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. Author manuscript; available in PMC: 2016 Aug 15.
Published in final edited form as: Bioorg Med Chem. 2015 Mar 4;23(16):5144–5150. doi: 10.1016/j.bmc.2015.02.050

Evaluation of spiropiperidine hydantoins as a novel class of antimalarial agents

Marvin J Meyers a,*, Elizabeth J Anderson a, Sarah A McNitt a, Thomas M Krenning a, Megh Singh a, Jing Xu b, Wentian Zeng b, Limei Qin c, Wanwan Xu c, Siting Zhao c, Li Qin c, Christopher S Eickhoff a, Jonathan Oliva a, Mary A Campbell a, Stacy D Arnett a, Michael J Prinsen a, David W Griggs a, Peter G Ruminski a, Daniel E Goldberg d, Ke Ding e, Xiaorong Liu b, Zhengchao Tu b, Micky D Tortorella b, Francis M Sverdrup a, Xiaoping Chen c,*
PMCID: PMC4550221  NIHMSID: NIHMS713405  PMID: 25797165

Abstract

Given the rise of parasite resistance to all currently used antimalarial drugs, the identification of novel chemotypes with unique mechanisms of action is of paramount importance. Since Plasmodium expresses a number of aspartic proteases necessary for its survival, we have mined antimalarial datasets for drug-like aspartic protease inhibitors. This effort led to the identification of spiropiperidine hydantoins, bearing similarity to known inhibitors of the human aspartic protease β-secretase (BACE), as new leads for antimalarial drug discovery. Spiropiperidine hydantoins have a dynamic structure-activity relationship profile with positions identified as being tolerant of a variety of substitution patterns as well as a key piperidine N-benzyl phenol pharmacophore. Lead compounds 4e (CWHM-123) and 12k (CWHM-505) are potent antimalarials with IC50 values against Plasmodium falciparum 3D7 of 0.310 μM and 0.099 μM, respectively, and the former features equivalent potency on the chloroquine-resistant Dd2 strain. Remarkably, these compounds do not inhibit human aspartic proteases BACE, cathepsins D and E, or Plasmodium plasmepsins II and IV despite their similarity to known BACE inhibitors. Although the current leads suffer from poor metabolic stability, they do fit into a drug-like chemical property space and provide a new class of potent antimalarial agents for further study.

Keywords: aspartic protease inhibitors, spiropiperidine hydantoins, antiplasmodial, antimalarial

Graphical Abstract

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1. Introduction

Malaria is caused by the parasite Plasmodium. In 2013, there were approximately 198 million cases of malaria leading to ~584,000 deaths, being particularly deadly to young children in sub-Saharan Africa.1 P. falciparum, the most lethal species, has developed varying degrees of resistance to all currently used antimalarial drugs.2–5 Approaches to combat parasite resistance include combination of antimalarial drugs as standard treatment regimens, as well as identification of new antimalarial drugs with unique mechanisms of action that can be combined with existing antimalarial drugs.

Plasmodium expresses a number of aspartic proteases necessary for its survival, including essential aspartic proteases Plasmepsin V (PMV or PM-5) and signal peptide peptidase (PfSPP).6–11 While a number of potent peptidomimetic inhibitors of Plasmodium aspartic proteases have been identified,7, 12–14 we have focused on repurposing classes of drug-like aspartic protease inhibitors developed by the pharmaceutical industry for human aspartic proteases such as β-secretase (BACE)15, 16 or renin.17

We have hypothesized that maintaining core structural motifs known to bind the aspartate residues in the active site may allow identification and optimization of novel classes of antimalarial compounds. Accordingly, we mined the Tres Cantos Anti-Malarial dataset (TCAMS) representing thousands of compounds18 for drug-like aspartic protease inhibitors. For example, we recently reported our identification and initial optimization of aminohydantoins as novel antimalarial compounds with selectivity for Plasmodium and in vivo antimalarial efficacy (e.g., CWHM-117) originating from BACE inhibitor 1 and database hit TCMDC-136879 (Figure 1a).19

Figure 1.

Figure 1

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Strategy to identify drug-like aspartic protease inhibitors as novel antimalarials.

Spiropiperidine-containing compounds such as 2 and 3 have been reported as non-peptidomimetic BACE inhibitors16, 20–22 and represent a novel scaffold for development of new antimalarial aspartic protease inhibitors (Figure 1b). The reported x-ray crystal structure of 2 (3FKT)16 demonstrates the mechanism by which the protonated piperidine nitrogen forms a salt bridge with a water molecule in the active site. Similarly, other related piperidine and pyrrolidine BACE, renin and HIV protease inhibitor crystal structures demonstrate similar binding modes,17, 23 leading us to hypothesize that the spiropiperidine scaffold may be an appropriate core for mining antimalarial phenotypic screening databases. Substructure-based searching of the TCAMS revealed a single hit, TCMDC-124587 (4a), with a reported XC50 of 0.840 μM. Given its modest molecular weight, favorable CLogP, and submicromolar antimalarial potency, an effort to validate this hit and evaluate the potential of this class of spiropiperidines as antimalarials was initiated.

2. Results and discussion

2.1. Validation of hit and initial SAR

Searches of commercially available compound databases revealed that TCMDC-124587 and closely-related analogs could be purchased from ChemBridge. Most commericially-available compounds were derivatized at the R8 position. Two iterations of sets of six spiropiperidines each, including TCMDC-124587, were purchased and evaluated for inhibition of parasite growth in P. falciparum 3D7-infected red blood cells. Key structure-activity relationships are shown in Figure 2. Of foremost importance, 4a was found to have similar 3D7 potency (IC50 = 0.940 μM) as reported in the screening dataset. Substituent position was found to be important. For example, moving the methoxy group from the 4′- to the 3′- or 5′-positions resulted in 6-fold loss or 2-fold improvement in potency, respectively (4b,c). While deletion of the methoxy group (4d) did not have a significant impact on potency, replacement with chlorine (4e) gave about a five-fold improvement in potency. Most striking is the dependence of potency on the presence of the phenol moiety. Capping the phenol with a methyl group (4g) or deletion (4f,h) led to 8- to 60-fold losses in potency.

Figure 2.

Figure 2

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Preliminary R8 Structure-Activity Relationships. Reported potencies are IC50 values in P. falciparum 3D7 infected erythrocytes.

The antimalarial activity of lead compound was determined to not be due to general cytoxicity (HepG2 72 h cytoxicity IC50 = 37 μM), having a selectivity index of >100-fold. We were further encouraged by identification of 4e in the Novartis-GNF antimalarial screening hit collection (GNF-Pf-5345, reported EC50 = 0.349 μM), although only a few related compounds were present in this collection.24 These data, along with the demonstration of a discrete SAR, encouraged us to investigate this class further by resynthesizing lead compound 4e and broadening the SAR.

2.2. Synthesis

The synthesis of 4e and related analogs is shown in Scheme 1. The spirohydantoin core 6 was prepared as previously described.25 The R3 alkyl group was then incorporated by simple alkylation with potassium carbonate. Subsequent alkylation with sodium hydride and R1X, followed by deprotection of the BOC group afforded intermediate 9. Finally, reductive amination provided R8 analogs such as 4e, 10a–b, 10d–e, 10g–i, 11a–d and 12a–u. Additionally, some R8 analogs were prepared from 8 standard amide coupling or alkylation conditions.

Scheme 1.

Scheme 1

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Reagents and Conditions: (a) KCN, (NH4)2CO3, aq. MeOH; (b) R3X, K2CO3, DMF; (c) NaH, R1X, DMF; (d) ArI, CuI, 2,2,6,6-tetramethyl-3,5-heptanedione, Cs2CO3; (e) HCl or TFA; (f) RCHO, Na(OAc)3BH, DMF; (g) RCO2H, EDC, HOBt, NEM, DCM; (h) R8Br, K2CO3, CH3CN.

Sterically hindered or otherwise incompatible R1 analogs were prepared instead by the approach reported by Carrera and Garvey26 shown in Scheme 2. In brief, the primary R1 amine is condensed with ketone 13 to furnish α-amino nitriles 14. Condensation with potassium cyanate and ring closure gives access to mono-substituted hydantoins 15. Subsequent alkylation, deprotection and reductive amination provided the final compounds 10c and 10f.

Scheme 2.

Scheme 2

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Reagents and Conditions: (a) R1NH2-HCl, KCN, aq. MeOH; (b) i. KOCN, AcOH, H2O; ii. aq. HCl; (c) NaH, EtI, DMF; (d) KOH, EtOH; (e) RCHO, Na(OAc)3BH, DMF

2.3. Structure-Activity Relationship Studies

Structure-activity relationships in the Pf3D7-infected red blood cell assay for R1 and R3 derivatives are shown in Figures 3 and 4. Resynthesized 4e was found to have a similar IC50 value as the commercial lot and was used a reference compound for subsequent SAR studies. Keeping R8 constant as the 5′-chloro-2′-hydoxybenzyl group, R1 and R3 were varied independently. R1 proved tolerant of modification provided that the substituents remained suitably large and flexible. For example, replacement of the isopentyl (4e) with hydrogen (10a) or ethyl (10b) led to a 20-fold or greater reduction in potency. Similarly, substitution with a phenyl ring (10d) proved detrimental to potency while cyclopentyl (10c) was well tolerated. This is presumably due to the rigidity of the phenyl ring since extension with one (10e) or two (10f) methylene linkers were roughly equipotent with the isopentyl group. Benzyl analogs with electron donating (10g) or withdrawing (10h,i) groups were tolerated with some modest effects on potency.

Figure 3. R1 Structure-Activity Relationships.

Figure 3

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Reported potencies are IC50 values in P. falciparum 3D7 infected erythrocytes.

Figure 4. R3 Structure-Activity Relationships.

Figure 4

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Reported potencies are IC50 values in P. falciparum 3D7 infected erythrocytes.

SAR at the R3 position also showed tolerance for a variety of lipophilic groups (Figure 4). Deletion of the ethyl group (11a) led to a dramatic loss in activity. Conversely, the ethyl group could be replaced with larger groups such as isopropyl (11b), which improved potency three-fold, or CH2-pyridyl (11c) and (CH2)3-pyridyl (11d) with only modest two-three-fold losses of potency.

Given the relative flexibility in SAR in the R1 and R3 positions, we elected to focus on expanding the more sensitive SAR in the R8 position (Figure 5). Moving the phenolic hydroxyl group to the 3′- or 4′-positions proved to be increasingly detrimental to 3D7 potency (12a,b) but not as dramatically as deletion of the hydroxyl group (4f). In contrast, the chlorine atom could be replaced by a variety of substituents. For example, while F is not an equivalent replacement (12c), bromo, methyl, and phenyl replacements are all well tolerated (12d,e,f).

Figure 5. Preliminary R8 Structure-Activity Relationships.

Figure 5

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Reported potencies are IC50 values in P. falciparum 3D7 infected erythrocytes.

Positioning of the chlorine atom was found to be important for optimal 3D7 potency for this series. 6′-Chloro analog 12g was found to be essentially equipotent to the 5′-chloro 4e. In contrast, the 3′-chloro and 4′-chloro analogs (12h,i) were three- to seven-fold less potent. 3′,5′-Dichloro and 5′,6′-dichloro analogs (12j,l) were equipotent to the 5′-chloro compound 4e. Interestingly, with an IC50 of 0.090 μM, 4′,5′-dichloro analog 12k proved to be the most potent compound we identified in this series.

To further refine our understanding of the importance of the basic amine and benzylic phenol functionalities, we prepared amide analog 12m. The lack of 3D7 potency of analog 12m, a direct comparator to lead 4e, demonstrates the importance of basic amine to the anti-plasmodium pharmacophore. This result is consistent with the hypothesis that these compounds may be inhibiting an aspartic protease, similar to their BACE-inhibiting predecessors 2 and 3. However, the basic amine functionality alone is not sufficient for potency as demonstrated by deletion analog 12n and phenol replacements and isosteres (12o-u) which were not efficacious up to 10 μM. The only phenol replacement to give a hint of potency was indole 12u.

2.4. Inhibition of Aspartic Proteases, Cytotoxicity and Mechanism of Action

We evaluated twelve of these compounds for inhibition against a panel of aspartic proteases: human proteases BACE-1, cathepsin D (CatD) and cathepsin E (CatE), as well as plasmodium proteases plasmepsin II and IV (PM-II and PM-IV). Remarkably, all twelve compounds had no inhibitory activity on these aspartic proteases up to 10 μM. Our previously described series,19 the aminohydantoins, represented by CWHM-117, are also not potent against human aspartic proteases, but exhibit low nanomolar inhibition of plasmepsins II and IV. This selectivity result is encouraging from a toxicology and drug discovery standpoint but calls into question whether these compounds are acting through an aspartic protease mechanism.

In addition to compound 4e, compounds 12f, 12h, and 12k were evaluated for cytotoxicity in HepG2 cells. All three compounds exhibited IC50 values >50 μM, corresponding to a selectivity index of greater than 500 for 12k.

The mechanism of action of these compounds is currently unknown. Notably, spiropiperidine 4e is equipotent against both chloroquine-sensitive (3D7) and multidrug-resistant (Dd2) strains of P. falciparum (3D7 IC50 = 0.31 μM; Dd2 IC50 = 0.22 μM). The Dd2 strain is resistant to antimalarial drugs chloroquine, quinine, pyrimethamine, and sulfadoxine.27 Thus, the mechanism of action of these spiropiperidine hydantoins appears to be unique and is not due to pathways affected by these existing agents.

2.5. Pharmacokinetic Profile

Finally, we evaluated the pharmacokinetic (PK) properties of this novel series of antimalarials. A subset of analogs were assessed for metabolic stability in mouse, rat and human liver microsome assays (MLM, RLM and HLM, respectively). Figure 6 depicts relationships between antimalarial activity, metabolic stability and lipophilicity. All of the compounds evaluated herein fall within generally acceptable lipophilicity ranges for druglike compounds (Fig. 6a). Not surprisingly, there is a correlation between lipophilicity and 3D7 potency with the more lipophilic compounds being generally more potent.

Figure 6. Relationship between 3D7 potency, metabolic stability and lipophilicity.

Figure 6

Figure 6

Figure 6

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(A) Plot of Pf 3D7 potency as a function of CLogP. (B) Plot of Pf 3D7 potency versus metabolic stability in mouse, rat and human liver microsomes (MLM, RLM and HLM). (C) Plot of metabolic stability in liver microsomes as a function of CLogP.

Most of the compounds evaluated have poor metabolic stability in liver microsomes with half-lives typically less than 10 minutes, regardless of species (Fig 6b). A handful of analogs, however, are metabolically stable (12n,o,r) but are not potent in the 3D7 assay. These stable compounds all have CLogP values of approximately 1.0 and do not contain an N-benzyl group. This data suggests that the metabolic stability for this series of compounds requires either compounds with low CLogP (less than 2), non-benzylic amines or a combination of both features.

Lead compound 4e was also evaluated in vivo in a rat PK experiment to determine if in vitro liver microsome assays are predictive of in vivo PK properties. Compound 4e has short half-lives in vitro (MLM, RLM and HLM t1/2 = 4.0, 3.0 and 9.0 min, respectively) and in vivo (rat PK t1/2 = 0.28 h, CL = 152 mL/min/kg, Vd = 3.7 L/kg and F = 10%). However, the modest oral bioavailability is encouraging.

3. Conclusions

We have identified spiropiperidine hydantoins as a novel series of antimalarial compounds with oral bioavailability but short half-lives. We have explored structure-activity relationships for the three pendant groups and found that the R1 and R3 positions tolerate a variety of functionality, suggesting that modulation of these positions should allow modulation of physiochemical properties without detrimental effects on potency. However, the R8 benzylic phenol was found to be very sensitive to modification. We were able to demonstrate ~10-fold improvement in antimalarial activity through addition of chlorine atoms in the 4′ and 5′ positions, but replacement of the phenol or basic amine functionality resulted in dramatic losses in antimalarial potency. Unfortunately, this dependency on a benzylic amine for potency results in a series of compounds that face significant metabolic stability challenges that will need to be overcome in lead optimization. Progress towards understanding the mechanism of action and identification of more metabolically stable compounds will be reported in due course.

4. Experimental

4.1 General

Commercially available reagents and solvents were used without further purification unless stated otherwise. LC-MS analyses were performed on an Agilent 1100 or 1200HPLC/MSD electrospray mass spectrometer in positive ion mode with scan range was 100–1000d. Preparative normal phase chromatography was performed on a Biotage SP1 with prepacked Biotage or Varian silica gel cartridges. Preparative reverse phase HPLC was performed on a Shimadzu LC-20AP or Biotage SP1 equipped with a C18 column and a methanol/water or acetonitrile/water/0.05% TFA gradient. The purity of tested compounds was ≥95% as determined by HPLC analysis conducted on an Agilent 1100 or 1260 system using a reverse phase C18 column with diode array detector unless stated otherwise. NMR spectra were recorded on a Bruker 400 MHz spectrometer. The signal of the deuterated solvent was used as internal reference. Chemical shifts (δ) are given in ppm and are referenced to residual not fully deuterated solvent signal. Coupling constants (J) are given in Hz.

4.2. Purchased Compounds

Compounds 4a–g and 11c–d were purchased from ChemBridge (www.hit2lead.com). Compound 4e was resynthesized as described in section 4.3.

4.3. Synthesis of CWHM-123 (4e)

tert-Butyl 2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (6)

A solution of 11.25 g KCN in 25 mL water was added drop wise to a suspension of 16.24 g 1-Bocpiperidone (Oakwood; 80 mmol) and 16.9 g ammonium carbonate in 45 mL water and 55 mL MeOH. During the addition, everything dissolved. The reaction flask was closed up with a balloon. After several hours a ppt began to form. The mixture was stirred at room temp over the weekend. After 72 h, the thick reaction mixture was filtered, washed with small portions of water and dried to give the desired product as a white solid: 16.1 g, 59.8 mmol, 75% yield. HPLC purity >98%. ES-MS m/z 292 (M+Na).

tert-Butyl 3-ethyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (7a)

A mixture of 6 (3.03 g, 11.3 mmol) and potassium carbonate in DMF (30 mL) was treated with ethyl iodide (1.0 mL, 12.4 mmol) dropwise at room temp. After 5 h, the reaction was diluted with EtOAc, washed with brine, dried over sodium sulfate, filtered and concentrated to give the crude product. The crude solid was recrystallized from EtOAc/heptane to give the title compound as a white solid (2.53 g, 8.51 mmol, 75% yield). HPLC purity >98%. ES-MS m/z 298 (M+H).

3-ethyl-1-isopentyl-1,3,8-triazaspiro[4.5]decane-2,4-dione hydrochloride (12n)

7a (3.16 g, 10.6 mmol) was dissolved in 30 mL DMF (anhydrous) and was treated with NaH (60% disp. in mineral oil, 483 mg, 12.1 mmol) at room temp. After 15 min of stirring, 1-iodo-3-methylbutane (1.7 mL, 12.9 mmol) was added dropwise. After 5 days, the reaction was quenched with water and partitioned between EtOAc and satd ammonium chloride. The organic layer was washed with satd ammonium chloride twice, and was dried with sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (0–30% EtOAc/hexane) to give 3.1 g of tert-butyl 3-ethyl-1-isopentyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a clear oil. The oil was then dissolved in 10 mL of diethyl ether, and 35 mL of 1 M HCl was added. The reaction was stirred at room temp for 48 h. The precipitate was then filtered and washed with diethyl ether, yielding the title compound as a white, powdery HCl salt. (2.13 g, 7.02 mmol, 66% yield). HPLC purity > 90%. ES-MS m/z 268 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.26 (br. s., 1 H), 3.39 (q, J=7.2 Hz, 2 H), 3.32 (d, J=6.9 Hz, 4 H), 3.18 (t, J=1.0 Hz, 2 H), 2.36 (dt, J=14.1, 9.2 Hz, 2 H), 1.86 (d, J=14.4 Hz, 2 H), 1.55 (spt, J=1.0 Hz, 1 H), 1.45 (q, J=1.0 Hz, 2 H), 1.08 (t, J=1.0 Hz, 3 H), 0.91 (d, J=1.0 Hz, 6 H).

8-(5-chloro-2-hydroxybenzyl)-3-ethyl-1-isopentyl-1,3,8-triazaspiro[4.5]decane-2,4-dione hydrochloride (CWHM-123; 4e)

A mixture of 299 hydrochloride (200 mg, 0.658 mmol) and 5-chloro-2-hydroxybenzaldehyde (113 mg, 0.724 mmol) in DCE (2 mL) was treated with sodium triacetoxyborohydride (279 mg, 1.32 mmol) followed by DMF (1 mL). The suspension was stirred at room temp overnight. The reaction was quenched with water, acidified with TFA, concentrated and purified by reverse phase HPLC (10 to 70% acetonitrile/water/0.05% TFA). Excess acetonitrile was removed under vacuum and the resultant aqueous solution was neutralized with saturated sodium bicarbonate, extracted with EtOAc, washed with brine, dried over sodium sulfate and concentrated to give a white foam (191 mg). The white foam was dissolved in diethyl ether and treated with 1 N HCl in diethyl ether (0.6 mL). The white ppt was filtered, washed with ether and dried to give the title compound a white HCl salt (194 mg, 0.436 mmol, 66% yield). HPLC purity > 95%. ES-MS m/z 408 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 7.63 (d, J = 2.45 Hz, 1H), 7.34 (dd, J = 2.73, 8.69 Hz, 1H), 7.00 (d, J = 8.85 Hz, 1H), 4.20 – 4.32 (m, 2H), 3.34 – 3.47 (m, 6H), 3.13 – 3.20 (m, 2H), 2.42 – 2.48 (m, 2H), 1.90 – 1.98 (m, 2H), 1.49 – 1.62 (m, 1H), 1.39 – 1.48 (m, 2H), 1.08 (t, J = 7.18 Hz, 3H), 0.90 (d, J = 6.59 Hz, 6H).

4.4. Supporting Information

Synthesis and characterization of all compounds and biological assay methods are included in the supporting information.

Supplementary Material

supplement

Acknowledgments

The authors would like to thank Eva Istvan for supplying the PM-II and PM-IV DNA constructs used to express PM-II and PM-IV and Anna Oksman for supplying red blood cells for the 3D7 assay.

Funding Sources

Research reported in this publication at Saint Louis University, was supported by Saint Louis University and the National Institute Of Allergy And Infectious Diseases of the National Institutes of Health under Award Number R01AI106498. Research reported in this publication at the Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, was supported by Bureau of Science and Information Technology of Guangzhou Municipality under Grant Number 2009Z1-E841 and Natural Science Foundation of China under Grant Number 81361120380. DEG is supported by the National Institute Of Allergy And Infectious Diseases of the National Institutes of Health under Award Number AI047798. The content is solely the responsibility of the authors and does not necessarily represent the official views of Saint Louis University, the Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, the Natural Science Foundation of China, Washington University or the National Institutes of Health.

Abbreviations

PM

plasmepsin

SPP

signal peptide peptidase

HIV

human immunodeficiency virus

SAR

structure-activity relationships

BACE

beta-site APP cleaving enzyme 1 or beta-secretase

TCAMS

Tres Cantos Antimalarial Set

RBC

red blood cells

CatD

cathepsin D

CatE

cathepsin E

MLM

mouse liver microsomes

RLM

rat liver microsomes

HLM

human liver microsomes

PK

pharmacokinetics

Footnotes

Author Contributions

All authors have given approval to the final version of the manuscript. The authors declare no competing financial interest.

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