Structure of 7-Methylisatin
CAS No.: 1127-59-9
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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. : | 1127-59-9 |
Formula : | C9H7NO2 |
M.W : | 161.16 |
SMILES Code : | CC1=C2NC(=O)C(=O)C2=CC=C1 |
MDL No. : | MFCD00022797 |
InChI Key : | UEHZKEABUOAZSH-UHFFFAOYSA-N |
Pubchem ID : | 14313 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H319-H412 |
Precautionary Statements: | P273-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 |
1.11 |
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 |
1.06 |
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) |
1.55 |
* 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 |
---|---|---|
77% | With bromine; In chloroform; at 20 - 80℃; for 24.25h; | Step 3: 5-bromo-7-methylindoline-2,3-dioneTo a stirred mixture of 7-methylindoline-2,3-dione (7 g, 0.043 mol) in chloroform (700 mL) was added a solution of bromine (2.8 mL, 0.053 mol) in chloroform (100 mL) dropwise over 15 min at room temperature. The reaction mixture was heated at 80C for 24 h and then cooled to 0C, which resulted in precipitation of the product as a red solid. The solid was collected by suction filtration and dried under vacuum to afford the title compound (8 g, 77%).XH NMR (400 MHz, DMSO-d6) : δ 11.20 (s, 1H), 7.64 (d, J = 1.2 Hz, 1H), 7.42 (d, J = 7.2 Hz, 1H), 2.18 (s, 3H); ESI-MS: Calculated mass: 238.96; Observed mass: 238.30 [M-H]". |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With ammonium hydroxide; dihydrogen peroxide; In dimethyl sulfoxide; at 20 - 30℃; for 4h;Sealed tube; | General procedure: A sealed tube was charged with isatin 1 (1a 147 mg, 1.0 mmol), ammonia hydrate 2 (25%, 421 mg, 3.0 mmol) and H2O2 (30%, 227 mg, 2.0 mmol) at room temperature, and then solvent DMSO (4 mL) was added. The resulting mixture was stirred at 30 C in a sealed vessel under air after 4 h, then added 50 mL water to the mixture, extracted with CH3COOC2H5 3 times (3 x 50 mL). The extract was washed with 30% NaCl solution (V/V), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (Petroleum ether/Ethyl acetate = 3:1) to yield the desired product 3a as a yellow solid (89% yield). |
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