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Design and synthesis of imidazo[1,2-a]pyridine-chalcone conjugates as antikinetoplastid agents
Agarwal, Devesh S. ; Beteck, Richard M. ; Ilbeigi, Kayhan , et al. Chem. Biol. Drug Des.,2024,103(1):e14400. DOI: 10.1111/cbdd.14400 PubMed ID: 37994272
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Abstract: A library of imidazo[1,2-a]pyridine-appended chalcones were synthesized and characterized using 1H NMR,13C NMR and HRMS. The synthesized analogs were screened for their antikinetoplastid activity against Trypanosoma cruzi, Trypanosoma brucei brucei, Trypanosoma brucei rhodesiense and Leishmania infantum. The analogs were also tested for their cytotoxicity activity against human lung fibroblasts and primary mouse macrophages. Among all screened derivatives, (E)-N-(4-(3-(2-chlorophenyl)acryloyl)phenyl)imidazo[1,2-a]pyridine-2-carboxamide was found to be the most active against T. cruzi and T. b. brucei exhibiting IC50 values of 8.5 and 1.35 μM, resp. Against T. b. rhodesiense, (E)-N-(4-(3-(4-bromophenyl)acryloyl)phenyl)imidazo[1,2-a]pyridine-2-carboxamide was found to be the most active with an IC50 value of 1.13 μM. All synthesized active analogs were found to be non-cytotoxic against MRC-5 and PMM with selectivity indexes of up to more than 50.
Keywords: antikinetoplastid ; chalcone ; drug likeliness properties ; imidazo[1,2-a]pyridine ; neglected tropical diseases (NTDs) ; Trypanosoma brucei brucei ; Trypanosoma brucei rhodesiense
Purchased from AmBeed: 613-45-6 ; 587-04-2 ; 1122-91-4 ; 64951-08-2 ; 99-92-3 ; 99-92-3 ; 456-48-4 ; 555-16-8 ; 94-41-7 ; 104-88-1 ; 1113-59-3 ; 459-57-4 ; 529-20-4 ; 6287-38-3 ; 1113-59-3
CAS No. : | 94-41-7 | MDL No. : | MFCD00003082 |
Formula : | C15H12O | Boiling Point : | - |
Linear Structure Formula : | C6H5C(O)CHCHC6H5 | InChI Key : | DQFBYFPFKXHELB-VAWYXSNFSA-N |
M.W : | 208.26 | Pubchem ID : | 637760 |
Synonyms : |
benzylideneacetophenone;phenyl styryl ketone;NSC 26612;β-phenylacrylophenone;benzalacetophenone
|
Chemical Name : | 2-Benzalacetophenone |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P264-P280-P302+P352+P332+P313+P362+P364-P305+P351+P338+P337+P313 | UN#: | N/A |
Hazard Statements: | H315-H319 | Packing Group: | N/A |
GHS Pictogram: |
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* 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 |
---|---|---|
With potassium hydroxide; In ethanol; for 10h;Reflux; | 1,3-Diphenyl propen-2-one (0.01mol) (1) were taken in a 250 mL round bottom flask and dissolved in ethanol (25 mL). To this guanidine chloride (0.01 mol) and ethanolic KOH (5 mL of 40 %) were added. The reaction mixture was refluxed for 10 h. The mixture was then poured into water (ice-cold) and neutralized with dil. HCl. After neutralization, the solid was filtered, washed with excess of water, dried and recrystallized from ethanol from ethanol to give pure product. Spectral data for compound 2: The IR of compound 2 exhibited nu (C=C) stretching = 1537-1494 cm-1, nu(N-H) (1 amine) stretching = 3302 cm-1 and 3475 cm-1, nu (C-N) stretching = 1220.98 cm-1, nu(C-H)(Sp2) stretching = 3180.72 cm-1. 1H NMR (400 MHz, DMSO-d6) delta ppm: 3.43 (s, 3H,-OCH3), 5.1 (s, 2H, -NH2), 7.0 to 8.0 (m, 20H, Ar-H and NH) [9]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35.6% | With potassium methanolate; In ethanol; at 70℃; for 20.67h;Heating / reflux; | 212.6 g (1.0 mol) of 98% 1,3-diphenyl-2-propen-1-one, 249.1 g (2.0 mol) of 98% guanidine nitrate and 1.51 of absolute ethanol are initially introduced at 70 C. 289.2 g (4.0 mol) of 97% potassium methoxide are then added in portions to the white suspension over the course of 40 minutes. After 20 hours at reflux, the yellow suspension is cooled to 50 C. and poured into 6 l of water, extracted with ethyl acetate, and concentrated by evaporation and the residue is recrystallized from isopropanol. 88.1 g of pale yellow crystals are obtained of the compound 1 [C00056] [00397] (=35.6% yield) with a melting point of 134-136 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With iodine; acetic acid; at 100℃; for 0.833333h; | General procedure: A mixture of a selected chalcone (0.5 mmol), 4-hydroxycoumarin (0.5 mmol),and iodine (0.5 mmol) was dissolved in 2-3mL acetic acid. Then, the mixture was stirred under reflux at 100 C for the time indicated in Table 1. The reaction mixture was cooled to room temperature and diluted with water, followed by Na2S2O3*H2O solution to quench excess iodine. The reaction mixture was filtered invacuo, and the residue was purified by column chromatography on silica gel (100-200mesh) usingh exane=EtOAc (10:2 to 10:1, v=v) as eluent to give the pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With sodium carbonate; In acetonitrile; at 80℃; | General procedure: The mixture of the chalcone 3 (0.2 g), amidine (1.2 eq), andsodium carbonate (2.4 eq) in acetonitrile (10 ml) was refluxed forovernight at 80 C. The time required for the product formationvaries from different products (24-48hrs). The progress of reactionwas monitored by the TLC in 30% ethylacetate/petroleum ether.After the completion of the reaction, the reaction mixture wasdried on the rotavapor. To the residue water was added and crudeproduct was extracted with with ethyl acetate. The organic portionwas separated and washed with water, brine, dried over anhydroussodium sulfate and rota-evaporated. Compounds were purifiedthrough column chromatography using chloroform and methanolas solvent. Final product formation was confirmed by EI-MS, CHNand HRMS. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10% | With tin dioxide; iodine; In toluene; at 110℃; for 12h; | General procedure: A mixture of 2-aminopyridine (1a, 1 mmol), 1,3-diphenyl-2-propen-1-one (2a, 1 mmol), SnO2 (10 mol %) and I2 (0.5 equivalent) were refluxed in toluene for 12 h. The reaction was monitored by TLC. After completion of the reaction, the resulting reaction mixture was cooled to room temperature and dissolved in ethyl acetate and the catalyst was separated using centrifugation. The obtained filtrate containing the product was washed using a saturated Na2S2O3 solution (15 mL) and then acidified with the 1N HCl (3 × 7 mL). After that, the aqueous acidic layer was separated and neutralized using a 1N NaOH solution. The precipitated product was filtered off and then confirmed by 1H and 13C NMR spectroscopic methods. . |
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