Methemoglobinemia Hemotoxicity of Some Antimalarial 8

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Methemoglobinemia Hemotoxicity of Some Antimalarial 8Aminoquinoline Analogues and Their Hydroxylated Derivatives: Density Functional Theory Computation of Ionization Potentials Yuanqing Ding, Haining Liu, Babu L Tekwani, N. P. Dhammika Nanayakkara, Ikhlas A Khan, Larry A. Walker, and Robert John Doerksen Chem. Res. Toxicol., Just Accepted Manuscript • DOI: 10.1021/acs.chemrestox.6b00063 • Publication Date (Web): 25 May 2016 Downloaded from http://pubs.acs.org on June 5, 2016

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Chemical Research in Toxicology

Methemoglobinemia

Hemotoxicity

of

Some

Antimalarial 8-Aminoquinoline Analogues and Their Hydroxylated

Derivatives:

Density

Functional

Theory Computation of Ionization Potentials

Yuanqing Ding,1 Haining Liu,2,† Babu L. Tekwani,1,2, N. P. Dhammika Nanayakkara,1 Ikhlas A. Khan,1,2 Larry A. Walker1,2,* and Robert J. Doerksen,1,2,* 1

National Center for Natural Products Research, Research Institute of Pharmaceutical Science, 2

Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, University, MS 38677, USA

Corresponding Authors *E-mail: [email protected]. Tel: (+1) 662-915-1005 *E-mail: [email protected]. Tel: (+1) 662-915-5880 †

Current address: Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, USA

ACS Paragon Plus Environment


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ABSTRACT The administration of primaquine (PQ), an essential drug for treatment and radical cure of malaria, can lead to methemoglobin formation and life-threatening hemolysis for glucose-6phosphate dehydrogenase deficient patients. The ionization potential (IP, a quantitative measure of the ability to lose an electron) of the metabolites generated by antimalarial 8-aminoquinoline (8-AQ) drugs like PQ has been believed to be correlated in part to this methemoglobinemia hemotoxicity: the lower the IP of an 8-AQ derivative, the more methemoglobin will be generated. In this work, demethoxylated primaquine (AQ02) was employed as a model, by intensive computation at the B3LYP-SCRF(PCM)/6-311++G**//B3LYP/6-31G** level in water, to study the effects of hydroxylation at various positions on the ionization potential. Compared to the parent AQ02, the IPs of AQ02’s metabolites hydroxylated at N1', C5, and C7 were lower by 61, 30, and 19 kJ/mol, respectively, while differences in the IP relative to PQ were small for hydroxylation at all other positions. The C6 position, at which the IP of the hydroxylated metabolite was greater than that of AQ02, by 2 kJ/mol, was found to be unique. Several literature and proposed 8-AQ analogs were studied to evaluate substituent effects on their potential to generate methemoglobin, with the finding that hydroxylations at N1' and C5 contribute the most to the potential hemotoxicity of PQ-based antimalarials, whereas hydroxylation at C7 has little effect. Phenoxylation at C5 in PQ-based 8-AQs can block the hydroxylation at C5 and reduce the potential for methemoglobin generation, while –CF3 and chlorines attached to the phenolic ring can further reduce the risk. The H-shift at N1' during the cationization of hydroxylated metabolites of 8-AQs sharply decreased their IPs, but this effect can be significantly reduced by the introduction of an electron-withdrawing group to the


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quinoline core. The results and this approach may be utilized for design of safer antimalarial 8AQ analogs.



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INTRODUCTION Malaria is one of the most prevalent infectious diseases, and was responsible for an estimated global peak of >1.8 million deaths in 2004.1 Currently, the only FDA-approved drug for the radical cure of relapsing Plasmodium vivax malaria is primaquine (PQ, Scheme 1), an 8aminoquinoline (8-AQ) first synthesized in 1946.2 PQ is also used as a prophylactic drug against all major forms of human malaria3 and has been found to have significant sporontocidal and gametocytocidal activity, which extend the utility of this drug for prevention of malarial transmission.4, 5 Despite the great success of using PQ for treatment and radical cure of malaria clinically, a serious problem of this class of drugs is the potentially fatal hemolysis6 which is caused in patients with genetic deficiency of glucose-6-phosphate dehydrogenase (G6PD),7 a deficiency found in hundreds of millions of people.8 A hallmark feature of the hemolysis caused by PQ administration to those patients is methemoglobinemia, which may be predictably induced by the reactive hydroxylated metabolites of PQ. Such metabolites are able to oxidize hemoglobin to methemoglobin, hence lowering the oxygen-carrying capacity of the blood.9-12 Among a number of metabolites of PQ (Scheme 1),13-21 it has been found that 5-hydroxyprimaquine (5OH-PQ), 5,6-dihydroxyprimaquine (5,6-2OH-PQ) and 6-methoxy-8-(N-hydroxy)aminoquinoline (6-MeO-8-(N-OH)-AQ) generate more methemoglobin than the parent PQ molecule.19,

20

In

contrast, carboxyprimaquine (cPQ) and 6-methoxy-8-aminoquinoline (6-MeO-8-AQ) result in less methemoglobin formation than PQ,12, 20, 22 and are hence considered to be non-hemotoxic metabolites of PQ. Because of this danger of administering PQ to G6PD-deficient patients, the development of new and less hemotoxic antimalarial drugs has attracted considerable interest.5 Recently, a number of


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8-AQ analogs have been studied in detail as antimalarial candidates.23-27 Among these, tafenoquine (TQ) is presently in phase II/III clinical trials and has been shown to be able to provide radical cure with a single dose (Scheme 2).28 An enantiomerically pure 8-AQ analog, NPC1161B, the (R)-isomer of NPC1161 (Scheme 2), has shown better antimalarial efficacy and lower hemotoxicity than PQ in animal models.29-31 NPC1161B is also significantly active against Leishmania29, 31-33 and Pneumocystis carinii infections.5, 29, 31 TQ was found to have a much longer half-life than PQ, such that it was sufficient to administer it once weekly or monthly for prophylaxis.34-42 However, use of TQ is still not safe for G6PD-deficient individuals. New 8-AQ analogs have shown improved antimalarial efficacies in animal models, but the potential hemotoxicity of these compounds is still a major concern. It is hence of significant importance to understand and predict the potential hemotoxicity of 8-AQ antimalarials. Recently, we proposed a mechanism according to which methemoglobin-forming potential is determined in part by the ability of 8-AQ derivatives to lose an electron, i.e., the higher the ionization potential (IP) of the compound, the lower the methemoglobin formation it will cause.43-46 Furthermore, we also employed intensive computational approaches to evaluate the potential hemotoxicity, feasibility of formation, and regioselectivity of formation of hydroxylated metabolites of NPC1161,47 and analyzed the effect of exocyclic substituents on the IP of primaquine.48 In the studies described in this paper, demethoxylated primaquine (AQ02) was employed as a model to investigate the effects on IP of hydroxylation at different positions. Further, the methemoglobin-forming potentials of a few 8-AQ analogs selected from literature reports (PQ, TQ, WR225448,49 and WR24970050) and of theoretically designed 8-AQ analogs



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(AQ01, AQ03, AQ04, and AQ05) and their hydroxylated derivatives were also predicted by employing computed IPs. COMPUTATIONAL METHODS AND SOFTWARE PACKAGES The 8-AQs employed in this study include literature analogues PQ, NPC1161, TQ, WR225448, and WR249700, as well as theoretically designed structures AQ01, AQ02, AQ03, AQ04, and AQ05 (Scheme 2). The geometry of a major conformer with extended side chain, found in our former conformational search for NPC1161,47 was selected as a starting point for geometry optimization of the above compounds at the B3LYP/6-31G** level in the gas phase. The substituents (-OH, -OMe, -OPh, -CF3, -Cl, etc.) were manually attached to or removed from positions such as C2, C5, C6, C7, and N1', if available for substitution/removal. The obtained structures of neutral species were then used as starting points for geometry optimization of cationized species at the same level. The formed species are radical cations having a single unpaired electron. Single point energies of the neutral and cationized species were calculated at the B3LYP/6-311++G**//B3LYP/6-31G** level in the gas phase, and at the B3LYPSCRF(PCM)/6-311++G**//B3LYP/6-31G** in water. The ionization potentials for each case were computed at the above levels, in which the zero-point vibrational energies (ZPVEs) at the B3LYP/6-31G** level in the gas phase were included. The ionization potentials (IPs) were calculated according to the following definition: IP = E(radical cation) − E(neutral) All computations were performed using the Gaussian 09 software packages.51 As we believe the data obtained at the B3LYP-SCRF(PCM)/6-311++G**//B3LYP/6-31G** in water to be the most


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accurate and reliable,47 hereafter if not mentioned elsewhere, the results from the solvation calculations at this level are presented and discussed, whereas those at all other levels are provided in the Supporting Information. As the properties we studied in this work are identical for enantiomers, only the calculations for the S-configurations (e.g., NPC1161A for NPC1161) were performed. RESULTS AND DISCUSSION Ionization Potentials of Primaquine (PQ) and Its Hydroxylated Metabolites. Since 5-OHPQ, 5,6-2OH-PQ and 6-MeO-8-(N-OH)-AQ have been found to generate more methemoglobin than the parent PQ molecule19, 20 and the metabolite hydroxylated at the N1' position was, on theoretical grounds, proposed to contribute the most to the methemoglobinemia hemotoxicity of NPC1161,47 we first calculated the IPs of the parent PQ and its metabolites hydroxylated at C5 and N1', and also considered the C2 and C7 positions in order to have a comparison. In a previous paper, we reported hydroxylation effects on the ionization potential of PQ, only, but in that work we used a different conformation and level of theory. The optimized geometries of the parent PQ and its hydroxylated metabolites for this work were obtained by the protocols described in the Methods section and are depicted in Figure 1, together with their calculated highest occupied molecular orbitals (HOMOs) calculated at the B3LYP/6-31G** level in the gas phase. Their calculated absolute and relative ionization potentials (IPs and ∆IPs, respectively) are listed in Table 1. The calculated IP of 5-OH-PQ is 34.88 kJ/mol below that of PQ at the B3LYP-SCRF(PCM)/6311++G**//B3LYP/6-31G** level in water (Scheme 3). When replacing the 5-hydroxyl in 5-



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OH-PQ with 5-phenoxyl, forming AQ01, the calculated IP increases to 16.15 kJ/mol below that of PQ. After attaching two chlorines to the phenoxyl ring to form NPC1161, the calculated IP lies only 9.20 kJ/mol below that of PQ.47 These findings indicate that hydroxylation at the C5 position in PQ is predicted significantly to increase the hemotoxicity relative to PQ, the introduction of the phenoxyl to the C5 position in AQ01 helps reduce this risk, and the inclusion of two chlorines on the phenoxyl in NPC1161 further reduces the risk. For metabolites of PQ hydroxylated at the C2 and C7 positions (2-OH-PQ and 7-OH-PQ), their calculated IPs lie only 9.08 and 9.86 kJ/mol, respectively, below that of PQ. When the hydroxylation occurs at the N1' position (N1'-OH-PQ), the metabolite’s calculated IP dramatically decreases to 52.96 kJ/mol below that of PQ, i.e., 18.08 kJ/mol lower than that of 5OH-PQ, indicating that hydroxylation at N1' has the greatest predicted contribution to methemoglobin formation. The calculated IPs strongly support the experimental observations of higher hemotoxicity of 5OH-PQ, 5,6-2OH-PQ and 6-MeO-8-(N-OH)-AQ compared to PQ.19, 20 This phenomenon may be attributed to the high electron density at the C5 and N1' positions in the HOMO (highest occupied molecular orbital) of both the neutral parent and hydroxylated PQs (Figure 1). The extremely high hemotoxicity of N1'-OH-PQ may be related to the hydrogen shift (H-shift) from OH at N1' in the neutral form to N1 in the cation (Figure 1). In changing to the cationized form, with loss of an electron, the distances (N1'O)H···N1 and N1'-O shorten from 1.73 and 1.43 Å, respectively, in the neutral form (N1'-OH-PQ in Figure 1) to 1.04 and 1.29 Å, respectively, in the cation (N1'-OH-PQ+ in Figure 1), and the (N1')O···H distance elongates from 0.99 Å in the


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neutral form to 1.66 Å in the cation. Similar H-shifts and extremely low IPs were also observed in the metabolite of NPC1161 hydroxylated at N1'47 and other 8-AQs analogs studied below. Ionization Potentials of AQ02 and Its Hydroxylated Metabolites. In order to examine systematically the hydroxylation position effects on predicted methemoglobinemia, we manually replaced the methoxyl at C6 in PQ with a hydrogen (to form a molecule denoted as AQ02), and calculated the IPs for AQ02 and its hydroxylated metabolites. The optimized geometries of parent and hydroxylated AQ02 are depicted in Figure 2 together with the calculated HOMO of AQ02. Their calculated IPs and ∆IPs are listed in Table 2. The calculated IP of AQ02 is 7.79 kJ/mol above that of PQ, with the only structural difference being that AQ02 does not have the methoxyl at C6 found in PQ (Scheme 3). The IPs of AQ02 hydroxylated at C2, C3, and C4 are just 4.71, 2.13, and 3.42 kJ/mol, respectively, less than that of AQ02, implying that hydroxylation at these positions will have a negligible effect on increasing the hemotoxicity of AQ02. The calculated IPs of 7-OH-AQ02, 5-OH-AQ02, and N1'OH-AQ02 lie 19.09, 30.42, and 61.18 kJ/mol, respectively, below that of AQ02, indicating that other than the hydroxylations at C5 and N1', the hydroxylation at C7 also is predicted prominently to increase the hemotoxicity of AQ02. Molecular orbital analysis at the B3LYP/631G** level in the gas phase shows high electron density in the p atomic orbitals at N1', C5, and C7, which are major contributors to the HOMO of neutral AQ02 (Figure 2). Mulliken population analysis at the B3LYP/6-311++G** level in the gas phase indicates that the top three fractional contributions to the HOMO of neutral AQ02 are 0.28, 0.22, and 0.18, from the p atomic orbitals of N1', C5, and C7, respectively (Table 3).



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Similarly, the extremely low IP for N1'-OH-AQ02 may be attributed to the H-shift (Figure 2). The structures of neutral and cationized N1'-OH-AQ02 are very similar to those of neutral and cationized N1'-OH-PQ. Along with the cationization of N1'-OH-AQ02, the distances (N1'O)H···N1 and N1'-O shorten from 1.76 and 1.43 Å, respectively, in the neutral form (N1'OH-AQ02 in Figure 2) to 1.04 and 1.29 Å, respectively, in the cation (N1'-OH-AQ02+ in Figure 2), and the (N1')O···H distance elongates from 0.99 Å in the neutral form to 1.65 Å in the cation. It is noticeable that C6 is a unique position in the quinoline core, as hydroxylation at this position does not increase but rather slightly decreases the predicted hemotoxicity of AQ02, as evidenced by the analysis that the calculated IP of 6-OH-AQ02 is 1.62 kJ/mol higher than that of AQ02. Ionization Potentials of WR238605, WR225448, and WR249700 and Their Hydroxylated Metabolites. Three lead 8-AQ analogs, namely WR238605 (tafenoquine, or TQ), WR225448, and WR249700, which have shown markedly improved antimalarial efficacy compared to PQ, were selected for computational studies. The optimized geometries and calculated HOMOs of the parents and their metabolites hydroxylated at the C2, C7 or N1' position, if able to be substituted at those positions, are depicted in Figure 3, while their calculated IPs and ∆IPs are listed in Table 4. The optimized geometries are similar to those of the 8-AQs described above, and they underwent a similar H-shift to N1 in their hydroxylated metabolite cations. Molecular orbital analysis showed that high electron density was maintained at the C5 and N1' positions in the HOMOs of these 8-AQ analogs and their respective hydroxylated metabolites. The structural difference between WR225448 and NPC1161 is the substituent attached to the phenoxyl ring at C5, specifically one –CF3 in WR225448 instead of two chlorines in NPC1161. The calculated IP of WR225448 lies only 1.09 kJ/mol (Scheme 3) below that of NPC1161.


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Comparing their structures and IPs with those of AQ01, one can find that the IP increase caused by –CF3 in WR225448 is similar to that caused by the two chlorines in NPC1161. The introduction of a methyl at N1' in WR225448, forming WR249700, does not make a significant difference from the viewpoint of predicted hemotoxicity of these two analogs. This is evident from their calculated IPs, which differ only by 2.13, 2.17, and 1.25 kJ/mol from those of their parent and its metabolites hydroxylated at C2 and C7, respectively. However, introduction of the methyl blocks hydroxylation at N1' in WR249700, which contributes the most to the predicted hemotoxicity of WR225448 since the calculated IP of N1'-OH-WR225448 is 44.06 kJ/mol lower than that of WR225448. Compared to WR225448, an additional methoxyl group is attached to C2 in TQ, with the consequence that the calculated IP of TQ lies 10.34 kJ/mol below that of WR225448. The calculated IP of TQ is also ~10 kJ/mol below those of NPC1161, WR249700, 2-OH-PQ and 7OH-PQ, and 20.63 kJ/mol below that of PQ, but 14.26 kJ/mol above that of 5-OH-PQ. Similarly, when a methoxyl moiety is attached to C2 in NPC1161 (denoted as AQ03), it also decreases the IP moderately, by 10.55 kJ/mol, such that the calculated IP of AQ03 sits only 0.88 kJ/mol above that of TQ, but lies 4.19 kJ/mol below that of 2-OH-NPC1161. The slight IP difference between TQ and AQ03 confirms that the –CF3 in TQ and the chlorines in NPC1161 play similar roles in reduction of predicted hemotoxicity, and further suggests that metabolites of NPC1161 and TQ will have similar hemotoxicity, if hydroxylation occurs at C2 in NPC1161, forming 2-OHNPC1161, and then further occurs at the N1' position in both 2-OH-NPC1161 and TQ, forming 2,N1'-2OH-NPC1161 and N1'-OH-TQ. The calculated IP of N1'-OH-TQ lies only 0.69 kJ/mol below that of N1'-OH-AQ03, which should be very close to the IP of 2,N1'-2OH-NPC1161.



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Noticeably, for the metabolites of the above-mentioned 8-AQs hydroxylated at the N1' position, the geometries of their cationized forms, after optimization, were similar, whereas those of their neutral forms were quite different. Specifically, the N1···H(ON1') distances in the neutral N1'OH-TQ and N1'-OH-AQ03 were both 1.44 Å, being 0.29, 0.32, and 0.28 Å shorter, respectively, than those in N1'-OH-PQ, N1'-OH-AQ02, and N1'-OH-WR225448. The (N1)H···O(N1') and (N1H)O···N1' distances in the neutral N1'-OH-TQ and N1'-OH-AQ03 were 0.08 Å longer and 0.09 Å shorter, respectively, than those in the neutral N1'-OH-PQ, N1'-OH-AQ02, and N1'-OHWR225448. This geometric difference may be attributed to the methoxyl substituent at C2 in N1'-OH-TQ and N1'-OH-AQ03, contrasted to a hydrogen at this position in N1'-OH-PQ, N1'OH-AQ02, and N1'-OH-WR225448. In order to confirm the uniqueness of the C6 position and the prominent contribution by the substituent at C7, as found in AQ02, the methoxyl at C6 in AQ03 was moved to C7 to form AQ04. The calculated IP of AQ04 is 18.47 kJ/mol lower than that of AQ03. This difference is very similar to the IP decrease from 6-OH-AQ02 to 7-OH-AQ02, which is 20.71 kJ/mol. This helps to confirm the uniqueness of the C6 position in the quinoline core of 8-AQs and the prediction that electron-donating substituents at C7 prominently increase the hemotoxicity of 8AQs. We can predict that the IP decrease caused by hydroxylation at C2 or C7 in WR analogs or AQ03 will be negligible. It should be emphasized again that, due to the H-shift from (N1')O to N1 as the cationization occurs, hydroxylation at N1' in the above 8-AQs is predicted similarly to contribute to their hemotoxicity. The calculated IPs of N1'-hydroxylated metabolites of PQ, NPC1161, AQ02, TQ,


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WR225448, and AQ03 are, respectively, 52.96, 53.57, 53.39, 54.86, 54.35, and 54.17 kJ/mol lower than that of PQ. These IPs differ by less than 2 kJ/mol. We have suggested that using electron-withdrawing groups (such as –CF3) as exocyclic substituents will reduce the hemotoxicity of 8-AQs, and hence lead to less hemotoxic antimalarials.48 Replacement of –OCH3 at C2 in TQ by –CF3 to form AQ05 yielded a calculated IP which is 16.17 and 26.51 kJ/mol higher than those of WR225448 and TQ, respectively. However, the IP of N1'-OH-AQ05 is 42.55 kJ/mol higher than that of N1'-OH-TQ, i.e., just 12.31 kJ/mol lower than that of PQ, indicating that the –CF3 at C2 is predicted significantly to reduce the potential methemoglobinemia hemotoxicity of AQ05. The optimized geometries of neutral and cationized N1'-OH-AQ05 were similar to those of neutral and cationized N1'hydroxylated metabolites of PQ, AQ02, and WR225448. A similar H-shift was also found to occur during the cationization of N1'-OH-AQ05. The distances (N1'O)H···N1 and N1'-O shorten from 1.79 and 1.42 Å, respectively, in the neutral form (N1'-OH-AQ05 in Figure 3) to 1.05 and 1.29 Å, respectively, in the cation (N1'-OH-AQ05+ in Figure 3), and the (N1')O···H distance elongates from 0.99 Å in the neutral form to 1.60 Å in the cation. CONCLUSIONS The ionization potentials (IPs) of the hydroxylated metabolites of antimalarial 8-aminoquinolines (8-AQ) are believed to be correlated in part to the methemoglobinemia hemotoxicity: the lower the IP value of an 8-AQ derivative, the more methemoglobin will be generated. C6 is a unique position in the quinoline core of 8-AQs, since hydroxylation at that position is predicted to decrease the hemotoxicity, while hydroxylation at all other positions is predicted to increase the



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hemotoxicity relative to the parent AQ02. Hydroxylations at N1', C5, and C7 are predicted to contribute the most to the hemotoxicity of AQ02, whereas contributions from hydroxylation at any other position are negligible. Molecular orbital and orbital population analyses show high electron density on and contribution from N1', C5, and C7 in the highest occupied molecular orbital of AQ02. Hydroxylation at C7 was predicted not significantly to increase the hemotoxicity of PQ-based 8-AQs. Interestingly, a phenoxyl group at C5 in 8-AQs not only blocks the hydroxylation at this position but also helps reduce the hemotoxicity, while chlorines and –CF3 attached to the phenolic core further reduce the hemotoxicity. Based on our calculated IPs, the extremely high hemotoxicity of the 8-AQs can be attributed to the H-shift to N1 during the cationization of their hydroxylated metabolites, and may be significantly reduced by the introduction of electron-withdrawing groups such as –CF3 to their quinoline core. FUNDING SOURCE This work was supported in part by the Joint Warfighter Medical Research Program (JWMRP), award No. W81XWH1020059 and W81XWH1320026 to the University of Mississippi, and the US Department of Agriculture-Agricultural Research Services Specific Cooperative Agreement No. 58-6408-2-0009. We thank the Mississippi Center for Supercomputing Research (MCSR) for computational facilities. This investigation was conducted in part in a facility constructed with support from Research Facilities Improvements Program (C06 RR-14503-01) from the NIH National Center for Research Resources. SUPPORTING INFORMATION


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Total energies and optimized xyz coordinates of neutral and ionized parent compounds and their derivatives from this work. This material is available free of charge via the Internet at http://pubs.acs.org. ABBREVIATIONS PQ, primaquine; IP, ionization potential; 8-AQ, 8-aminoquinoline; G6PD, glucose-6-phosphate dehydrogenase; TQ, tafenoquine; ZPVE, zero-point vibrational energy; HOMO, highest occupied molecular orbital. References (1)

Murray, C. J. L., Rosenfeld, L. C., Lim, S. S., Andrews, K. G., Foreman, K. J., Haring, D., Fullman, N., Naghavi, M., Lozano, R., and Lopez, A. D. (2012) Global malaria mortality between 1980 and 2010: a systematic analysis. Lancet 379, 413-431.

(2)

Panisko, D. M., and Keystone, J. S. (1990) Treatment of malaria - 1990. Drugs 39, 160189.

(3)

Baird, J. K., and Hoffman, S. L. (2004) Primaquine Therapy for Malaria. Clin. Infect. Dis. 39, 1336-1345

(4)

Rieckmann, K. H., McNamara, J. V., Kass, L., and Powell, R. D. (1969) Gametocytocidal and sporontocidal effects of primaquine upon two strains of Plasmodium falciparum. Mil. Med. 134, 802-819.

(5)

Tekwani, B. L., and Walker, L. A. (2006) 8-Aminoquinolines: future role as antiprotozoal drugs. Curr. Opin. Infect. Dis. 19, 623-631.

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24

Figures

PQ

2-OH-PQ

5-OH-PQ

7-OH-PQ

1.04

1.73

1.66 0.99

1.39

1.43

1.40

1.29

N1'-OH-PQ

N1'-OH-PQ +

NPC1161

AQ01

PQ

2-OH-PQ

5-OH-PQ

7-OH-PQ

N1'-OH-PQ

NPC1161

AQ01

Figure 1.


Page 25 of 30

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


25

AQ02

2-OH-AQ02

3-OH-AQ02

4-OH-AQ02

1.76

0.99

1.43 1.39

5-OH-AQ02

1.04

6-OH-AQ02

7-OH-AQ02

1.65

1.29 1.40

N1'-OH-AQ02+

AQ02

Figure 2.


N1'-OH-AQ02


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 26 of 30

26

1.05 1.63

1.44 1.07

1.40 1.29

1.37 1.34

TQ

7-OH-TQ

N1'-OH-TQ +

1'-OH-TQ

1.72 0.99 1.39 1.43

WR225448

2-OH-WR225448

7-OH-WR225448

N1'-OH-WR225448

WR249700

2-OH-WR249700

7-OH-WR249700

1.05 1.61 1.40 1.30

N1'-OH-WR225448 +

1.05 1.63

1.44 1.07 1.37

AQ03

7-OH-AQ03

1.40 1.29

1.34

N1'-OH-AQ03

N1'-OH-AQ03+

1.05 1.60

1.79 0.99 1.38 1.42

1.40

1.29

AQ04

AQ05

N1'-OH-AQ05

N1'-OH-AQ05+

TQ

N1'-OH-TQ

WR225448

N1'-OH-WR225448

WR249700

AQ03

N1'-OH-AQ03

AQ04

AQ05

N1'-OH-AQ05

Figure 3.


Page 27 of 30

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48


Schemes

Scheme 1



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48

Page 28 of 30

28

Scheme 2


Page 29 of 30

29

9.41 7.79

6-OH-AQ02

AQ02 4.37

0.00

5.88 5.65

AQ05

3-OH-AQ02

4-OH-AQ02

3.08 2-OH-AQ02

PQ

-9.08 2-OH-PQ -9.86

-9.20 NPC1161

7-OH-PQ -10.29

-11.30

-11.62

WR225448

7-OH-AQ02

7-OH-WR249700 -12.31

-12.43

-12.47 -12.88

7-OH-NPC1161

N1'-OH-AQ05

WR249700

7-OH-WR225448 -15.56

∆IP (kJ/mol)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48


2-OH-NPC1161

-15.87

-16.15

2-OH-WR225448

AQ01

-18.04 -19.12

2-OH-WR249700

7-OH-TQ

-19.75

-20.63 -22.64

-18.39 7-OH-AQ03 AQ03

TQ

5-OH-AQ02 -34.88 -38.22

5-OH-PQ

AQ04 -52.96 N1'-OH-PQ

-53.57 N1'-OH-NPC1161

Scheme 3

-53.39 N1'-OH-AQ02

-54.86 N1'-OH-TQ

-54.35 N1'-OH-WR225448


-54.17 N1'-OH-AQ03


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

250x151mm (72 x 72 DPI)


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Methemoglobinemia Hemotoxicity of Some Antimalarial 8

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