New Molecules of Diterpene Origin with Inhibitory Properties toward α-Glucosidase
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Inhibition of Yeast α-Glucosidase
2.3. The Mechanism of α-Glucosidase Inhibition by Compound 45
2.4. Docking Studies for Compound 45
2.5. ADMET Profiling of Compound 45
3. Materials and Methods
3.1. General
3.2. Synthesis of Compounds 42 and 44
3.3. Synthesis of Methyl 1-Hydroxy-13-Isopropyl-1′-(Ethoxycarbonyl)-7,10a,2′-Trimethyl-5,6,6b,7,8,9,10,10a,10b,11,12,13-Dodecahydro-12,4b-Ethenophenanthro-[2,1-g]indole-7-Carboxylate (43)
3.4. Synthesis of Compounds 45, 46 and 49
3.5. Synthesis of Compounds 47 and 50
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Compound | IC50 ± SE (µM) |
---|---|
1 | 59.59 ± 0.18 |
2 | >255 |
3 | >255 |
4 | >255 |
5 | >255 |
6 | 1.63 ± 0.006 |
7 | 2.50 ± 0.011 |
8 | 35.57 ± 0.92 |
9 | 35.24 ± 0.71 |
10 | >255 |
11 | >255 |
12 | >255 |
13 | >255 |
14 | >255 |
15 | >255 |
16 | >255 |
17 | >255 |
18 | >255 |
19 | >255 |
20 | >255 |
21 | >255 |
22 | >255 |
23 | >255 |
24 | >255 |
25 | >255 |
26 | 13.08 ± 0.01 |
27 | >255 |
28 | 12.73 ± 0.21 |
29 | 1.63 ± 0.041 |
30 | 38.80 ± 0.33 |
31 | >255 |
32 | 9.66 ± 0.77 |
33 | 65.98 ± 0.03 |
34 | >255 |
35 | 7.95 ± 0.20 |
36 | 8.94 ± 0.96 |
37 | 7.28 ± 0.40 |
38 | 0.39 ± 0.03 |
39 | 44.77 ± 0.96 |
40 | 7.088 ± 0.12 |
41 | >255 |
42 | 2.52 ± 0.34 |
43 | >255 |
44 | 68.22 ± 0.03 |
45 | 0.15 ± 0.008 |
46 | >255 |
47 | 4.95 ± 0.25 |
48 | 0.68 ± 0.045 |
49 | >255 |
50 | 0.23 ± 0.01 |
Acarbose (reference drug) | 181.02 ± 3.1 |
Property | ADMETlab [46] | ADMETlab 2.0 [47] | SwissADME [48] | ProTox-II [49] | Consensus Value |
---|---|---|---|---|---|
Physicochemical | |||||
Water solubility (μg/mL) | 1.94 | 2.57 | 0.02 | 1.51 | |
LogP | 6.21 | 4.93 | 6.30 | 6.69 | 5.81 |
Absorption | |||||
Human intestinal absorption | Yes | No | Low | No | |
Human oral bioavailability | No | No | No | ||
Caco-2 permeability | Yes | No | − | ||
P-glycoprotein substrate | No | No | No | No | |
P-glycoprotein inhibitor | Yes | Yes | Yes | ||
Distribution | |||||
Plasma protein binding (%) | 87.09 | 99.83 | 93.46 | ||
BBB permeability | No | No | No | No | |
Metabolism | |||||
CYP1A2 inhibitor | No | No | No | No | |
CYP2C19 inhibitor | Yes | Yes | No | Yes | |
CYP2C9 inhibitor | Yes | Yes | Yes | Yes | |
CYP2D6 inhibitor | No | Yes | No | No | |
CYP2D6 substrate | No | No | No | ||
CYP3A4 inhibitor | Yes | Yes | No | Yes | |
CYP3A4 substrate | Yes | Yes | Yes | ||
Excretion | |||||
Total Clearance (mL/min/kg) | 1.77 | 4.03 | 2.9 | ||
T1/2 (h) | 2.13 | 0.15 | 1.14 | ||
Toxicity | |||||
AMES toxicity | No | No | No | No | |
hERG inhibitor | Yes | No | − | ||
Rat acute oral LD50 (mg/kg) | 121.4 | 520 | 320.7 | ||
Hepatotoxicity | Yes | No | No | No | |
Skin Sensitisation | No | No | No | ||
Carcinogenicity | No | No | No |
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Tretyakova, E.; Smirnova, I.; Kazakova, O.; Nguyen, H.T.T.; Shevchenko, A.; Sokolova, E.; Babkov, D.; Spasov, A. New Molecules of Diterpene Origin with Inhibitory Properties toward α-Glucosidase. Int. J. Mol. Sci. 2022, 23, 13535. https://doi.org/10.3390/ijms232113535
Tretyakova E, Smirnova I, Kazakova O, Nguyen HTT, Shevchenko A, Sokolova E, Babkov D, Spasov A. New Molecules of Diterpene Origin with Inhibitory Properties toward α-Glucosidase. International Journal of Molecular Sciences. 2022; 23(21):13535. https://doi.org/10.3390/ijms232113535
Chicago/Turabian StyleTretyakova, Elena, Irina Smirnova, Oxana Kazakova, Ha Thi Thu Nguyen, Alina Shevchenko, Elena Sokolova, Denis Babkov, and Alexander Spasov. 2022. "New Molecules of Diterpene Origin with Inhibitory Properties toward α-Glucosidase" International Journal of Molecular Sciences 23, no. 21: 13535. https://doi.org/10.3390/ijms232113535