WO2024094235A1 - Use of benzoxaborole-based compounds in therapy of diseases caused by amoebas of the naegleria genus - Google Patents

Use of benzoxaborole-based compounds in therapy of diseases caused by amoebas of the naegleria genus Download PDF

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WO2024094235A1
WO2024094235A1 PCT/CZ2022/050116 CZ2022050116W WO2024094235A1 WO 2024094235 A1 WO2024094235 A1 WO 2024094235A1 CZ 2022050116 W CZ2022050116 W CZ 2022050116W WO 2024094235 A1 WO2024094235 A1 WO 2024094235A1
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ddd
mmol
activity
fowleri
compounds
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Martin Zoltner
Robert SUTAK
Katerina ZENISKOVA
Jan Mach
Lukas Werner
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Univerzita Karlova
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/69—Boron compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/04—Amoebicides

Definitions

  • the invention relates to the field of medical science, specifically to medicinal preparations containing boron compounds as organic active ingredients and their use as antiparasitic agents against protozoa.
  • Naegleria fowleri is an amphizoic amoeba-flagellate of the genus Naegleria that can be found in warm fresh water, soil, and mud around the world. While it primarily feeds on bacteria, N. fowleri can—as the only species of genus Naegleria —infect people causing so-called primary amoebic meningoencephalitis (PAM). Human infection usually occurs when water containing N. fowleri is splashed or inhaled into the nasal cavity, for example during recreational water activities or a ritual sinus flush. PAM cases caused by an inhalation of N. fowleri cysts are described as well. Once the trophozoite stage of N.
  • PAM primary amoebic meningoencephalitis
  • fowleri reaches the nasal cavity, it attaches to the nasal mucosa and then migrates along the olfactory nerve through the cribriform plate to the olfactory bulbs in the central nervous system (CNS).
  • CNS central nervous system
  • N. fowleri causes severe neuronal destruction leading to cerebral hemorrhage, necrosis, inflammation, and increased intracranial pressure, ultimately leading to death.
  • PAM progression is rapid with death usually occurring within 3–7 days after the first symptoms, which are indistinguishable from those caused by a viral or bacterial meningoencephalitis, such as fever, headache, neck stiffness, nausea, seizures, and photophobia. Due to the rapid manifestation of the disease, early and correct diagnosis and timely and effective treatment are essential for the survival of infected patients.
  • computed tomography and magnetic resonance imaging can detect various CNS changes, such as diffuse cerebral edema, effusion in the cortical sulcus, and hydrocephalic herniation, or later necrotic areas, stenoses, and aneurysms.
  • CNS changes such as diffuse cerebral edema, effusion in the cortical sulcus, and hydrocephalic herniation, or later necrotic areas, stenoses, and aneurysms.
  • the presence of N. fowleri can be detected in the patient’s cerebrospinal fluid by various diagnostic methods, such as microbiological culture combined with microscopy and Gram and Wright-Giemsa staining, flow cytometry, immunofluorescence staining, enzyme-linked immunosorbent assay, or diagnostic polymerase chain reaction (PCR).
  • PCR diagnostic polymerase chain reaction
  • Benzoxaboroles are a class of organic compounds containing boron-heterocyclic scaffolds with pharmacological activities known from prior art.
  • document US8461336 describes a use of various aminomethylphenoxy-benzoxaboroles for treatment of inflammatory conditions and Zhang, N., Zoltner, M., Leung, K.-F., Scullion, P., Hutchinson, S., del Pino, R.C., et al. Host-parasite co-metabolic activation of antitrypanosomal aminomethyl-benzoxaboroles.
  • PLoS Pathog .
  • Goal of the presented invention is to provide substances with an efficient pharmaceutical activity against N. fowleri that can be used for a treatment of PAM and other amoeba-caused diseases, thereby overcoming the shortcomings of prior art.
  • Subject of the presented invention is a use of compounds with activity against Naegleria fowleri characterized by general formula I, wherein: R 1 , R 2 , R 3 , R 4 , and R 5 are independently selected from a group comprising -H (or -F as a common pharmacological replacement for hydrogen), aminomethyl group, formyl group, and aminomethyl group carrying a protecting group, and their pharmaceutically acceptable salts and hydrates for treatment of diseases caused by N. fowleri .
  • the graph depicts survival curves for experimental PAM treatment in a mouse infection model using compound IIa.
  • the graph contains a control group (A), group of untreated mice (B), group of mice treated for 5 days (C), and group of mice treated for 10 days (D).
  • Example 1 describes synthesis of compound IIa.
  • reaction mixture is then cooled to approximately 40 °C and filtered through sintered glass and the filtrate is diluted with aqueous hydrochloric acid (36 %, 30 mL) and stirred additional 20 hours at 70 °C.
  • the mixture is then cooled to room temperature (RT), diluted with brine (200 mL), and extracted with ethyl acetate (5 x 200 mL). Combined organic layers are dried over magnesium sulphate, filtered, and concentrated under vacuum.
  • NaBH 4 (162 mg, 4.3 mmol) is added in two portions to a cold (4°C) solution of 4-(3-formyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)benzonitrile (150 mg, 0.43 mmol) in methanol (3 mL). Reaction is allowed to reach RT and hydrochloric acid (5 mL, 36 %) is added dropwise. Acidified mixture is then stirred for 17 hours at RT.
  • Example 2 describes synthesis of compound IId.
  • Propargylbromide (50 ⁇ L, 80 % toluene solution) is added to a solution of 5-(4-(aminomethyl)phenoxy)benzo[c][1,2]oxaborol-1(3H)-ol (50 mg, 0.20 mmol) in N,N -dimethylformamide (1 mL). The reaction mixture is stirred for 16 hours at 40 °C, then diluted with toluene (5 mL) and concentrated under vacuum to distill off the N,N -dimethylformamide.
  • Example 3 describes synthesis of compound III.
  • Example 4 describes synthesis of compound IV.
  • NaBH 4 (95 mg, 2.55 mmol) is added in two portions to a cold (4 °C) solution of 4-(3-(1,3-dioxolan-2-yl)phenoxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (200 mg, 0.51 mmol) in methanol (3 mL). Reaction is allowed to reach RT and hydrochloric acid (5 mL, 36 %) is added dropwise. Acidified mixture is then stirred for 16 hours at 50 °C.
  • Example 5 describes synthesis of compound V.
  • NaNO 2 (180 mg, 2.6 mmol) is added into a suspension of (5-(3-(1,3-dioxolan-2-yl)phenoxy)-2-aminophenyl)methanol (150 mg, 0.52 mmol) in water (0.5 mL).
  • Hydrobromic acid (48 %, 2 mL) is added dropwise over 30 minutes period to the resulting suspension.
  • CuBr 2 (582 mg, 2.6 mmol) is added to the intermediary solution of diazonium salt and mixture is heated to 60 °C for 6 hours. Reaction mixture is diluted with cold water (5mL) and extracted with ethyl acetate (5 x 10 mL) and combined organic layers are dried over magnesium sulphate.
  • the resulting powdery solid is purified by column chromatography (CHCl 3 /CH 3 OH/NH 3 100:1:0.1 ⁇ 10:1:0.1) to yield 5-(3-(aminomethyl)phenoxy)benzo[c][1,2]oxaborol-1(3H)-ol (13 mg, 62 % yield).
  • Example 6 describes culturing of N. fowleri .
  • Naegleria fowleri strain HB-1 is cultured under aerobic condition in 2 % animal-origin pancreatic enzymatic digest of casein supplemented with 10 % heat-inactivated fetal bovine serum and with the addition of penicillin (100 U/mL) and streptomycin (100 ⁇ g/mL).
  • Cells are cultivated in a 25 cm 2 cultivation flasks under aerobic conditions at 37 °C. To maintain the exponential growth, the culture is 100x diluted and transferred to a new cultivation flask every 3 days.
  • Example 7 describes drug-potency testing for growth-inhibition of N. fowleri with different benzoxaboroles.
  • the culture medium is supplemented with 10 nM purified human MAO-B.
  • Cell viability is determined after 72 h of exposure using a luminescent cell viability assay and the luminescent signal is read in a plate reader and the resulting data are analyzed.
  • Example 8 describes results of dose–response analysis for growth-inhibition of N. fowleri with different benzoxaboroles.
  • Example 9 describes testing of activity of compound IIa in a murine model.
  • a group of 14 BALB/c mice, 12 weeks old and weighing 20 g, are intranasally infected with 2x104 cells of N. fowleri in phosphate-buffered saline (PBS) in a total volume of 30 ⁇ L under diethyl ether anesthesia.
  • PBS phosphate-buffered saline
  • To obtain virulent N. fowleri cells they are passaged through mice and each time, the brain is extracted postmortem, washed in a growth medium, and parasites are cultured in a cultivation flask at 37 °C. This procedure is repeated at least three times before experimental treatment.
  • the experimental treatment of PAM begins 24 h after intranasal infection by N. fowleri cells.
  • 50 mg/kg of compound IIa in PBS in a total volume of 200 ⁇ L is administered intraperitoneally in a group of 7 mice every 8 hours for 5 or 10 days.
  • the untreated control group containing 7 infected mice is treated in parallel with 200 ⁇ l PBS omitting the drug.
  • Three uninfected mice are given the same IIa doses as the treated group as a toxicity control.

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Abstract

Compounds based on benzoxaborole moiety with activity against parasitic amoeba of genus Naegleria can be used in treatment of diseases caused by such parasites. Activity of the compounds against Naegleria fowleri was proven by a phenotypic screening approach, which detected potent activity of aminomethylphenoxy-benzoxaboroles with nanomolar or low-micromolar potency depending on the position of the aminomethyl substitution. Potential of the compounds to be used for treatment of primary amoebic meningoencephalitis was demonstrated and proven in murine model infected with N. fowleri. Further, activity of compounds carrying a formyl group as direct metabolites of aminomethyl-derivatives as well as activity of prodrugs with a protecting group attached to the amino group that is cleavable under physiological conditions was also shown.

Description

Use of benzoxaborole-based compounds in therapy of diseases caused by amoebas of the Naegleria genus
The invention relates to the field of medical science, specifically to medicinal preparations containing boron compounds as organic active ingredients and their use as antiparasitic agents against protozoa.
Naegleria fowleri is an amphizoic amoeba-flagellate of the genus Naegleria that can be found in warm fresh water, soil, and mud around the world. While it primarily feeds on bacteria, N. fowleri can—as the only species of genus Naegleria—infect people causing so-called primary amoebic meningoencephalitis (PAM). Human infection usually occurs when water containing N. fowleri is splashed or inhaled into the nasal cavity, for example during recreational water activities or a ritual sinus flush. PAM cases caused by an inhalation of N. fowleri cysts are described as well. Once the trophozoite stage of N. fowleri reaches the nasal cavity, it attaches to the nasal mucosa and then migrates along the olfactory nerve through the cribriform plate to the olfactory bulbs in the central nervous system (CNS). There, N. fowleri causes severe neuronal destruction leading to cerebral hemorrhage, necrosis, inflammation, and increased intracranial pressure, ultimately leading to death. PAM progression is rapid with death usually occurring within 3–7 days after the first symptoms, which are indistinguishable from those caused by a viral or bacterial meningoencephalitis, such as fever, headache, neck stiffness, nausea, seizures, and photophobia. Due to the rapid manifestation of the disease, early and correct diagnosis and timely and effective treatment are essential for the survival of infected patients. At the onset of the disease, computed tomography and magnetic resonance imaging can detect various CNS changes, such as diffuse cerebral edema, effusion in the cortical sulcus, and hydrocephalic herniation, or later necrotic areas, stenoses, and aneurysms. The presence of N. fowleri can be detected in the patient’s cerebrospinal fluid by various diagnostic methods, such as microbiological culture combined with microscopy and Gram and Wright-Giemsa staining, flow cytometry, immunofluorescence staining, enzyme-linked immunosorbent assay, or diagnostic polymerase chain reaction (PCR).
Due to its fast progression, PAM has an extremely high mortality rate and most cases of PAM are diagnosed only post-mortem. From 1935 to 2019, 381 cases of PAM have been reported worldwide with only 7 survivors. In these individuals, recovery was achieved by an administration of amphotericin B, either intravenously or intrathecally, alone or in a combination with other drugs such as fluconazole, miconazole, azithromycin, rifampin, or miltefosine. However, there is currently no efficient treatment for PAM available and no known pharmaceutically active substances with a significant activity against N. fowleri. The selection of a drug candidate is further complicated by the cerebral localization of N. fowleri. Thus, an effective drug must not only have a rapid and potent effect, but also the crucial ability to efficiently cross the blood–brain barrier.
Benzoxaboroles are a class of organic compounds containing boron-heterocyclic scaffolds with pharmacological activities known from prior art. For example, document US8461336 describes a use of various aminomethylphenoxy-benzoxaboroles for treatment of inflammatory conditions and Zhang, N., Zoltner, M., Leung, K.-F., Scullion, P., Hutchinson, S., del Pino, R.C., et al. Host-parasite co-metabolic activation of antitrypanosomal aminomethyl-benzoxaboroles. PLoS Pathog. 2018, 14(2): e1006850 shows their activity against Trypanosoma brucei; document US10105377 describes a use of 5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole as an antifungal agent; documents US9440994, US10301329, WO2014121124, and WO2011019616 describe a use of benzoxaboroles carrying an amide moiety as antiprotozoals; document WO2020123881 describes antiprotozoal activity of benzoxaboroles carrying carbamate group and its various thio-analogues; document WO2019108982 describes antiprotozoal activity of benzoxaboroles carrying structurally variying substituents with a low molecular weight; document US10011616 describes a use of benzoxaboroles carrying pyrazinoxy substituents as antiprotozoals; document US9346834 describes a use of benzoxaboroles carrying alkoxy substituents as antiprotozoals; document WO2011022337 describes antiprotozoal activity of benzoxaboroles substituted with an alkyl chain carrying a carboxyl or an ester group; and document WO2011019612 describes a use of benzoxaboroles carrying carbamide or thiocarbamide groups as antiprotozoals. However, none of these documents mention a specific activity of benzoxaboroles against N. fowleri or any other amoeba.
Goal of the presented invention is to provide substances with an efficient pharmaceutical activity against N. fowleri that can be used for a treatment of PAM and other amoeba-caused diseases, thereby overcoming the shortcomings of prior art.
Subject of the presented invention is a use of compounds with activity against Naegleria fowleri characterized by general formula I,

wherein:
R1, R2, R3, R4, and R5 are independently selected from a group comprising -H (or -F as a common pharmacological replacement for hydrogen), aminomethyl group, formyl group, and aminomethyl group carrying a protecting group,
and their pharmaceutically acceptable salts and hydrates for treatment of diseases caused by N. fowleri.
Activity of compounds of general formula I against N. fowleri was demonstrated by a phenotypic screening approach, which detected potent activity of aminomethylphenoxy-benzoxaboroles with nanomolar or low-micromolar potency depending on the position of the aminomethyl substitution with compound of formula IIa showing the highest potency with a half-maximal effective concentration (EC50) of 150 nM. Therefore, this compound was selected for an assessment in a murine infection model.
Further, activity of compounds carrying a formyl group as direct metabolites of aminomethyl-derivatives was proven using bovine serum with inherent amine oxidase present in the phenotypic screening as well as in in vivo experiments. Consistently, the aldehyde metabolite IIb has a similar potency as IIa when applied directly. On the other hand, the respective carboxylic derivative IIc has no significant activity against N. fowleri.

Potential use of compounds of formula I in a form of prodrugs with a protecting group that is cleavable under physiological conditions attached to the amino group was also demonstrated. Compound of formula IId carrying a propargyl protecting group showed activity comparable to compound IIa in the presence of 10 nM of human monoamine oxidase B (MAO-B) enzyme, which is abundant in brain tissue.
 Fig.1
depicts results of dose–response analysis for growth-inhibition of N. fowler i using compound IIa.
depicts survival curves for experimental PAM treatment in a mouse infection model using compound IIa. The graph contains a control group (A), group of untreated mice (B), group of mice treated for 5 days (C), and group of mice treated for 10 days (D).
 Example 1
Example 1 describes synthesis of compound IIa.
4-fluorobenzonitrile (1.48 g 12.24 mmol) and benzo[c][1,2]oxaborole-1,6(3H)-diol (1.0 g, 4.08 mmol) are added to a suspension of Cs2CO3 (13.29 g, 40.80 mmol) and K2CO3 (5.64g, 40.8 mmol) in N,N-dimethylformamide (30mL). The resulting slurry is heated to 100 °C and stirred for 16 hours. The reaction mixture is then cooled to approximately 40 °C and filtered through sintered glass and the filtrate is diluted with aqueous hydrochloric acid (36 %, 30 mL) and stirred additional 20 hours at 70 °C. The mixture is then cooled to room temperature (RT), diluted with brine (200 mL), and extracted with ethyl acetate (5 x 200 mL). Combined organic layers are dried over magnesium sulphate, filtered, and concentrated under vacuum. A silica column chromatography (CHCl3/CH3OH 100:1 → 10:1) yields two products: 4-(4-bromo-3-formylphenoxy)benzonitrile (368 mg, 30 % yield) and 4-(4-bromo-3-formylphenoxy)benzoic acid (326 mg, 25 % yield).

1H NMR: δ 7.00-7.19 (3H, 7.06 (ddd, J = 8.3, 1.3, 0.5 Hz), 7.13 (dd, J = 8.2, 1.4 Hz)), 7.29 (1H, dd, J = 8.2, 0.5 Hz), 7.68 (1H, dd, J = 1.4, 0.5 Hz), 8.10 (2H, ddd, J = 8.3, 1.9, 0.5 Hz), 10.03 (1H, s).
MS Calculated for C14H9BrNO2 +: 301.98112, Found: 301.95823

1H NMR: δ 7.04-7.20 (3H, 7.11 (ddd, J = 8.5, 1.4, 0.4 Hz), 7.14 (dd, J = 8.2, 1.4 Hz)), 7.29 (1H, dd, J = 8.2, 0.5 Hz), 7.68 (1H, dd, J = 1.4, 0.5 Hz), 7.93 (2H, ddd, J = 8.5, 1.4, 0.4 Hz), 10.03 (1H, s).
MS Calculated for C14H8BrO4 -: 318.96114, Found: 318.97423
In the next stage, 4-(4-bromo-3-formylphenoxy)benzonitrile (0.2 g, 0.66 mmol) is added to a flask charged with bis(pinacolato)diboran (335 mg, 1.3 mmol), PdCl2(dppf) (24 mg, 0.033 mmol), CH3COOK (130 mg, 1.3 mmol). Anhydrous 1,4-dioxan (4 mL) is added to all the solids and the resulting cloudy suspension is stirred for 3 hours while heated to 100 °C under argon atmosphere. TLC (thin-layer chromatography) (CHCl3/CH3OH/NH3 100:2:0.2) indicates consumption of the starting material. The mixture is concentrated under vacuum and subjected to column chromatography (CHCl3/CH3OH 100:2). Combined chromatographic fractions yields 4-(3-formyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)benzonitrile (209 mg, 91 % yield).

1H NMR: δ 1.35 (12H, s), 7.00-7.20 (3H, 7.07 (ddd, J = 8.6, 1.4, 0.5 Hz), 7.13 (dd, J = 8.4, 1.4 Hz)), 7.29 (1H, dd, J = 8.4, 0.5 Hz), 7.60 (1H, dd, J = 1.4, 0.5 Hz), 8.08 (2H, ddd, J = 8.6, 1.9, 0.5 Hz), 10.07 (1H, s).
MS Calculated for C20H21BNO4 +: 350.15582, Found: 350.16212
In the next stage, NaBH4 (162 mg, 4.3 mmol) is added in two portions to a cold (4°C) solution of 4-(3-formyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)benzonitrile (150 mg, 0.43 mmol) in methanol (3 mL). Reaction is allowed to reach RT and hydrochloric acid (5 mL, 36 %) is added dropwise. Acidified mixture is then stirred for 17 hours at RT. Mixture is concentrated under vacuum and the residuum is purified by column chromatography (CHCl3/CH3OH 100:1 → 100:5) to yield 4-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)benzonitrile (93 mg, 86 % yield).

1H NMR: δ 4.77 (2H, d, J = 14.3 Hz), 6.53 (1H, dd, J = 2.4, 0.5 Hz), 6.99-7.13 (3H, 7.06 (dd, J = 8.1, 2.4 Hz), 7.06 (ddd, J = 8.6, 1.4, 0.5 Hz)), 7.35 (1H, dd, J = 8.1, 0.5 Hz), 8.09 (2H, ddd, J = 8.6, 1.9, 0.5 Hz).
MS Calculated for C14H11BNO3 +: 252.08265, Found: 252.09172
In the next stage, ethanol (6 mL) is added to a flask charged with Pd/C (10 %, 30 mg) and 4-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)benzonitrile (100 mg, 0.40 mmol). Reaction vessel is submitted to H2/vacuum cycle (4x) to remove residual oxygen. After the last cycle, the reaction is stirred (16 hours) under H2 atmosphere. After TLC (CHCl3/CH3OH/NH3 10:1:0.1) indicates a consumption of the starting material, the mixture is filtered through a pad of celite and concentrated under vacuum. Column chromatography (CHCl3/CH3OH/NH3 100:10:0.1 → 10:1:0.1) of crude product yields 5-(4-(aminomethyl)phenoxy)benzo[c][1,2]oxaborol-1(3H)-ol (80 mg, 79 % yield).

1H NMR: δ 3.68 (2H, s), 4.77 (2H, d, J = 14.3 Hz), 6.61 (1H, dd, J = 2.4, 0.5 Hz), 6.92 (2H, ddd, J = 8.2, 1.3, 0.5 Hz), 7.15-7.41 (4H, 7.21 (dd, J = 8.1, 2.4 Hz), 7.23 (ddd, J = 8.2, 1.3, 0.5 Hz), 7.34 (dd, J = 8.1, 0.5 Hz).
MS Calculated for C14H15BNO3 +: 256.11395, Found: 256.12547
Example 2
Example 2 describes synthesis of compound IId.
Propargylbromide (50 µL, 80 % toluene solution) is added to a solution of 5-(4-(aminomethyl)phenoxy)benzo[c][1,2]oxaborol-1(3H)-ol (50 mg, 0.20 mmol) in N,N-dimethylformamide (1 mL). The reaction mixture is stirred for 16 hours at 40 °C, then diluted with toluene (5 mL) and concentrated under vacuum to distill off the N,N-dimethylformamide. The crude product is purified with column chromatography (CHCl3/CH3OH/NH3 100:10:0.1 → 10:1:0.1) to yield 5-(4-((prop-2-yn-1-ylamino)methyl)phenoxy)benzo[c][1,2]oxaborol-1(3H)-ol (12 mg, 21 % yield).
1H NMR: δ 2.80 (1H, s), 3.06 (2H, s), 3.59 (2H, s), 4.77 (2H, d, J = 14.3 Hz), 6.61 (1H, dd, J = 2.4, 0.5 Hz), 6.92 (2H, ddd, J = 8.2, 1.3, 0.5 Hz), 7.21 (1H, dd, J = 8.1, 2.4 Hz), 7.28-7.41 (3H, 7.34 (dd, J = 8.1, 0.5 Hz), 7.35 (ddd, J = 8.2, 1.2, 0.5 Hz).
MS Calculated for C17H17BNO3 +: 294.12960, Found: 294.12235
Example 3
Example 3 describes synthesis of compound III.
4-Fluorobenzonitrile (726 mg, 6 mmol) and benzo[c][1,2]oxaborole-1,6(3H)-diol (300 mg, 2 mmol) are added to a suspension of Cs2CO3 (6.52 g, 20 mmol) and K2CO3 (2.76 g, 20 mmol) in N,N-dimethylformamide (10 mL). The resulting slurry is heated to 95 °C and stirred for 19 hours. The reaction mixture is then cooled to RT, diluted with ethanol (10 mL), and filtered. Filtrate is acidified with hydrochloride acid (5 mL, 36 %) and stirred for 12 hours at RT. The solution is concentrated under vacuum and crude product is purified on silica by column chromatography (CHCl3/CH3OH/NH3 100:1 → 10:1) to yield 4-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)benzonitrile (142 mg, 33 % yield).

1H NMR: δ 4.74 (2H, d, J = 13.8 Hz), 7.00-7.20 (3H, 7.06 (ddd, J = 8.3, 1.3, 0.5 Hz), 7.13 (dd, J = 8.4, 2.7 Hz)), 7.26 (1H, dd, J = 8.4, 0.5 Hz), 7.42 (1H, dd, J = 2.7, 0.5 Hz), 8.09 (2H, ddd, J = 8.3, 1.9, 0.5 Hz).
MS Calculated for C14H11BNO3 +: 252.08265, Found: 252.07985
In the next stage, ethanol (4 mL) is added to a flask charged with Pd/C (10 %, 25 mg) and dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)benzonitrile (100 mg, 0.4 mmol). Reaction vessel is submitted to H2/vacuum cycle (4x) to remove residual oxygen. After the last cycle, the reaction is stirred for 16 hours under H2 atmosphere. After TLC (CHCl3/CH3OH/NH3 10:1:0.1) indicates consumption of the starting material, the mixture is filtered through a pad of celite and concentrated under vacuum. Column chromatography (CHCl3/CH3OH/NH3 100:10:0.1 → 10:1:0.1) of crude product yields 6-(4-(aminomethyl)phenoxy)benzo[c][1,2]oxaborol-1(3H)-ol (84 mg, 83 % yield).

1H NMR: δ 3.70 (2H, s), 4.76 (2H, d, J = 13.8 Hz), 6.86-7.11 (3H, 6.92 (ddd, J = 8.2, 1.5, 0.5 Hz), 7.05 (dd, J = 8.5, 2.8 Hz)), 7.16-7.31 (3H, 7.23 (ddd, J = 8.2, 1.3, 0.5 Hz), 7.25 (dd, J = 8.5, 0.5 Hz)), 7.40 (1H, dd, J = 2.8, 0.5 Hz).
MS Calculated for C14H15BNO3 +: 256.11395, Found: 256.12359
Example 4
Example 4 describes synthesis of compound IV.
3-(1,3-Dioxolan-2-yl)phenol (1.23g, 7.39 mmol) and 2-bromo-4-fluorobenzaldehyde (1.0 g, 4.92 mmol) are added to a suspension of Cs2CO3 (8.0 g, 24.6 mmol) and K2CO3 (3.4 g, 24.5 mmol) in N,N-dimethylformamide (20 mL). The resulting slurry is heated to 95 °C and stirred for 16 hours. The reaction mixture is then cooled to RT, diluted with ethanol (20 mL), and filtered through glass frit. The column chromatography (CHCl3/CH3OH 100:1 → 100:5) of crude product yields 4-(3-(1,3-dioxolan-2-yl)phenoxy)-2-bromobenzaldehyde (1.15 g, 67 % yield).

1H NMR: δ 3.78-3.99 (4H, 3.86 (ddd, J = 11.6, 5.7, 5.3 Hz), 3.91 (ddd, J = 11.6, 5.6, 5.3 Hz)), 5.44 (1H, s), 6.83-7.21 (4H, 6.89 (dd, J = 8.1, 2.0 Hz), 6.97 (ddd, J = 8.1, 2.8, 1.3 Hz), 7.04 (ddd, J = 8.0, 2.5, 1.3 Hz), 7.15 (ddd, J = 2.8, 2.5, 0.6 Hz)), 7.39 (1H, ddd, J = 8.1, 8.0, 0.6 Hz), 7.52 (1H, dd, J = 2.0, 0.5 Hz), 8.10 (1H, dd, J = 8.1, 0.5 Hz), 9.99 (1H, s).
MS Calculated for C16H14BrO4 +: 349.00700, Found: 349.01256
In the next stage, 4-(3-(1,3-dioxolan-2-yl)phenoxy)-2-bromobenzaldehyde (0.5 g, 1.26 mmol) is added into a flask charged with bis(pinacolato)diboran (639 mg, 2.52 mmol), PdCl2(dppf) (46 mg, 0.06 mmol), and CH3COOK (247 mg, 2.52 mmol). Anhydrous 1,4-dioxan (10 mL) is added to all the solids and the cloudy suspension is stirred for 3 hours while heated to 100 °C under argon atmosphere. TLC (CHCl3/CH3OH/NH3 100:2:0.2) indicates consumption of the starting material. The mixture is concentrated under vacuum and subjected to column chromatography (CHCl3/CH3OH 100:2). Combined chromatographic fractions yield 4-(3-(1,3-dioxolan-2-yl)phenoxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (404 mg, 81 % yield).

1H NMR: δ 1.36 (12H, s), 3.78-3.99 (4H, 3.86 (ddd, J = 11.6, 5.7, 5.3 Hz), 3.91 (ddd, J = 11.6, 5.6, 5.3 Hz)), 5.44 (1H, s), 6.84-7.21 (4H, 6.91 (dd, J = 7.9, 2.0 Hz), 6.97 (ddd, J = 8.1, 2.8, 1.3 Hz), 7.03 (ddd, J = 8.0, 2.6, 1.3 Hz), 7.15 (ddd, J = 2.8, 2.6, 0.6 Hz)), 7.32-7.55 (2H, 7.39 (ddd, J = 8.1, 8.0, 0.6 Hz), 7.50 (dd, J = 2.0, 0.5 Hz)), 7.73 (1H, dd, J = 7.9, 0.5 Hz), 10.04 (1H, s).
MS Calculated for C22H26BO6 +: 397.18170, Found: 397.18257
In the next stage, NaBH4 (95 mg, 2.55 mmol) is added in two portions to a cold (4 °C) solution of 4-(3-(1,3-dioxolan-2-yl)phenoxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (200 mg, 0.51 mmol) in methanol (3 mL). Reaction is allowed to reach RT and hydrochloric acid (5 mL, 36 %) is added dropwise. Acidified mixture is then stirred for 16 hours at 50 °C. Mixture is concentrated under vacuum and the residuum is purified by column chromatography (CHCl3/CH3OH 100:1 → 100:5) to yield 3-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)-benzaldehyde (61 mg, 47 % yield).

1H NMR: δ 4.76 (2H, d, J = 13.8 Hz), 6.92-7.11 (2H, 6.98 (dt, J = 8.2, 1.4 Hz), 7.05 (dd, J = 8.5, 2.8 Hz)), 7.25 (1H, dd, J = 8.5, 0.5 Hz), 7.35-7.53 (2H, 7.40 (dd, J = 2.8, 0.5 Hz), 7.46 (ddd, J = 8.3, 8.2, 0.4 Hz)), 7.68 (1H, ddd, J = 1.7, 1.4, 0.4 Hz), 7.93 (1H, ddd, J = 8.3, 1.7, 1.4 Hz), 10.00 (1H, s).
MS Calculated for C14H12BO4 +: 255.08232, Found: 255.09120
In the next stage, NH4 +HCCO- (186 mg, 2.95mmol) and NaBH3CN (120 mg, 1.9 mmol) are added in one portion to a solution of 3-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)benzaldehyde (50 mg, 0.19 mmol) in methanol (3 mL). The resulting mixture is stirred for 14 hours at RT, concentrated under vacuum and subjected to column chromatography (CHCl3/CH3OH/NH3 100:1:0.1 → 10:1:0.1). The combined fractions yield 6-(3-(aminomethyl)phenoxy)benzo[c][1,2]oxaborol-1(3H)-ol (37 mg, 77 % yield).

1H NMR: δ 3.78 (2H, s), 4.76 (2H, d, J = 13.8 Hz), 6.86-7.33 (6H, 6.92 (ddd, J = 8.2, 2.8, 1.4 Hz), 7.02 (ddd, J = 2.8, 2.6, 0.5 Hz), 7.05 (dd, J = 8.5, 2.8 Hz), 7.13 (ddd, J = 7.9, 2.6, 1.4 Hz), 7.25 (ddd, J = 8.2, 7.9, 0.5 Hz), 7.25 (dd, J = 8.5, 0.5 Hz)), 7.40 (1H, dd, J = 2.8, 0.5 Hz).
MS Calculated for C14H15BNO3 +: 256.11395, Found: 256.11268
Example 5
Example 5 describes synthesis of compound V.
3-(1,3-Dioxolan-2-yl)phenol (1 g, 6 mmol) and methyl 5-fluoro-2-nitrobenzoate (1.198 g, 6 mmol) are added into a flask charged with Cs2CO3 (9.77 g, 30 mmol), K2CO3 (4.16 g, 30 mmol), and N,N-dimethylformamide (20 mL). Reaction mixture is sonicated for 120 minutes, then stirred for 24 hours and heated to 90 °C. Reaction mixture is then washed with ethyl-acetate (3 x 500 mL) and brine (250 mL). Combined organic layer is dried over magnesium sulfate and concentrated under vacuum. Crude product is purified by column chromatography (petroleum ether/ethy acetate 10:1→2:1) to yield methyl 5-(3-(1,3-dioxolan-2-yl)phenoxy)-2-nitrobenzoate (1.12 g, 54 % yield).

1H NMR: δ 3.65 (3H, s), 3.78-3.99 (4H, 3.86 (ddd, J = 11.6, 5.7, 5.3 Hz), 3.91 (ddd, J = 11.6, 5.6, 5.3 Hz)), 5.45 (1H, s), 6.92-7.22 (3H, 6.99 (ddd, J = 8.1, 2.8, 1.3 Hz), 7.04 (ddd, J = 8.0, 2.5, 1.3 Hz), 7.16 (ddd, J = 2.8, 2.5, 0.6 Hz)), 7.36-7.57 (2H, 7.43 (ddd, J = 8.1, 8.0, 0.6 Hz), 7.51 (dd, J = 8.6, 1.5 Hz)), 7.99 (1H, dd, J = 1.5, 0.5 Hz), 8.13 (1H, dd, J = 8.6, 0.5 Hz).
MS Calculated for C17H16NO7 +: 346.09213, Found: 346.08920
In the next stage, LiAlH4 (5 mL, 2 M in tetrahydrofuran (THF)) is added to a solution of methyl 5-(3-(1,3-dioxolan-2-yl)phenoxy)-2-nitrobenzoate (350 mg, 1 mmol) in anhydrous tetrahydrofurane (5 mL). After 4 hours of stirring at RT, the reaction is quenched by addition of silica (5 g) and filtered through sintered glass. The filtrate is diluted with acetone (5 mL) and concentrated under vacuum and the crude product is purified by column chromatography (CHCl3/CH3OH/NH3 100:1:0.1 → 10:1:0.1) to yield (5-(3-(1,3-dioxolan-2-yl)phenoxy)-2-aminophenyl)methanol (183 mg, 64 % yield).

1H NMR: δ 3.78-3.99 (4H, 3.86 (ddd, J = 11.6, 5.7, 5.3 Hz), 3.91 (ddd, J = 11.6, 5.6, 5.3 Hz)), 4.48 (2H, s), 5.46 (1H, s), 6.44 (1H, dd, J = 8.4, 0.5 Hz), 6.64-6.86 (2H, 6.70 (dd, J = 2.8, 0.5 Hz), 6.80 (dd, J = 8.4, 2.8 Hz)), 6.86-7.18 (3H, 6.93 (ddd, J = 8.2, 2.8, 1.3 Hz), 7.02 (ddd, J = 8.1, 2.6, 1.3 Hz), 7.13 (ddd, J = 2.8, 2.6, 0.5 Hz)), 7.37 (1H, td, J = 8.1, 0.5 Hz).
MS Calculated for C16H18NO4 +: 288.12303, Found: 288.11923
In the next stage, NaNO2 (180 mg, 2.6 mmol) is added into a suspension of (5-(3-(1,3-dioxolan-2-yl)phenoxy)-2-aminophenyl)methanol (150 mg, 0.52 mmol) in water (0.5 mL). Hydrobromic acid (48 %, 2 mL) is added dropwise over 30 minutes period to the resulting suspension. CuBr2 (582 mg, 2.6 mmol) is added to the intermediary solution of diazonium salt and mixture is heated to 60 °C for 6 hours. Reaction mixture is diluted with cold water (5mL) and extracted with ethyl acetate (5 x 10 mL) and combined organic layers are dried over magnesium sulphate. Magnesium sulphate is filtered, filtrate is concentrated under vacuum, and the crude product is purified by column chromatography (CHCl3/CH3OH/NH3 100:1:0.1 → 10:1:0.1) to yield 3-(4-bromo-3-(hydroxymethyl)phenoxy)benzaldehyde (65 mg, 41 % yield).

1H NMR: δ 4.62 (2H, s), 6.79 (1H, dd, J = 2.9, 0.6 Hz), 6.87-7.04 (2H, 6.93 (dd, J = 8.3, 2.9 Hz), 6.98 (dt, J = 8.2, 1.4 Hz)), 7.32 (1H, dd, J = 8.3, 0.6 Hz), 7.46 (1H, ddd, J = 8.3, 8.2, 0.4 Hz), 7.68 (1H, ddd, J = 1.7, 1.4, 0.4 Hz), 7.93 (1H, ddd, J = 8.3, 1.7, 1.4 Hz), 10.00 (1H, s).
MS Calculated for C14H12BrO3 +: 306.99643, Found: 306.98562
In the next stage, 3-(4-bromo-3-(hydroxymethyl)phenoxy)benzaldehyde (50 mg, 0.16 mmol) is added into a flask charged with bis(pinacolato)diboran (83 mg, 0.32 mmol), PdCl2(dppf) (6 mg, 0.08 mmol), and CH3COOK (32 mg, 0.32 mmol). Anhydrous 1,4-dioxan (2 mL) is added to all the solids and the cloudy suspension is stirred for 1.5 hours while heated to 95 °C under argon atmosphere. TLC (CHCl3/CH3OH/NH3 100:5:0.5) indicates consumption of the starting material. The mixture is concentrated under vacuum and subjected to column chromatography (CHCl3/CH3OH 100:2 → 100:5). Combined chromatographic fractions yield 3-(3-(hydroxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)benzaldehyde (37 mg, 66 % yield).

1H NMR: δ 1.35 (12H, s), 4.51 (2H, s), 6.51 (1H, dd, J = 2.4, 0.5 Hz), 6.89-7.06 (2H, 6.96 (dd, J = 8.1, 2.4 Hz), 6.99 (dt, J = 8.2, 1.4 Hz)), 7.28-7.54 (2H, 7.34 (dd, J = 8.1, 0.5 Hz), 7.47 (ddd, J = 8.3, 8.2, 0.4 Hz)), 7.70 (1H, td, J = 1.4, 0.4 Hz), 7.94 (1H, dt, J = 8.3, 1.4 Hz), 10.00 (1H, s).
MS Calculated for C20H24BO5 +: 355.17113, Found: 355.16910
In the next stage, NH4 +HCCO- (80 mg, 1.23 mmol) and NaBH3CN (53 mg, 0.85 mmol) are added in one portion to a solution of 3-(3-(hydroxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)benzaldehyde (30 mg, 0.085 mmol) in methanol (2 mL). The resulting mixture is stirred for 14 hours at RT, reaction is quenched with aqueous hydrochlorid acid (3 mL, 36 %) and stirred for additional 12 hours. The pH of the mixture is adjusted to approximately 7 by addition of NaOH (1M), mixture is frozen to -50°C and freeze-dried. The resulting powdery solid is purified by column chromatography (CHCl3/CH3OH/NH3 100:1:0.1 → 10:1:0.1) to yield 5-(3-(aminomethyl)phenoxy)benzo[c][1,2]oxaborol-1(3H)-ol (13 mg, 62 % yield).

1H NMR: δ 3.78 (2H, s), 4.77 (2H, d, J = 14.3 Hz), 6.61 (1H, dd, J = 2.4, 0.5 Hz), 6.87-7.41 (6H, 6.93 (ddd, J = 8.2, 2.8, 1.4 Hz), 7.03 (ddd, J = 2.8, 2.6, 0.5 Hz), 7.14 (ddd, J = 7.9, 2.6, 1.4 Hz), 7.21 (dd, J = 8.1, 2.4 Hz), 7.26 (ddd, J = 8.2, 7.9, 0.5 Hz), 7.35 (dd, J = 8.1, 0.5 Hz).
MS Calculated for C14H15BNO3 +: 256.11395, Found: 256.10985
Example 6
Example 6 describes culturing of N. fowleri.
Naegleria fowleri strain HB-1 is cultured under aerobic condition in 2 % animal-origin pancreatic enzymatic digest of casein supplemented with 10 % heat-inactivated fetal bovine serum and with the addition of penicillin (100 U/mL) and streptomycin (100 µg/mL). Cells are cultivated in a 25 cm2 cultivation flasks under aerobic conditions at 37 °C. To maintain the exponential growth, the culture is 100x diluted and transferred to a new cultivation flask every 3 days.
Example 7
Example 7 describes drug-potency testing for growth-inhibition of N. fowleri with different benzoxaboroles.
The EC50is determined by exposing N. fowleri cells to various benzoxaborole-based compounds at different concentrations for 72 hours in 96-well plates (n=3). Each well contains 550 cells in a total volume of 100 µL of culture medium. For in vitro activation of MAO-B-sensitive methylamine prodrug derivatives, the culture medium is supplemented with 10 nM purified human MAO-B. Cell viability is determined after 72 h of exposure using a luminescent cell viability assay and the luminescent signal is read in a plate reader and the resulting data are analyzed.
Example 8
Example 8 describes results of dose–response analysis for growth-inhibition of N. fowleri with different benzoxaboroles.
EC50 = 0.15 µM
EC50 = 0.18 µM
EC50 > 50 µM
EC50=0.16 µM
(in the presence of 10 nM MAO-B)
EC50 = 2.17 µM
EC50 = 0.92 µM
EC50 = 1.96 µM
Example 9
Example 9 describes testing of activity of compound IIa in a murine model.
A group of 14 BALB/c mice, 12 weeks old and weighing 20 g, are intranasally infected with 2x104 cells of N. fowleri in phosphate-buffered saline (PBS) in a total volume of 30 μL under diethyl ether anesthesia. To obtain virulent N. fowleri cells, they are passaged through mice and each time, the brain is extracted postmortem, washed in a growth medium, and parasites are cultured in a cultivation flask at 37 °C. This procedure is repeated at least three times before experimental treatment.
The experimental treatment of PAM begins 24 h after intranasal infection by N. fowleri cells. 50 mg/kg of compound IIa in PBS in a total volume of 200 μL is administered intraperitoneally in a group of 7 mice every 8 hours for 5 or 10 days. The untreated control group containing 7 infected mice is treated in parallel with 200 μl PBS omitting the drug. Three uninfected mice are given the same IIa doses as the treated group as a toxicity control.
Use of benzoxaborole-based compounds in therapy of diseases caused by amoebas of the Naegleria genus is industrially applicable in the development and production of medicinal products against diseases caused by Naegleria fowleri.

Claims (1)

  1. Benzoxaborole-based compounds of general formula I,

    wherein:
    R1, R2, R3, R4, and R5 are independently selected from a group comprising -H, -F, aminomethyl group, formyl group, and aminomethyl group carrying a protecting group,
    and their pharmaceutically acceptable salts and hydrates
    for use in treatment of diseases caused by Naegleria fowleri.
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