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Lish, Matthew S ; McKeon, Jillian EM ; Palmentiero, Caroline M , et al. JMC,2024,67(20):18265-18289. DOI: 10.1021/acs.jmedchem.4c01630 PubMed ID: 39402986
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Abstract: Primary amoebic meningoencephalitis (PAM) is a human brain infection caused by Naegleria fowleri with a 97% mortality rate. Quinazolinones resulting from a Mannich-coupled domino rearrangement were recently identified as inhibitors of the amoeba. Herein, we resolved the effective concentrations for 25 pilot compounds and then, using the Mannich protocol and a key late-stage, N-demethylation/functionalization, we synthesized 53 additional analogs to improve potency, solubility and microsomal stability. We established an antiamoebic quinazolinone pharmacophore, culminating in (±)-trans-57b which featured the best combination of potency, selectivity index, solubility, and microsomal stability. Enantiomeric separation afforded (4aS,13bR)-57b (BDGR-20237) with a 41-fold potency advantage over its enantiomer. ADME and mouse pharmacokinetic profiling for BDGR-20237 revealed high brain penetrance but a limited half-life which did not statistically enhance the mouse survival in a pilot efficacy study. The pharmacophoric model, supported by 88 quinazolinones, several of which exhibit subnanomolar potency, will guide further scaffold optimization.
Purchased from AmBeed: 657408-07-6 ; 52409-22-0 ; 72287-26-4 ; 1122-58-3
CAS No. : | 657408-07-6 | MDL No. : | MFCD05861611 |
Formula : | C26H35O2P | Boiling Point : | - |
Linear Structure Formula : | (C6H11)2P(C6H4C6H3(OCH3)2) | InChI Key : | VNFWTIYUKDMAOP-UHFFFAOYSA-N |
M.W : | 410.53 | Pubchem ID : | 11269872 |
Synonyms : |
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Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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 |
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With N2;tris-(dibenzylideneacetone)dipalladium(0); Pd2(dba)3; In tetrahydrofuran; 5,5-dimethyl-1,3-cyclohexadiene; hexane; dichloromethane; toluene; | A mixture of 9-phenyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-carbazole (12 g, 32.5 mmol), 3-bromo-9H-carbazole (6.66 g, 27.1 mmol), and potassium phosphate (34.5 g, 162 mmol) in 500 mL of toluene and 50 mL of H2O was bubbled with N2 for 20 min. Dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine (0.445 g, 1.083 mmol) and Pd2(dba)3 (0.248 g, 0.271 mmol) were then added, and the mixture was heated to reflux under N2 for 5 h. TLC indicated the reaction was done. The reaction was extracted with dichloromethane and washed with brine and dried with magnesium sulfate. The solution was heated up to boil. Hexane was added. The dichloromethane was boiled off and hexanes volume reached about 1200 mL. Precipitate formed during boiling off dichloromethane. The solution was cooled to room temperature and stirred overnight. The precipitate was filtered and dissolved in THF and ran a short silica gel plug. After dried under vacuum at 60 C., 9.6 g (87%) of product was obtained. Synthesis of Compound 1. A mixture of <strong>[5408-56-0]2-iododibenzo[b,d]furan</strong> (2.59 g, 8.81 mmol), 9-phenyl-9H,9'H-3,3'-bicarbazole (3 g. 7.34 mmol), and sodium t-butoxide (1.764 g, 18.36 mmol) in 200 mL of xylene was bubbled with N2 for 20 min. Dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine (0.121 g, 0.294 mmol) and Pd2(dba)3 (0.067 g, 0.073 mmol) were then added, and the mixture was heated to reflux under N2 for 24 h. The mixture was cooled and filtered through Celite. After solvent evaporation, the residue was coated on Celite and purified by column chromatography 3.7 g of product was obtained after column. |
Yield | Reaction Conditions | Operation in experiment |
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With potassium phosphate;tris-(dibenzylideneacetone)dipalladium(0); In dichloromethane; water; ethyl acetate; toluene; | Example 4 Synthesis of Benzo[b]phenanthro[9,10-d]thiophene The synthesis is based on Tetrahedron, 37(1), 75-81, 1981. To a 500 mL 3-neck round bottom flask was added <strong>[6287-82-7]2,3-dibromobenzo[b]thiophene</strong> (5.0 g, 17.12 mmol), phenylboronic acid (5.2 g, 42.81 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (281 mg, 0.68 mmol), K3PO4 (11.8 g, 51.36 mmol), 150 mL of toluene and 5 mL of water. N2 was bubbled directly into the flask for 20 minutes. Pd2(dba)3 (157 mg, 0.171 mmol) was added to the reaction mixture which was then heated to reflux for 5 h. Water was added to the cooled reaction mixture and the layers were separated. The aqueous layer was extracted twice with CH2Cl2 and the organic extracts were dried over MgSO4, filtered, and evaporated to yield a red oil which was dried to give 5.71 g of a red solid. The solid was purified by silica gel column chromatography (10-20% CH2Cl2 in hexanes) to yield 4.81 g of the product as a white solid. A photoreactor was loaded with 2,3-diphenylbenzo[b]thiophene (4.81 g, 16.8 mmol) and 800 mL toluene. The solution was irradiated using a medium pressure mercury lamp for 12 h. The solvent was evaporated and the residue was purified by silica gel column chromatography (0-20% of EtOAc in hexanes). The product was collected and recrystallized from hexanes (with a small amount of EtOAc to initially dissolve the material) to yield 1.61 g of product an off-white solid. Benzo[b]phenanthro[9,10-d]thiophene showed a triplet energy of 488 nm at 77 Kin 2-methylTHF. |
Yield | Reaction Conditions | Operation in experiment |
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With nitrogen; In water; toluene; | 2-chlorobenzofuro[2,3-b]pyridine (1.33 g, 6.53 mmol), phenylboronic acid (1.19 g, 9.80 mmol), potassium phosphate (4.51 g, 19.59 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (0.214 g, 0.522 mmol) and Pd2(bda)3 (0.119 g, 0.13 mmol) were to toluene (40 mL) and water (4 mL). Nitrogen was bubbled through the solution for 30 minutes and then the solution was refluxed for overnight in an atmosphere of nitrogen. The reaction was then allowed to cool to room temperature and the organic phase was separated from the aqueous phase. The aqueous phase was extracted with ethylacetate and the organic fractions were combined and dried over sodium sulfate and the solvent removed under vacuum. The product was chromatographed using silica gel with ethylacetate and hexanes as the eluent. The solvent was removed to give 1.45 g of title compound. Synthesis of Compound 8: Iridium intermediate (1.15 g, 1.55 mmol) and 2-phenylbenzofuro[2,3-b]pyridine (1.14 g, 4.66 mmol) was mixed in 30 mL of anhydrous ethanol. |