Structure of 4-Phenoxybenzaldehyde
CAS No.: 67-36-7
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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Robenidine derivatives as potential antischistosomal drug candidates
Christian N. Lotz ; Alina Krollenbrock ; Lea Imhof ; Michael Riscoe ; Jennifer Keiser ;
Abstract: Schistosomiasis caused by Schistosoma spp. is a disease that causes a considerable health burden to millions of people worldwide. The limited availability of effective drugs on the market and the increased risk of resistance development due to extensive usage, highlight the urgent need for new antischistosomal drugs. Recent studies have shown that robenidine derivatives, containing an aminoguanidine core, exhibit promising activities against Plasmodium falciparum, motivating further investigation into their efficacy against Schistosoma mansoni, due to their similar habitat and the resulting related cellular mechanisms like the heme detoxification pathway. The conducted phenotypic screening of robenidine and 80 derivatives against newly transformed schistosomula and adult Schistosoma mansoni yielded 11 candidates with low EC50 values for newly transformed schistosomula (1.12–4.63 μM) and adults (2.78–9.47 μM). The structure-activity relationship revealed that electron-withdrawing groups at the phenyl moiety, as well as the presence of methyl groups adjacent to the guanidine moiety, enhanced the activity of derivatives against both stages of Schistosoma mansoni. The two compounds 2,2′-Bis[(3-cyano-4-fluorophenyl)methylene] carbonimidic Dihydrazide Hydrochloride (1) and 2,2′-Bis[(4-difluoromethoxyphenyl) ethylidene] carbonimidic Dihydrazide Hydrochloride (19), were selected for an in vivo study in Schistosoma mansoni-infected mice based on their potency, cytotoxicity, pharmacokinetic-, and physicochemical properties, but failed to reduce the worm burden significantly (worm burden reduction <20%). Thus, robenidine derivatives require further refinements to obtain higher antischistosomal specificity and in vivo activity.
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Keywords: Robenidine derivative ; Aminoguanidine ; Schistosoma mansoni ; Drug discovery ; Structure-activity relationship
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Purchased from AmBeed: 101048-76-4 ; 90-98-2 ; 36062-19-8 ; 99-61-6 ; 1261759-41-4 ; 218301-22-5 ; 67-36-7 ; 35714-48-8
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CAS No. : | 67-36-7 |
Formula : | C13H10O2 |
M.W : | 198.22 |
SMILES Code : | O=CC1=CC=C(OC2=CC=CC=C2)C=C1 |
MDL No. : | MFCD00003383 |
InChI Key : | QWLHJVDRPZNVBS-UHFFFAOYSA-N |
Pubchem ID : | 66139 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 15 |
Num. arom. heavy atoms | 12 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 3 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 58.35 |
TPSA ? Topological Polar Surface Area: Calculated from |
26.3 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.28 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
3.07 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
3.29 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.61 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
3.22 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.89 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.4 |
Solubility | 0.0795 mg/ml ; 0.000401 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.29 |
Solubility | 0.102 mg/ml ; 0.000514 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-4.61 |
Solubility | 0.00489 mg/ml ; 0.0000247 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
Yes |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
Yes |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
Yes |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-5.33 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
1.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
1.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.36 |
* 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 |
---|---|---|
80% | REFERENCE EXAMPLE 34 4-Phenoxybenzonitrile The title compound was obtained from 4-phenoxybenzaldehyde by the method similar to that in Reference Example 32. Yield: 80%. 1H NMR (CDCl3) δ 6.97-7.19 (4H, m), 7.20-7.28 (1H, m), 7.37-7.46 (2H, m), 7.57-7.64 (2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With triethylamine; In methanol; for 12h;Reflux; | General procedure: A solution of the corresponding aromatic aldehyde (0.8-10.3 mmol), 2-sulfanylacetic acid (1.0-1.3 equiv) and the corresponding aromatic nitrile (1.0-1.3 equiv) and triethylamine (1.5-15.0 equiv) in methanol was refluxed over night. The reaction mixture was evaporated under reduced pressure and the crude product was recrystallized from ethanol and washed with acetone. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With diisobutylaluminium hydride; at -70 - 20℃;Inert atmosphere; | General procedure: To a round bottom flask containing THF, the appropriate aryl nitrileanalogue (1.0 equiv.) was added followed by the addition of nitrogengas. Next, the solution was cooled to 70 C before the addition of aDIBAL-H (1.1 equiv.) solution (1.0 M in THF). After, the mixture wasstirred at 40 C for 5 h under nitrogen until TLC indicated the startingmaterial had been fully consumed. Subsequently, the reaction vessel wasplaced in an ice bath and quenched with 1 mL ethyl acetate and 20 mLHCl (1.0 M). After, the resulting solution was partitioned between EtOAcand brine. Using additional EtOAc, the aqueous brine solution waswashed three times and the combined organic layers were dried overNa2SO4, filtered, and concentrated via vacuum. The resulting concentratewas purified by silica gel chromatography.4.2.6.1. 4-phenoxybenzaldehyde (15a). White solid, yield 82%. 1H NMR(400 MHz, CDCl3) δ: 9.92 (s, 1H), 7.84 (d, J = 8.8 Hz, 2H), 7.46 - 7.37(m, 2H), 7.23 (t, J = 7.4 Hz, 1H), 7.09 (dd, J = 8.7, 1.1 Hz, 2H), 7.06 (d,J = 8.4 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ: 190.9, 163.3, 155.2,132.1, 131.4, 130.3, 125.1, 120.5, 117.7. HRMS (ESI + ) [M + H]+ calcdfor C13H11O2: 199.0754, found: 199.0753. |
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