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Hydrazinated geraniol derivatives as potential broad-spectrum antiprotozoal agents
Jooste, Joelien ; Legoabe, Lesetja J ; Ilbeigi, Kayhan , et al. Arch. Pharm.,2024,e2400430.
Abstract: Geraniol, a primary component of several essential oils, has been associated with broad-spectrum antiprotozoal activities, although moderate to weak. This study primarily concentrated on the synthesis of hydrazinated geraniol derivatives aspotential antiprotozoal agents. The synthesised compounds were tested in vitro against different parasitic protozoans of clinical relevance, including Trypanosoma brucei brucei, Trypanosoma brucei rhodesiense, Trypanosoma cruzi and Leishmania infantum. Compounds 6, 8, 13, 14 and 15 demonstrated low micromolar activity against the different parasites. Compounds 8, 13, 14 and 15 had the highest efficacy against Trypanosoma brucei rhodesiense, as indicated by their respective IC50 values of 0.74, 0.56, 1.26 and 1.00 μM. Compounds 6, 14 and 15 displayed the best activity against Trypanosoma brucei brucei, with IC50 values of 1.49, 1.48 and 1.85 μM, respectively. The activity of compounds 6, 14 and 15 also extended to intracellular Trypanosoma cruzi, with IC50 values of 5.14, 6.30 and 4.90 μM, respectively. Compound 6, with an IC50 value of 11.73 μM, and compound 14, with an IC50 value of 8.14 μM, demonstrated some modest antileishmanial activity.
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Keywords: geraniol ; Leishmania infantum ; Trypanosoma brucei brucei ; Trypanosoma brucei rhodesiense ; Trypanosoma cruzi
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Arylnitro monocarbonyl curcumin analogues: Synthesis and in vitro antitubercular evaluation
du Preez, Charne ; Legoabe, Lesetja J. ; Jordaan, Audrey , et al. Chem. Biol. Drug Des.,2023,101(3):717-726.
Abstract: Curcumin is a natural product that has been reported to exhibit myriad pharmacol. properties, one of which is antitubercular activity. It demonstrates antitubercular activity by directly inhibiting Mycobacterium tuberculosis (M.tb) and also enhances immune responses that ultimately lead to the elimination of M.tb by macrophages. This natural product is, however, unstable, and several analogs, noticeably monocarbonyl analogs, have been synthesized to overcome this challenge. Curcumin and its monocarbonyl analogs reported so far exhibit moderate antitubercular activity in the range of 7 to 16 μM. Herein, we report a straightforward synthesis of novel monocarbonyl curcumin analogs, their antitubercular activity, and the structure-activity relationship. The hit compound from this study, 3a, exhibits potent MIC90 values in the range of 0.2 to 0.9 μM in both ADC and CAS media.
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Keywords: analogues ; aryl nitro ; curcumin ; synthesis ; tuberculosis
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Purchased from AmBeed: 552-89-6 ; 458-37-7 ; 698-63-5 ; 99-61-6 ; 30626-03-0 ; 30625-98-0 ; 1675220-86-6 ; 30625-99-1
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Nitrothiazole-Thiazolidinone Hybrids: Synthesis and in Vitro Antimicrobial Evaluation
Dylan Hart ; Lesetja J. Legoabe ; Omobolanle J. Jesumoroti , et al. Chem. Biodivers.,2022,19(11):e202200729.
Abstract: Herein we report the synthesis of novel compounds inspired by the antimicrobial activities of nitroazole and thiazolidin-4-one based compounds reported in the literature. Target compounds were investigated in?vitro for antitubercular, antibacterial, antifungal, and overt cell toxicity properties. All compounds exhibited potent antitubercular activity. Most compounds exhibited low micromolar activity against S. aureus and C. albicans with no overt cell toxicity against HEK-293 cells nor haemolysis against human red blood cells. Notably, compound 3b exhibited low to sub-micromolar activities against Mtb, MRSA, and C. albicans. 3b showed superior activity (0.25?μg/ml) against MRSA compared to vancomycin (1?μg/ml).
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CAS No. : | 552-89-6 |
Formula : | C7H5NO3 |
M.W : | 151.12 |
SMILES Code : | O=CC1=CC=CC=C1N(=O)=O |
MDL No. : | MFCD00007132 |
InChI Key : | CMWKITSNTDAEDT-UHFFFAOYSA-N |
Pubchem ID : | 11101 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335-H412 |
Precautionary Statements: | P261-P264-P270-P271-P273-P280-P301+P312+P330-P302+P352-P304+P340+P312-P305+P351+P338-P332+P313-P337+P313-P403+P233-P405-P501 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With hydrogenchloride; acetic acid; In methanol; ethanol; water; | 4-Hydroxymethyl-2-(2-nitrophenyl)-benzimidazole (3) 2,3-Diaminobenzyl alcohol 2 (3.45 g, 25 mmol) was dissolved in a MeOH/H2O mixture (200 mL, v/v=1:1). Acetic acid (3 mL), 2-nitro-benzaldehyde (5.3 g, 35 mmol) in MeOH (50 mL) and Cu(OAc)2.H2O (7.0 g, 35 mmol) in water (100 mL), were added sequentially to the stirring solution. It was then heated to reflux under vigorous stirring for 3 hr, after which a pale yellow precipitate was formed. The mixture was filtered hot and then washed with water to afford a gray-yellow solid. The precipitate was redissolved in EtOH (150 mL) and concentrated HCl (24 mL), and then a solution of Na2S.9H2O (12.8 g, 50 mmol) in water (100 mL) was added. The mixture was heated at reflux for 1 hour resulting in a black slurry. It was then allowed to cool to room temperature, and filtered through a pad of celite to remove the resulting CuS. The filtrate was neutralized with ammonium hydroxide to pH=8-9 and then concentrated by rotary evaporation to yield a green-yellow precipitate. After filtration and vacuum evaporation, 4-hydroxymethyl-2-(2-nitrophenyl)-benzimidazole (5.55 g, 82%) was obtained as a green-yellow solid. Rf=0.28 (hexane/ethyl acetate=1:2); 1H NMR (200 MHz, DMSO) delta 4.84 (broad s, 2H), 5.22 (broad s, 1H), 7.28 (m, 2H), 7.49 (d, J=6.8 Hz, 1H), 7.71-8.06 (m, 4H), 12.93 (broad s, 1H); HRMS: Calcd. for C14H11N3O3 269.0800, found 269.0845. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With sodium cyanoborohydride; acetic acid; In ethyl acetate; at 20℃; for 15h; | Example 111: Preparation of Compound 111.Step 1.; Aminoproline (8g, 34 mmol) and nitrobenzaldehyde (15g, 102 mmol) were taken up in ethyl acetate (20OmL) in a 50OmL round bottomed flask. The reaction was stirred with a magnetic stirrer at room temperature. Sodium cyanoborohydride (6.4g, 102 mmol) and acetic acid (6.ImL, 102 mmol) were added and the reaction was allowed to stir at room temperature for 15 h. The reaction mixture was then quenched with saturated sodium bicarbonate solution and the layers separated. The organic layer was washed with brine, dried with sodium sulfate, and concentrated. Purification was performed via flash chromatography (hexanes/ethyl acetate) to provide 5g (40percent yield) of the desired nitrobenzyl adduct.This product was then taken up in ethanol (10OmL) in a round bottomed flask, and activated palladium on carbon (10percent) was added. The flask was then charged with hydrogen gas and stirred for 2 hours at room temperature. The reaction mixed was then filtered through a fritted funnel to remove the palladium on carbon. The filtrate was concentrated and then purified via flash column chromatography to provide3.5g (70percent yield) of the desired diamine. EPO <DP n="146"/> |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Dissolve <strong>[21917-76-0]2-methyl-thiazole-4-carbonitrile</strong> (3. 50G, 28.19 mmol) in 200 ml of tetrahydrofuran (THF) and cool in a dry ice/acetone bath for 1.5 hours. Slowly add n- butyllithium (26.4 ml of a 1.6M solution in hexanes, 42.28 mmol) and stir for one hour. Add a THF solution of 2-nitrobenzaldehyde (4.69g, 31. 01 mmol, in 50 ml of THF) and stir in cold bath for 12 hours. Allow the reaction mixture to warm to room temperature, and add 100 ml of saturated aqueous ammonium chloride to quench the reaction. Extract three times with ethyl acetate, combine organic layers and dry over sodium sulfate. Remove solvent under reduced pressure. Purification via flash chromatography, eluting with a step gradient starting with hexanes and going to 75% hexanes with 25% ethyl acetate, gives the title compound: Mass Spectrum (m/e): 276 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8%; 20%; 9%; 8%; 14%; 12%; 13% | With N-Bromosuccinimide; sulfuric acid; at 25℃; for 3h; | Treatment of 1 (504 mg, 3.33 mmol) and NBS (1.48 g, 8.30 mmol) in H2SO4 (3.0 mL) as described above provided after purification by chromatography (hexanes/EtOAc, 85:15) the following fractions in order of elution: (I) 7 (65 mg, 0.21 mmol, 9percent); (II) 2 (153 mg, 20percent), 4 (58 mg, 8percent), and 6 (128 mg, 12percent); (III) 5 (108 mg, 14percent), 8 (129 mg, 13percent), and 1 (17 mg, 3percent); (IV) 3 (57 mg, 0.25 mmol, 8percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21%; 1%; 9%; 20%; 5% | With N-Bromosuccinimide; sulfuric acid; at 25℃; for 3h; | N-Bromosuccinimide (NBS) (1.48 g, 8.32 mmol) was added to a solution of 1 (1.01 g, 6.71 mmol) in H2SO4 (concentrated 5.0 mL). The resulting mixture was stirred at ambient temperature (3 h). The reaction was quenched with ice and extracted with ethyl acetate (320mL). The combined organic phases were washed with saturated NaCl (aqueous, 30 mL), dried (MgSO4), and filtered through a silica gel plug, and the solvents were evaporated under reduced pressure. The resulting brown oil was purified by column chromatography (hexanes=EtOAc, 8:2) to afford the following fractions in order of elution: (I) 7 (28 mg, 0.09 mmol, 1percent) as an off-white solid; (II) 2 (328 mg, 21percent), 4 (140 mg, 9percent), and 3,4-dibromo-2-nitrobenzaldehyde (6) (94 mg, 5percent); (III) 5 (310 mg, 20percent), 8 (65 mg, 3percent), 1 (168 mg, 17percent); (IV) 3 (54 mg, 0.23 mmol, 4percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19%; 1%; 12%; 24% | With N-Bromosuccinimide; sulfuric acid; at 25℃; for 3h; | Treatment of 1 (986 mg, 6.53 mmol) with NBS (878 mg, 4.93 mmol) in H2SO4 (conc. 5.0 mL), as described in the paper gave after chromatography (hexanes/EtOAc, 8:2) the following fractions in order of elution: (I) 4-bromo-2-nitrobenzaldehyde (2)1 (216 mg, 19percent), 5-bromo-2-nitrobenzaldehyde (4)2 (134 mg, 12percent), and 4,5-dibromo-2-nitrobenzaldehyde (7) (18 mg, 1percent) as a yellow solid; (II) 6-bromo-2-nitrobenzaldehyde (5) (268 mg, 24percent),3 3,6-dibromo-2-nitrobenzaldehyde (8) (25 mg, 2percent),4 and 1 (409 mg, 41percent) as a yellow oil; (III) 3-bromo-2-nitrobenzaldehyde (3)5 as a yellow solid (60 mg, 0.26 mmol, 4percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10%; 2%; 8%; 9% | With N-Bromosuccinimide; sulfuric acid; at 60℃; for 3h; | Treatment of 1 (459 mg, 3.03 mmol) and NBS (677 mg, 3.80 mmol) in H2SO4 (3.0 mL) at 60 oC as described above afforded the following fractions in order of elution: (I) 7 (21 mg, 0.07 mmol, 2percent); (II) 2 (66 mg, 9percent) and 4 (24 mg, 3percent); (III): 2 (5 mg, 0.7percent) and 3,4-dibromo-2-nitrobenzaldehyde 6 (85 mg, 9percent); (IV) 5 (59 mg, 8percent), 8 (13 mg, 1percent), and 1 (18 mg, 4percent); (V) 3 (20 mg, 0.09 mmol, 3percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74.5% | In ethanol;Reflux; | General procedure: solutionof acid hydrazide (0.01 mol) and appropriate benzaldehyde/acetophenone (0.01 mol) in ethanol was refluxed for 5-6 h. The precipitated title compounds were then filtered off, washed with water and recrystallized from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With acetic acid; In ethanol; at 80℃; for 0.166667h;Microwave irradiation; | General procedure: 2-(2-Arylidenehydrazino)-6-fluorobenzothiazoles 6a-r. General Procedure D. A mixture of compound 2 (0.0549 g, 0.0003 mol), the appropriate aromatic aldehyde (0.00033 mol) and glacial acetic acid (0.1 mL) in ethanol (5 mL) was heated under microwave (20 W) at 80 °C for 10 min. On cooling, the precipitated solid was collected by filtration, washed with water, dried and crystallized from the appropriate solvent to give the desired compounds 6a-r. |
In ethanol; at 70 - 80℃; for 3h; | General procedure: The mixture of <strong>[78364-55-3]6-fluoro-2-hydrazinylbenzo[d]thiazole</strong> (2) (0.01 mol) and benzalde-hyde/substituted benzaldehyde (0.01 mol) was reuxed in ethanol (15 ml) at 70?80 °C for 3 h. The separated product obtained was ltered off, washed withdistilled water and recrystallized from methanol to give the correspondinghydrazone. The product obtained was further dissolved in acetic acid (20 ml) atroom temperature followed by the addition of sodium acetate (0.5 g). Bromine(2 mmol) in acetic acid (10 ml) was added dropwise to the reuxing reactionmixture. After 1 h, the mixture was poured onto crushed ice (100 g). The precipitateobtained was ltered off and crystallized from ethanol-dimethylformamide (1:1) togive crystals of (3a?3t). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; for 1h;Reflux; | General procedure: Hydrazones 4b and 4c were prepared according to the literature procedure [1] . The new hydrazones are prepared as follow: The hydrazine (15 mmol) was dissolved in a sufficient amount of boiling ethanol and the aldehyd (15 mmol), dissolved in 20 ml ethanol, was added dropwise. After that, the solution was stirred and heated under reflux for 1 h. The formed hydrazone was filtered from the cooled solution and used in the next reaction without any purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With methanol; sodium cyanoborohydride; at 20℃; for 12h; | Step 1: Ter<strong>[392331-66-7]t-butyl 4-(aminomethyl)-4-hydroxypiperidine-1-carboxylate</strong> (3.1 g, 13 mmol) obtained by the method described in WO2005/000837 was dissolved in methanol (150 mL), and 2-nitrobenzaldehyde (2.0 g, 13 mmol) and sodium cyanoborohydride (1.3 g, 26 mmol) were added thereto, and the resulting mixture was stirred at room temperature for 12 hours. After the reaction mixture was concentrated under reduced pressure, water was added thereto, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate. A residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (a hexane/ethyl acetate mixed solvent), whereby tert-butyl 4-hydroxy-4-[(2-nitrobenzylamino)methyl]piperidine-1-carboxylate (2.2 g, yield: 40%) was obtained. (0297) 1H-NMR (400 MHz, CDCl3, delta): 7.97 (dd, J=8.0, 0.8 Hz, 1H), 7.64-7.45 (m, 3H), 5.32 (s, 1H), 4.10 (s, 2H), 3.86 (br s, 2H), 3.18 (t, J=12 Hz, 2H), 2.59 (s, 2H), 1.55-1.40 (m, 13H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12% | General procedure: Trans-2-phenylcyclopropylamine hydrochloride (1.0 eq.), acetic acid (1.0eq.) and the appropriate aldehyde (0.9 eq.) were dissolved in around bottom flask in 10 mL dry DCE. The reaction mixture was stirred gently at room temperature for 2 h before sodium triacetoxyborohydride (3.0 eq.) was added in small portions to the reaction vessel. The reaction was monitored by TLC and quenched using 10 mL of an aqueous (5%) NaHCO3 solution. The organic layer was separated and the aqueous layer extracted three times with10 mL of DCE. All organic layers were combined, dried over anhydrous Na2SO4, concentrated in vacuo and purified using flash chromatography (silica gel; cyclohexane/ethyl acetate) to give the desired compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.0% | The compound (II) o-nitrobenzaldehyde (0.80 g, 5.30 mmol) and concentrated sulfuric acid (98 wtpercent, 6.4 ml) were placed in a reaction flask and stirred under a cold well for 10 minutes.Then, NBS (1.13 g, 6.36 mmol) was slowly added and stirred for 5 minutes, and finally transferred to an oil bath at 45 ° C and allowed to react under light for 45 minutes.After the reaction was completed, it was cooled to room temperature, and the reaction mixture was poured into crushed ice and quenched, and then extracted with ethyl acetate (50 ml).Wash with saturated aqueous sodium hydrogencarbonate (50 ml), dry over anhydrous sodiumdry,Obtained 281 mg of bromo o-nitrobenzaldehyde (III) as a brownish yellow solid, yield 92.0percent, purity ?98percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | for 0.15h;Microwave irradiation; | General procedure: Second step consists of condensation of <strong>[6761-52-0]3-aminopyrazine-2-carbohydrazide</strong> (0.5 gm, 0.003 mol) with aromatic aldehydes (0.5 gm, 0.008 mol) using microwaveirradiation (8 - 10 min, 350 W). After cooling and filtration,the product was recrystallized using ethanol [6, 9] (Fig. 1). |
Tags: 552-89-6 synthesis path| 552-89-6 SDS| 552-89-6 COA| 552-89-6 purity| 552-89-6 application| 552-89-6 NMR| 552-89-6 COA| 552-89-6 structure
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P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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* Country/Region
* Quantity Required :
* Cat. No.:
* CAS No :
* Product Name :
* Additional Information :
Calculate the required mass, volume, or concentration of the solution. The Ambeed Molarity calculator is based on the following equation:
Concentration (mol/L) × Volume (L) × Molecular Weight (g/mol)= Mass (g)
Concentration
Volume
Molecular Weight
Mass
* When preparing stock solution, always refer to the molecular weight of the corresponding batch as shown on the product label or MSDS/COA (available for download on the product page).
Total Compounds: mg
The concentration of the dissolution solution you need to prepare is mg/mL