative potential region extending beyond the van der Waals surface of the molecule. In general, higher intrinsic lipophilicity is associated with greater neurotoxicity.

Introduction Malaria continues to be a major endemic infectious disease in tropical and subtropical countries, requiring widespread research efforts aimed at its control and eradication. Almost 500 million people are annually infected with the disease, and about 2 million, mostly children, die every year (1). Of even greater concern is the ever-increasing multidrug resistance to current antimalarial drugs (2, 3). Artemisinin (1, qinghaosu, Figure 1) is an endoperoxide sesquiterpene derived from Chinese medicinal plants (4) used traditionally for the treatment of fever and malaria (5). Its structure and absolute configuration were determined by X-ray crystallography (6). A potent antimalarial agent artemisinin is active against multidrug resistant Plasmodium falciparum (7). The endoperoxide linkage is essential for its potency, and it is generally believed that the drug acts through a carbon-centered free radical mechanism where the free radicals are generated by iron and/or heme and alkylate essential parasite proteins or heme (8, 9). Artemisinin analogues are at various stages of preclinical and clinical studies and clinical use as a single agent or in combination with established antimalarial agents (10). Sodium artesunate, the hemisuccinate of the R-anomer of 9, artemether (7), and dihydroartemisinin (9) have been administered in China and Southeast Asia. The World Health Organization is currently sponsoring clinical studies with arteether (8), and the U.S. Army is completing preclinical studies with artelinic acid (6). However, in vivo toxicity studies in dogs, rats, and monkeys with intramuscularly injected artemether and arteether revealed a dose-dependent neurotoxicity associated with movement disturbances and spasticity (1113). Brewer et al. (11) found that dogs receiving total * Corresponding author.

10.1021/tx9802116

Figure 1. Chemical structure of artemisinin and eight analogues. The numbering and lettering scheme for selected atoms and rings is shown on compound 1.

doses as low as 160 mg/kg, and daily doses as low as 15 mg/kg, exhibited severe neurologic symptoms and neuropathologic lesions. Artemisinin analogues are also toxic to neuronal cells in vitro (14, 15). These observations of drug-induced neurotoxicity have generated a concern about ensuring the safety of these compounds for human use, particularly with repeated or continuous dosing. Since interactions between molecules are governed by their stereoelectronic attributes arising from the distribution of electrons, and not by atoms per se, the stereoelectronic properties of 1 and its analogues will have

This article not subject to U.S. Copyright. Published 1999 by the American Chemical Society Published on Web 04/09/1999

Stereoelectronic Predictors of Neurotoxicity

profound effects on their biological potency. Additionally, since the stereoelectronic properties of molecules are established by the three-dimensional placement of the atoms, molecular conformation and configuration also govern biological potency. Although some artemisinin analogues have been studied at the ab initio level (16, 17), these compounds were studied in relation to antimalarial potency, not neurotoxicity. The molecular configuration of 1 and its analogues have been shown to be important to neurotoxicity in vitro by Wesche et al. (15), who observed that stereoisomerism at position 10 of the artemisinin backbone influences the degree of neurotoxicity. As a continuation of our studies of the stereoelectronic properties of antimalarial agents (18, 19), this study was performed to develop a profile of quantum chemical descriptors of steric and electronic properties associated with neurotoxicity by artemisinin analogues and to improve the understanding of the molecular electronic structure of the artemisinin analogues. Although the data set is limited to the artemisinin analogues for which biological data are available (15), these analogues include the compounds that are the current focus in clinical studies. Certain electronic features of the most neurotoxic compounds differ from the less neurotoxic compounds, including molecular polarity, electrostatic potentials, and bond strength of the endoperoxide.

Methodology Computations. Initially, a conformational search analysis of each compound was made at the AM1 single-point level using Spartan version 5.0 (20) running on a Silicon Graphics Indigo Extreme R4000 workstation. The lowest-energy and most abundant (population density of >75%) conformers were chosen, and their geometry was fully optimized at the ab initio quantum chemical level using the 3-21G* split valence basis sets in Gaussian 94 (21) running on a Silicon Graphics R8000 workstation. Electronic properties such as molecular electrostatic potentials (MEPs1), dipole moment, highest occupied molecular orbitals (HOMOs), and lowest unoccupied molecular orbitals (LUMOs) were calculated on the 3-21G*-optimized geometry of the compounds and displayed graphically using Spartan. The effect of aqueous solvation on the compounds was calculated using the quantum mechanical solvent continuum reaction field (SCRF) method to simulate aqueous biological environments. In this method, the solvent is considered to be a continuum dielectric medium, which reacts against the solute charge distribution generating a reaction field and which is then introduced as a perturbation operator in the solute Hamiltonian. The method as implemented in Spartan is based on the SMx model of Dixon et al. (22). Molecular electrostatic potentials were sampled over the accessible surface of the molecule (surface of a constant 0.002 e/au3 electron density corresponding roughly to a van der Waals contact surface), providing a measure of charge distribution from the point of view of an approaching molecule. The regions of positive electrostatic potential represent excess positive charge, i.e., repulsion of the positively charged test probe, while regions of negative potential represent areas of excess negative charge, i.e., attraction of the positively charged test probe. Isopotential surfaces extending outward from the surface of each molecule at -10 kcal/mol were also generated. Homolytic scission of the endoperoxide bond on the optimized geometry of 1-9 was enforced in Spartan, and energy calculations on this species were performed using the 3-21G* split 1 Abbreviations: MEP, molecular electrostatic potential; HOMO, highest occupied molecular orbital; LUMO, lowest unoccupied molecular orbital.

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Figure 2. 3-21G*-optimized geometry of 1-9. The direction of the dipole moment is shown by the blue arrow with the tail end representing the positive end and the arrowhead representing the negative end of the dipole moment. The arrowhead points directly at the peroxide bond only for compounds 7-9. valence basis set. The protonation energy of the ester or ether analogues of 1 was determined by subtracting the ∆Hf of the unprotonated form from the ∆Hf of the compound protonated on the oxygen atom attached to C10 calculated using the 3-21G* split valence basis set. Neurotoxicity Evaluation. In vitro neurotoxicity was evaluated by Wesche et al. (15). Neurotoxicity was quantified as the concentration of the test compound that inhibited by 50% the uptake of radiolabeled leucine into mouse neuroblastoma-rat glioma hybrid NG108-15 cells growing in cultures. Compound 1 was arbitrarily assigned a toxicity of 1. The relative toxicity values used in this study represent the ratio of the 50% inhibitory concentration of 1 to the 50% inhibitory concentration of the analogue. The highest concentration assayed was 100 µM.

Results and Discussion Molecular Conformation. The ab initio 3-21G*optimized geometry of compounds 1-9 (Figure 2) matches the reported crystal structures of compounds 1, 3, 7, and 9 (6, 23-25) within 0.05 Å for bond lengths and 1.5° for bond angles (see the Supporting Information). For compounds 2-9 with a fully saturated D ring, the D ring is in a chair conformation with equatorial R-substituents and axial β-substituents in agreement with crystal structures (23). The semiempirical AM1-optimized geometry of compounds 1-9 poorly matches the crystalline geometry, demonstrating the necessity to optimize geometry at a higher level of theory. AM1-optimized geometry was particularly inaccurate about the peroxide bond resulting in O-O bond distances of only 1.28 Å, about 0.2 Å shorter than the 3-21G* calculated and observed O-O bond distances. Electronic Features Demonstrating a Relationship with Neurotoxicity. Lower molecular polarity (Table 1) and a dipole moment whose negative end points toward the endoperoxide moiety are associated with higher neurotoxicity. Figure 2 shows that the dipole moment points toward the endoperoxide moiety only for the three most neurotoxic compounds (7-9). The three most neurotoxic compounds have dipole moments of 5000 ng/mL.

Figure 3. Molecular electrostatic potential plotted onto the 0.002 e/au3 isodensity surface. The deepest blue is the most positive potential, and the deepest red is the most negative potential. The molecules are oriented in the same manner as shown in Figure 2 with O11 and O13 facing the viewer and the peroxide O1 and O2 atoms on the backside. The surface of ring C (upper right region) is less blue for compounds 7-9 than for compounds 1-6.

tween 3.5 and 7.8 D. The lower polarity of the three most neurotoxic compounds indicates that these compounds are more lipophilic or hydrophobic, enabling them to pass more freely through the central nervous system barrier by passive diffusion, as very polar compounds do not easily penetrate the central nervous system barrier (2628). The distribution of positive potential over the accessible surface of the molecules differs depending upon the relative neurotoxicity. MEPs plotted onto a 0.002 e/au3 electron isodensity surface (Figure 3) demonstrate that the surface over ring C for the less neurotoxic compounds (1-6) is lighter blue and, therefore, less positive than those for compounds 7-9. Additionally, the magnitude of the most positive potential over ring C for compounds 7-9 is less than 26 kcal/mol, whereas the most positive potential over ring C for compounds 1-6 is greater than 27 kcal/mol (Table 1), indicating a link between increased intrinsic electrophilicity and neurotoxicity. Widely distributed weak positive electrostatic field regions (green bands in Figure 4) on the accessible molecular surface of the more neurotoxic compounds (79) is an indication of large hydrophobic or lipophilic

Figure 4. Discrete bands of molecular electrostatic potential (MEP) plotted onto the 0.002 e/au3 isodensity surface of compound 2 (top row) and compound 8 (bottom row) with 8 displaying a much higher percentage of green regions than 2. Both sides of the molecules are shown. The blue band represents a MEP of greater than 10 kcal/mol; the green band represents a MEP between -10 and 10 kcal/mol, and the red band represents a MEP of less than -10 kcal/mol.

regions (29, 30). Lipophilicity of compounds is generally acknowledged as an important factor contributing to neurotoxicity (31), primarily because lipophilicity enables an easier passage through the blood-brain barrier (32, 33). Although the site for the most negative potential varies about the oxygen atoms in the molecules displaying no specific structure-activity pattern, the negative potential adjacent to the peroxide bond of the three most neurotoxic compounds is less than -44 kcal/mol (Table 1). The potentials for all other compounds are at least -41 kcal/ mol except for compound 4. This suggests an importance for the electron density about the peroxide bond for neurotoxicity. The three-dimensional electrostatic potential profiles beyond the van der Waals surface of the compounds at -10 kcal/mol are different for the more and less neurotoxic compounds (Figure 5). The less neurotoxic compounds (1-5) have only one large negative potential region extending from the trioxane ring to the lone pairs of the oxygen atom attached to C10. The more neurotoxic

Stereoelectronic Predictors of Neurotoxicity

Figure 5. Isopotential surfaces at -10 kcal/mol display only one surface about the artemisinin backbone for compounds 1-5.

compounds (7-9) possess two well-defined negative potential zones about the artemisinin backbone: by the trioxane ring system and by the C10 oxygen and C9 atoms. The electrostatic features beyond the van der Waals surface are considered to be the key features through which a drug recognizes its receptor at longer distances and hence promotes interaction between the complementary sites with the receptor. It is believed that these potential profiles of a molecule are primarily responsible for interaction with other systems in its vicinity (34). Thus, in this investigation, the more neurotoxic compounds are likely to experience two separate recognition interactions with the receptor rather than the singular recognition interaction for the less neurotoxic compounds. The exception is compound 6 which has two negative potential regions similar to the most neurotoxic compounds. However, 6 possesses a large electrostatic bulk by the carboxyl group which may mask the smaller electrostatic bulk by atom C10. Molecular Orbital Energy. Both the HOMO and the LUMO energies are small, ranging between -0.412 and -0.377 and 0.088 and 0.229 eV, respectively. This indicates the fragile nature of the bound electrons. Thus, 1-9 are likely to be very reactive as both rapid electron transfer and exchange are equally possible while the compounds are interacting with the receptor. Also, since a small HOMO-LUMO gap signifies less stability (26), 1-9 are likely to undergo changes in their charge distribution through rapid electron transfer between the HOMO and LUMO (35). However, the difference in the HOMO-LUMO gap between the most and least neurotoxic compounds appears to be too small at 6 . 2. A similar rank order was observed recently in an in vivo pharmacokinetic study involving compounds 6-8 and artesunic acid in rats (39). Metabolic transformation into 9 may acerbate the intrinsic neurotoxicity of these compounds in vivo. Desoxy Analogue of 1. When the endoperoxide of compound 1 is replaced by a single oxygen atom, the resulting cyclic ether loses both antimalarial activity and neurotoxicity (9, 15, 42, 43). Although the lack of a peroxide group may be sufficient to reduce neurotoxicity, three calculated stereoelectronic values of the desoxy analogue indicate that the desoxy analogue does not have the attributes to be highly neurotoxic. These values include a polarity of 5.96 D, a positive potential of 32.4

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kcal/mol on ring C, and a single extended negative electrostatic isopotential region (-10.0 kcal/mol) beyond the van der Waals surface. Electronic Features in Relation to Antimalarial Potencies of 1-9. The most neurotoxic compound (9) is also the most potent antimalarial in vitro (Table 1) (24, 43-46). However, in vitro antimalarial potency does not always correlate with in vitro neurotoxicity and does not have an apparent relationship with the energy required for scission of the peroxide bond and the MEP over either ring C or the peroxide bond despite the requirement of the peroxide moiety for high antimalarial potency (43). Antimalarial potency does have a relationship to the dipole moment and the aqueous solvent polarization energy where lower values appear to be more conducive to higher antimalarial potency. The inactive compound (3) with an IC50 of >5000 ng/mL has the largest dipole moment and relative aqueous polarization energy. Structural Aspects in Relation to Neurotoxicity. Stereoisomerism of the ethyl ether moiety of compounds 2 and 8 causes a 4-fold difference in the relative in vitro neurotoxicities and a corresponding difference in electronic properties (Table 1). Thermodynamically, compound 8 is about 5 kcal/mol more stable than 2. Relative to 2, 8 has a lower dipole moment with a clear tilt of the electric field direction toward the peroxide bond. Similarly, the aqueous polarization energy is nearly 9-fold lower. Thus, the greater intrinsic hydrophobic character of 8 with an electric field direction toward the peroxide bond may have a link with neurotoxic potency. In addition, the electrophilic nature of ring C (maximum positive potential over ring C) decreases by 7.2 kcal/mol at the same time as an increase in intrinsic nucleophilicity of the peroxide bond region by about 5.7 kcal/mol occurs. The different patterns of -10 kcal/mol isopotential surfaces surrounding 2 and 8 indicate a potentially altered recognition by approaching molecules. An identical trend of change in the above electronic properties is also observed between compounds 5 and 9 which differ chemically by the replacement of an oxirane ring in 3 with a methyl group in 9 at C9 and in neurotoxicity by >100-fold. Since the three most neurotoxic compounds (7-9) generally differ insignificantly in the calculated electronic properties listed in Table 1 despite large differences in their experimental in vitro neurotoxicity, differential interaction with specific receptors may be the reason for their marked difference in neurotoxicity. This hypothesis is consistent with the specificity of 7 and 8 to cause damage in specific regions of the brain (11, 13). The exceptional neurotoxic potency of compound 9 may be linked to specific binding affinity with receptor proteins. This binding affinity may be due to compound 9’s ability to form hydrogen bonds with a receptor as it has a favorable large positive potential (68.4 kcal/mol) localized at its hydroxyl proton. Compound 5, a less neurotoxic analogue with a hydroxyl group at C10, has an oxirane group at C9 which may interfere with specific interaction with the receptor as well as its other electronic attributes that indicate a hydrophilicity higher than those of 7-9. Lack of Correlation with CLogP Values. CLogP values calculated using MacLogP (47) have no apparent relationship with neurotoxicity. These empirically calculated values are 1.68, 2.77, 1.44, 2.59, 0.23, 3.92, 2.24, 2.77, and 1.78 for compounds 1-9, respectively. Experimentally determined partition coefficients for the

Bhattacharjee and Karle

artemisinin compounds have not been published. An examination of the CLogP values indicates inconsistencies with anticipated experimental partition values. Particularly dramatic is the CLogP value for compound 6, which has a carboxylic acid moiety, which is >100 times less soluble in water than compound 1 or 9, and the CLogP value for compound 5 indicating much greater water solubility than the other compounds. Another issue is whether the octanol/water partition coefficients of artemisinin compounds provide a reasonable estimate of the ability of the artemisinin compounds to pass through the blood-brain barrier. There is no way of knowing the answer without experimental octanol/ water partition and blood-brain partition values. However, other researchers have examined this question for other series of compounds. With histidine H2 antagonists, blood-brain partition values correlate best with experimentally determined cyclohexane/water partition coefficients, particularly when a calculated volume descriptor is included. Octanol/water partition coefficients did not correlate (48, 49).

Conclusion This study relates specific molecular electronic properties to the observed in vitro neurotoxicity of the artemisinin compounds providing a profile of electronic features associated with neurotoxicity and molecular level information of reactive centers such as the endoperoxide moiety. Not only is the peroxide bond necessary for significant neurotoxicity (15, 42), but stereoelectronic attributes related to the peroxide bond are associated with higher neurotoxicity. These include a lower energy requirement for breaking of the peroxide bond, a more negative potential over the peroxide O-O bond, and the molecule’s overall polarity pointing toward the peroxide bond. Thus, more potent in vitro neurotoxicity by artemisinin analogues for which experimental neurotoxicity data are available is associated with (1) an electric field direction with the negative end toward the endoperoxide bond, (2) a dipole moment of less than 3 D, (3) a positive potential of less than 26 kcal/mol in magnitude over ring C, (4) negative potential by the peroxide bond of less than -44 kcal/mol, (5) two large extended but distinctly localized negative potential regions beyond the van der Waals surface of the molecules, and (6) a less stable peroxide bond. This profile should aid in better understanding the mechanism of neurotoxicity and guide the design of safer artemisinin antimalarials. The greater lipophilicity or hydrophobicity of the more neurotoxic compounds as demonstrated by their lower polarity, less positive potential above ring C, and large areas of weak positive potential on the molecule’s accessible surface suggest a greater ease of passing through blood-brain barrier. Although decreasing dipole moment and aqueous polarization energy of the more neurotoxic compounds indicate a link between the hydrophobic nature and neurotoxicity, hydrophobicity alone does not explain the relative differences in neurotoxicity of compounds 7-9. The large differences in relative neurotoxicity created by differences in the substituents on C10 of compounds 7-9 strongly suggest the important role of the constraints of a receptor-ligand interaction.

Stereoelectronic Predictors of Neurotoxicity

Acknowledgment. We thank the National Research Council, Washington, DC, for their support of A.K.B. We gratefully acknowledge the suggestions of the reviewers regarding the improvement of the manuscript. Supporting Information Available: Calculated energies, bond distances, bond angles, and torsion angles for 1-9 with a comparison to structural parameter values obtained from crystal structures. This material is available free of charge via the Internet at http://pubs.acs.org.

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