Structure of 608-05-9
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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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The evaluation of isatin analogues as inhibitors of monoamine oxidase
Prinsloo, Izak F. ; Petzer, Jacobus P. ; Cloete, Theunis T. ; Petzer, Anel ;
Abstract: The small mol., isatin, is a well-known reversible inhibitor of the monoamine oxidase (MAO) enzymes with IC50 values of 12.3 and 4.86μM for MAO-A and MAO-B, resp. While the interaction of isatin with MAO-B has been characterized, only a few studies have explored structure-activity relationships (SARs) of MAO inhibition by isatin analogs. The current study therefore evaluated a series of 14 isatin analogs as in vitro inhibitors of human MAO-A and MAO-B. The results indicated good potency MAO inhibition for some isatin analogs with five compounds exhibiting IC50 < 1μM. 4-Chloroisatin (1b) and 5-bromoisatin (1f) were the most potent inhibitors with IC50 values of 0.812 and 0.125μM for MAO-A and MAO-B, resp. These compounds were also found to be competitive inhibitors of MAO-A and MAO-B with Ki values of 0.311 and 0.033μM, resp. Among the SARs, it was interesting to note that C5-substitution was particularly beneficial for MAO-B inhibition. MAO inhibitors are established drugs for the treatment of neuropsychiatric and neurodegenerative disorders, while potential new roles in prostate cancer and cardiovascular disease are being investigated.
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Keywords: competitive ; inhibition ; isatin ; monoamine oxidase ; structure-activity relationship
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Purchased from AmBeed: 6341-92-0 ; 91-56-5 ; 1127-59-9 ; 611-09-6 ; 7477-63-6 ; 6344-05-4 ; 443-69-6 ; 87-48-9 ; 39603-24-2 ; 608-05-9 ; 17630-76-1 ; 20205-43-0 ; 131609-60-4 ; 150560-58-0 ; 57816-97-4
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CAS No. : | 608-05-9 |
Formula : | C9H7NO2 |
M.W : | 161.16 |
SMILES Code : | O=C1NC2=C(C=C(C)C=C2)C1=O |
MDL No. : | MFCD00005721 |
InChI Key : | VAJCSPZKMVQIAP-UHFFFAOYSA-N |
Pubchem ID : | 11840 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H332-H335 |
Precautionary Statements: | P261-P280-P305+P351+P338 |
Num. heavy atoms | 12 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.11 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 47.12 |
TPSA ? Topological Polar Surface Area: Calculated from |
46.17 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.03 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.19 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.56 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.49 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.98 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.05 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.96 |
Solubility | 1.77 mg/ml ; 0.011 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.76 |
Solubility | 2.83 mg/ml ; 0.0176 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.15 |
Solubility | 0.113 mg/ml ; 0.000701 mol/l |
Class? Solubility class: Log S scale |
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) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
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 |
-6.44 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) |
1.5 |
* 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 |
---|---|---|
63% | With acetic acid; In ethanol;Reflux; | General procedure: 6-Fluoro-2-(2-(5-(un)substituted-2-oxoindolin-3-ylidene)hydrazino)benzothiazoles 5a-c. General Procedure C. A mixture of compound 2 (0.183 g, 0.001 mol), the appropriate isatin (0.001 mol) and glacial acetic acid (0.1 mL) in ethanol (20 mL) was heated at reflux temperature for 4-6 h. The precipitated yellow to orange solid was collected by filtration, washed with ethanol, dried and crystallized from methanol to yield compounds 5a-c. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With acetic acid; In water; at 90℃; for 6h;Green chemistry; | General procedure: The mixture of isatin (1 mmol), 3-amino-1-phenyl-1H-pyrazol-5(4H)-one (1 mmol), 1,2-diarylethan-1-one, 2,3-dihydroinden-1-one (1 mmol) or 3,4-dihydronaphthalen-1(2H)-one (1 mmol), H2O (6 mL), HOAc (2 mL) was put in a reaction flask under 90 C about 5-7 h (monitored by TLC). After completion, the reaction mixture was cooled to room temperature and the products would be isolated out at same time. Then, compound 4 was recrystallized from DMF, however, the pure products of 6 and 8 were filtered from water, dried, without further recrystallization. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With iodine pentoxide; In dimethyl sulfoxide; at 80℃; | General procedure: Indoles 1 (0.5 mmol), DMSO (3mL) and I2O5 (1 mmol) were added into a flask and vigorously stirred at 80oC under air. The reaction was stopped until indoles were completely consumed as monitored by TLC analysis. After the completion of reaction, saturated Na2S2O3 solution (20 mL) was added to the mixture. The mixture was extracted with EtOAc (3×20 mL) and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator. Then, the crude product was purified by column chromatography on silica gel using ethyl acetate and petroleum ether as the eluent to give the products 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With acetic acid; In ethanol; at 40 - 50℃; | General procedure: For the synthesis of Schiffbase, 1-3 substituted isatin was treated with commercially available different aromatic amines (1:1) in ethanol (30 mL) containing a few drops of glacial acetic acid. The resulting reaction mixture was heated at 40 -50 C for 3-4 h. The progress of the reaction was checked by TLC. After the completion of the reaction, the reaction mixture was cooled at room temperature, concentrated, poured into ice cold water and basified with 2 M NaOH (pH 10) resulting in the formation of a precipitate. The precipitate was filtered, washed with water and dried over CaCl 2 in the vacuum chamber to obtain the crude prod- uct. The product was then purified by column chromatography and finally crystallized using ethanol. |