Analgesic and Anticancer Activity of Benzoxazole Clubbed 2-Pyrrolidinones as Novel Inhibitors of Monoacylglycerol Lipase
Abstract
:1. Introduction
2. Results
2.1. Chemistry
2.2. Human MAGL Assay
2.3. Human FAAH Assay
2.4. Molecular Docking Study
2.5. Pharmacokinetic and Physicochemical Characteristics
2.6. In Silico Absorption and Toxicity Profile
2.7. Analgesic Activity
2.8. Anticancer Activity
3. Discussion
4. Experimental
4.1. Chemistry
4.1.1. Synthesis of 1-(Aryl Substituted)-5-Oxopyrrolidine-3-Carboxylic Acids (1–10)
Method-1 (for compound 1)
Method-2 (for compounds 2–10)
4.1.2. Synthesis of 4-(Benzoxazolyl)-1-(Aryl Substituted)Pyrrolidin-2-Ones (11–20)
4.2. Human MAGL Assay
4.3. Human FAAH Assay
4.4. Molecular Docking Study
4.5. Physicochemical and Pharmacokinetic Characteristics
4.6. In Silico Absorption and Toxicity Profile
4.7. Analgesic Activity
4.8. Anticancer Screening: Sulforhodamine B Assay
4.9. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Sample Availability
References
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| |||
Compound | R | hMAGL; IC50 | hFAAH; IC50 |
---|---|---|---|
11 | | >100 μM | ND |
12 | | >100 μM | ND |
13 | | 85 ± 1.5 μM | ND |
14 | | 72 ± 2.1 μM | ND |
15 | | 65 ± 3.2 nM | 28 ± 1.8 μM |
16 | | 34 ± 1.7 nM | 25 ± 2.3 μM |
17 | | 62 ± 2.7 μM | ND |
18 | | 42 ± 1.5 nM | 37 ± 2.2 μM |
19 | | 8.4 ± 1.9 nM | 55 ± 2.7 μM |
20 | | 7.6 ± 0.8 nM | 68 ± 2.1 μM |
CAY10499 | -- | 415 ± 3.2 nM | -- |
JZL184 | -- | 10 ± 0.8 nM | -- |
URB597 | -- | -- | 5 ± 0.6 nM |
S. No. | Property | Description | Range of Properties in CNS Drugs | Compound 19 | Compound 20 | |||
---|---|---|---|---|---|---|---|---|
QL | PL | PU | QU | |||||
1 | #stars | drug likeness penalty; the higher the value, the less drug-like the molecule | 0 | 0 | 0 | 3 | 0 | 0 |
2 | #amine | no. of basic amines | 0 | 1 | 1 | 2 | 0 | 0 |
3 | #amidine | no. of amidines groups | 0 | 0 | 0 | 0 | 0 | 0 |
4 | #acid | no. of carboxylic acid groups | 0 | 0 | 0 | 0 | 0 | 0 |
5 | #amide | no. of amides groups | 0 | 0 | 0 | 1 | 0 | 0 |
6 | #rotor | no. of rotatable bonds (without CX3, alkene, amide, small ring) | 0 | 3 | 6 | 8 | 1 | 2 |
7 | CNS | a qualitative CNS activity parameter | −2 | 0 | 1 | 2 | −2 | −2 |
8 | dipole | computed dipole moment | 0.67 | 1.1 | 3.9 | 8.9 | 9.47 | 10.22 |
9 | SASA | solvent accessible surface area | 348 | 487 | 620 | 798 | 584.85 | 617.51 |
10 | FOSA | SASA on saturated carbon and attached hydrogen | 16 | 178 | 314 | 464 | 91.99 | 91.96 |
11 | FISA | SASA on N, O, and H attached to heteroatoms | 0 | 0 | 64 | 176 | 167.04 | 210.06 |
12 | PISA | π component of SASA | 0 | 160 | 292 | 343 | 325.81 | 313.57 |
13 | WPSA | weakly polar component of the SASA (halogens, P, and S) | 0 | 0 | 0 | 126 | 0 | 1.94 |
14 | volume | solvent accessible volume (Å3) | 492 | 830 | 1104 | 1388 | 1002.52 | 1065.46 |
15 | donorHB | estimated no. of hydrogen bonds that would be donated to the solvent water | 0 | 0 | 1 | 3 | 0 | 2 |
16 | accptHB | estimated no. of hydrogen bonds that would be accepted from the solvent water | 1 | 2.8 | 5.2 | 8.3 | 6 | 9.5 |
17 | glob | a globularity descriptor (1 for a sphere) | 0.77 | 0.82 | 0.88 | 0.93 | 0.82 | 0.81 |
18 | QPpolrz | predicted polarizability (Å3) | 14 | 28 | 38 | 49 | 36.43 | 38.19 |
19 | QPlogPo/w | octanol−water logP | −0.16 | 2.5 | 4.7 | 6.0 | 2.13 | 0.90 |
20 | QPlogS | solubility in log(moles/liter) | −6.5 | −4.6 | −2.5 | −0.42 | −3.99 | −3.99 |
21 | CIQPlogS | log of conformation-independent solubility | −6.3 | −4.2 | −2.3 | 0.36 | −4.16 | −3.77 |
22 | QPPCaco | apparent Caco-2 cell permeability | 0 | 0 | 810 | 3269 | 258.09 | 100.92 |
23 | QPlogBB | brain/blood partition coefficient | −1.2 | −0.06 | 0.75 | 1.2 | −1.12 | −1.65 |
24 | QPPMDCK | predicted apparent MDCK cell permeability (nm/s) | 0 | 0 | 634 | 5899 | 114.43 | 42.50 |
25 | QPlogKhsa | prediction of binding to human serum albumin | −1 | 0.04 | 0.78 | 1.04 | −0.11 | −0.34 |
26 | HumanOralAbsorption | Human oral absorption | 2 | 3 | 3 | 3 | 3 | 3 |
27 | PercentHuman OralAbsorption | Percent of human oral absorption | 61 | 95 | 100 | 100 | 82.63 | 68.11 |
28 | TPSA | van der Waals surface area of polar nitrogen and oxygen atoms | 3.8 | 12 | 54 | 109 | 98.65 | 119.08 |
29 | #NandO | no. of N and O atoms | 1 | 2 | 4 | 7 | 7 | 7 |
30 | RuleOfFive | no. of violations of Lipinski’s rule of five | 0 | 0 | 0 | 1 | 0 | 0 |
31 | RuleOfThree | no. of violations of Jorgensen’s rule of three | 0 | 0 | 0 | 1 | 0 | 0 |
32 | #in34 | no. of atoms in three- or four-membered rings | 0 | 0 | 0 | 0 | 0 | 0 |
33 | #in56 | no. of atoms in five- or six-membered rings | 5 | 11 | 17 | 24 | 20 | 20 |
34 | #noncon | no. of atoms not able to form conjugation in nonaromatic rings | 0 | 0 | 4 | 10 | 3 | 3 |
35 | #nonHatm | no. of non-H atoms | 8 | 19 | 25 | 30 | 24 | 25 |
Compound | BBB | HIA | HOB | AMES test | Carcinogenicity | Rat Acute Toxicity (LD50, mol/kg) |
---|---|---|---|---|---|---|
19 | Yes | Yes | Yes | Mutagenic | Non-carcinogen | 2.30 |
20 | Yes | Yes | Yes | Non-Mutagenic | Non-carcinogen | 2.21 |
Panel | Cell Line | Compound 19 (NSC: 778839) | Compound 20 (NSC: 778842) | ||
---|---|---|---|---|---|
% G | % GI | % G | % GI | ||
Leukemia | CCRF-CEM | 93.58 | 6.42 | 94.48 | 5.52 |
HL-60(TB) | 100.09 | −0.09 | 96.15 | 3.85 | |
K-562 | 98.41 | 1.59 | 98.83 | 1.17 | |
MOLT-4 | 93.64 | 6.36 | 92.47 | 7.53 | |
RPMI-8226 | 101.28 | −1.28 | 103.53 | −3.53 | |
SR | 88.92 | 11.08 | 93.20 | 6.80 | |
Non-Small Cell Lung Cancer | A549/ATCC | 100.60 | −0.60 | 95.28 | 4.72 |
HOP-62 | 85.04 | 14.96 | 81.97 | 18.03 | |
HOP-92 | 104.72 | −4.72 | 77.78 | 22.22 | |
NCI-H226 | 98.63 | 1.37 | 92.75 | 7.25 | |
NCI-H23 | 93.07 | 6.93 | 92.19 | 7.81 | |
NCI-H322M | 94.18 | 5.82 | 99.10 | 0.90 | |
NCI-H460 | 102.33 | −2.33 | 104.20 | −4.20 | |
Colon Cancer | COLO 205 | 103.79 | −3.79 | 104.05 | −4.05 |
HCC-2998 | 102.05 | −2.05 | 100.24 | −0.24 | |
HCT-116 | 102.14 | −2.14 | 95.78 | −4.22 | |
HCT-15 | 98.10 | 1.9 | 101.16 | −1.16 | |
HT29 | 99.25 | 0.75 | 103.23 | −3.23 | |
KM12 | 105.43 | −5.43 | 101.16 | −1.16 | |
SW-620 | 102.52 | −2.52 | 102.95 | −2.95 | |
CNS Cancer | SF-268 | 91.85 | 8.15 | 87.43 | 12.57 |
SF-295 | 98.21 | 1.79 | 93.71 | 6.29 | |
SF-539 | 95.59 | 4.41 | 87.58 | 12.42 | |
SNB-19 | 99.29 | 0.71 | 97.02 | 2.98 | |
SNB-75 | 64.51 | 35.49 | 68.12 | 31.88 | |
U251 | 100.97 | −0.97 | 95.21 | 4.79 | |
Melanoma | LOX IMVI | 89.06 | 10.94 | 92.99 | 7.01 |
MALME-3M | 88.53 | 11.47 | 93.29 | 6.71 | |
M14 | 101.37 | −1.37 | 98.58 | 1.42 | |
MDA-MB-435 | 95.05 | 4.95 | 100.55 | −0.55 | |
SK-MEL-2 | 102.31 | −2.31 | 111.54 | −11.54 | |
SK-MEL-28 | 111.25 | −11.25 | 101.79 | −1.79 | |
SK-MEL-5 | 98.72 | 1.28 | 98.82 | −1.18 | |
UACC-257 | 106.92 | −6.92 | 110.78 | −10.78 | |
UACC-62 | 97.59 | 2.41 | 92.78 | 7.22 | |
Ovarian Cancer | IGROV1 | 104.14 | −4.14 | 101.63 | −1.63 |
OVCAR-3 | 98.56 | 1.44 | 98.53 | 1.47 | |
OVCAR-4 | 106.27 | −6.27 | 99.47 | 0.53 | |
OVCAR-5 | 98.30 | 1.70 | 92.08 | 7.92 | |
OVCAR-8 | 101.95 | −1.95 | 97.49 | 2.51 | |
NCI/ADR-RES | 98.37 | 1.63 | 101.45 | −1.45 | |
SK-OV-3 | 88.34 | 11.66 | 94.77 | 5.23 | |
Renal Cancer | 786-0 | 104.06 | −4.06 | 98.99 | 1.01 |
A498 | 113.46 | −13.46 | 113.94 | −13.94 | |
ACHN | 91.70 | 8.3 | 89.48 | 10.52 | |
CAKI-1 | 97.19 | 2.81 | 92.35 | 7.65 | |
SN12C | 97.21 | 2.79 | 95.50 | 4.50 | |
TK-10 | 110.14 | −10.14 | 114.82 | −14.82 | |
UO-31 | 78.82 | 21.18 | 70.05 | 29.95 | |
Prostate Cancer | PC-3 | 91.14 | 8.86 | 88.11 | 11.89 |
DU-145 | 110.09 | −10.09 | 111.62 | −11.62 | |
Breast Cancer | MCF7 | 99.19 | 0.81 | 92.32 | 7.68 |
MDA-MB-231/ATCC | 88.41 | 11.59 | 80.11 | 19.89 | |
HS 578T | 101.81 | −1.81 | 104.19 | −4.19 | |
T-47D | 80.01 | 19.99 | 83.24 | 16.24 | |
MDA-MB-468 | 98.03 | 1.97 | 100.34 | −0.34 |
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Afzal, O.; Altamimi, A.S.A.; Shahroz, M.M.; Sharma, H.K.; Riadi, Y.; Hassan, M.Q. Analgesic and Anticancer Activity of Benzoxazole Clubbed 2-Pyrrolidinones as Novel Inhibitors of Monoacylglycerol Lipase. Molecules 2021, 26, 2389. https://doi.org/10.3390/molecules26082389
Afzal O, Altamimi ASA, Shahroz MM, Sharma HK, Riadi Y, Hassan MQ. Analgesic and Anticancer Activity of Benzoxazole Clubbed 2-Pyrrolidinones as Novel Inhibitors of Monoacylglycerol Lipase. Molecules. 2021; 26(8):2389. https://doi.org/10.3390/molecules26082389
Chicago/Turabian StyleAfzal, Obaid, Abdulmalik Saleh Alfawaz Altamimi, Mir Mohammad Shahroz, Hemant Kumar Sharma, Yassine Riadi, and Md Quamrul Hassan. 2021. "Analgesic and Anticancer Activity of Benzoxazole Clubbed 2-Pyrrolidinones as Novel Inhibitors of Monoacylglycerol Lipase" Molecules 26, no. 8: 2389. https://doi.org/10.3390/molecules26082389