X-ray Crystal Structure, Hirshfeld Surface Analysis, DFT, and Anticancer Effect of 3-Hydroxy-4-phenyl-1,5-benzodiazepin-2-one Derivatives
Abstract
:1. Introduction
2. Materials and Methods
2.1. General Procedures
2.1.1. Synthesis of 3-Hydroxy-4-phenyl tetrahydro-1,5-benzodiazepin-2-one (3)
2.1.2. Synthesis of the Alkylated Compounds (4) and (5)
2.2. Anticancer Activity
2.3. Computational Methodology
2.4. X-ray Crystallography
2.5. In Silico Physicochemical Properties
3. Results and Discussion
3.1. Structural Elucidation of Compounds 3a, 3b, 4, and 5
3.2. Plausible Mechanisms for the Formation of the Synthesized Compounds
3.3. Description of the Structures of 3b, 4, and 5
3.4. Hirshfeld Surface Analysis
3.5. dnorm Mapping
3.5.1. Curvedness and Shape Index
3.5.2. Distribution of Individual Intermolecular Interactions
3.6. DFT Density Functional Theory (DFT) Examination
3.6.1. Refinement of Structural Configuration
3.6.2. Molecular Electrostatic Nature of Interactions—MESP for 3b, 4, and 5
- A pronounced electron cloud localized at the oxygen atoms in both the carbonyl and the hydroxide groups, appearing as a red ellipse, most likely results from the lone pairs of electrons present in these functional groups.
- Surrounding these structures is a light blue hue, suggestive of slightly positive regions. This can largely be attributed to the hydrogen atoms enveloping the structure. However, for those derivatives with nitrogen substitutions, the light blue distribution varies.
3.6.3. The Global Descriptors
3.6.4. The Local Descriptors
3.7. Anticancer Effect
3.8. In Silico Studies of the Pharmacokinetics and Pharmacodynamics Properties
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
Correction Statement
References
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Compound | 3b | 4 | 5 |
---|---|---|---|
Identification code | JTM1628_0m_a | JTM1656_0m_a | JTM1739_0m_a |
Molecular formula | C17H18N2O2 | C19H22N2O2 | C21H26N2O2 |
Formula weight (g/mol) | 282.33 | 310.38 | 338.44 |
Temperature (K) | 125 (2) | 150 (2) | 150 (2) |
Crystal system | triclinic | triclinic | monoclinic |
Space group | P-1 | P-1 | P21/c |
a (Å) | 6.2187 (2) | 8.0149 (2) | 9.9993 (4) |
b (Å) | 9.8850 (3) | 10.0579 (3) | 18.0468 (7) |
c (Å) | 11.7626 (3) | 10.7774 (3) | 10.2148 (4) |
α (°) | 84.040 (2) | 77.129 (1) | 90 |
β (°) | 84.611 (2) | 72.229 (1) | 96.951 (1) |
γ (°) | 89.181 (2) | 86.879 (1) | 90 |
Volume (Å3) | 715.97 (4) | 806.47 (4) | 1829.77 (12) |
Z | 2 | 2 | 4 |
ρcalc (g/cm3) | 1.31 | 1.278 | 1.229 |
μ (mm−1) | 0.697 | 0.083 | 0.625 |
F(000) | 300 | 332 | 728 |
Crystal size (mm) | 0.242 × 0.068 × 0.023 | 0.284 × 0.278 × 0.192 | 0.189 × 0.158 × 0.058 |
Radiation | CuKα (λ = 1.54178) | MoKα (λ = 0.71073) | CuKα (λ = 1.54178) |
2θ range for data collection (°) | 7.59 to 136.58 | 6.524 to 66.668 | 12.686 to 144.864 |
Index ranges | −7 ≤ h ≤ 7, −11 ≤ k ≤ 11, −14 ≤ l ≤ 13 | −12 ≤ h ≤ 12, −15 ≤ k ≤ 15, −16 ≤ l ≤ 16 | −12 ≤ h ≤ 12, −20 ≤ k ≤ 21, −12 ≤ l ≤ 12 |
Reflections collected | 5914 | 43,213 | 64,905 |
Independent reflections | 2544 [Rint = 0.0371, Rsigma = 0.0471] | 6209 [Rint = 0.0309, Rsigma = 0.0187] | 3599 [Rint = 0.0315, Rsigma = 0.0105] |
Data/restraints/parameters | 2544/3/201 | 6209/2/219 | 3599/0/234 |
Goodness-of-fit on F2 | 1.03 | 1.025 | 1.057 |
Final R indexes [I ≥ 2σ (I)] | R1 = 0.0460, wR2 = 0.1196 | R1 = 0.0402, wR2 = 0.1164 | R1 = 0.0402, R2 = 0.1164 |
Final R indexes [all data] | R1 = 0.0571, wR2 = 0.1288 | R1 = 0.0453, wR2 = 0.1212 | R1 = 0.0453, wR2 = 0.1212 |
Largest diff. peak/hole (e Å−3) | 0.20/−0.20 | 0.44/−0.18 | 0.44/−0.18 |
Compound | Bond | D—H | H⋯A | D⋯A | D—H⋯A |
---|---|---|---|---|---|
3b | O1—H1⋯O2 1 | 0.847 (10) | 2.00 (2) | 2.5758 (16) | 125 (2) |
N2—H2A⋯O1 2 | 0.915 (10) | 2.042 (11) | 2.9342 (18) | 165 (2) | |
C2—H2⋯O2 3 | 0.95 | 2.49 | 3.406 (2) | 161 | |
N1—H1A⋯Cg2 a | 0.91 (1) | 2.80 (2) | 3.5178 (16) | 136.6 (15) | |
4 | O2—H2A⋯O1 4 | 0.866 (9) | 1.994 (10) | 2.8388 (9) | 164.9 (15) |
C15—H15⋯O1 4 | 0.95 | 2.42 | 3.2902 (10) | 152 | |
C11—H11B⋯O2 5 | 0.98 | 2.58 | 3.5612 (11) | 176 | |
N2—H2B⋯Cg2 b | 0.904 (2) | 2.892 (9) | 3.7868 (7) | 170.6 (10) | |
C12—H12B⋯Cg2 c | 0.99 | 2.87 | 3.5953 (8) | 131 | |
5 | N2—H2A⋯O1 6 | 0.895 (16) | 2.160 (17) | 3.0509 (13) | 172.9 (14) |
Interaction | 3b (%) | 4 (%) | 5 (%) |
---|---|---|---|
H···C | 22.1 | 21.5 | 14.3 |
H···O | 14.3 | 13.1 | 8.0 |
H···H | 61.4 | 62.6 | 73.9 |
O···N | 0.4 | 0.0 | 0.0 |
C···O | 0.6 | 0.0 | 1.4 |
H···N | 0.5 | 2.6 | 2.3 |
C···C | 0.6 | 0.1 | 0.1 |
O···O | 0.1 | 0.0 | 0 |
C···N | 0.0 | 0.1 | 0 |
Descriptor | 3b | 4 | 5 |
---|---|---|---|
EHOMO(N) (eV) | −5.4646 | −5.4602 | −6.198 |
EHOMO(N + 1) (eV) | 2.5356 | 2.3165 | 2.292 |
EHOMO(N − 1) (eV) | −9.7231 | −9.7903 | −9.7199 |
Vertical IP (eV) | 7.0644 | 7.0099 | 6.9389 |
Vertical EA (eV) | −1.0934 | −0.9187 | −0.9208 |
Softness (S) (eV−1) | 0.1226 | 0.1261 | 0.1272 |
Chemical potential (μ) (eV) | −2.9855 | −3.0456 | −3.009 |
Mulliken electronegativity (χ) (eV) | 2.9855 | 3.0456 | 3.009 |
Hardness (=fundamental gap) (η) (eV) | 8.1577 | 7.9286 | 7.8596 |
Electrophilicity index (ω) (eV) | 0.5463 | 0.585 | 0.576 |
Nucleophilicity index (N) (eV) | 3.6566 | 3.661 | 2.9232 |
3b | 4 | 5 | ||||||
---|---|---|---|---|---|---|---|---|
Atoms | Atoms | Atoms | ||||||
N2 | −0.81523 | 1.70776 | N1 | −1.0742 | 1.569363 | N1 | −0.99572 | 2.60541 |
C1 | 4.364464 | 4.695817 | C6 | 4.233849 | 4.685395 | C6 | 4.403757 | 4.700334 |
C6 | −0.23677 | 2.656078 | C1 | 0.278835 | 2.472727 | C1 | 0.651523 | 2.891619 |
N1 | 0.093498 | 8.150168 | N2 | 0.132574 | 8.514583 | N2 | 0.147622 | 7.599681 |
C7 | 0.764232 | 1.039095 | C9 | 0.717864 | 0.159432 | C9 | 0.811308 | 0.113281 |
C8 | 0.299734 | 0.047021 | C8 | 0.374048 | 0.06811 | C8 | 0.478512 | 0.061443 |
C9 | 4.25872 | −0.38055 | C7 | 3.93085 | −0.3735 | C7 | 2.966424 | −0.78557 |
C5 | 1.649882 | −0.08838 | C2 | 0.686135 | 0.408878 | C2 | 0.110342 | −0.31979 |
C4 | 6.176008 | 1.368489 | C3 | 5.918044 | 0.844043 | C3 | 5.949011 | 1.756523 |
C3 | −1.78267 | 5.488594 | C4 | −1.46781 | 5.716408 | C4 | −1.02328 | 4.864718 |
C2 | 3.361996 | −2.37504 | C5 | 2.690282 | −2.41474 | C5 | 1.981643 | −2.25166 |
O2 | 2.349759 | 1.568846 | O1 | 1.94684 | 1.748795 | O1 | 1.763163 | 2.543232 |
C12 | 1.690944 | 1.376978 | C14 | 2.863483 | 1.5609 | C16 | 3.133093 | 1.299018 |
C13 | 2.532755 | 0.53767 | C15 | −0.18901 | 0.210181 | C17 | 2.844816 | 0.434321 |
C14 | −0.84578 | −0.2538 | C16 | 0.943256 | 0.074042 | C18 | −1.26424 | −0.21489 |
C15 | 1.993534 | 1.183478 | C17 | 3.522135 | 1.149981 | C19 | 3.79765 | 0.942249 |
C16 | 1.930213 | 0.066096 | C18 | −1.07477 | −0.29579 | C20 | 1.300351 | −0.00046 |
C17 | −0.73313 | 0.044953 | C19 | 2.389406 | 0.540772 | C21 | −0.38823 | 0.256794 |
O1 | 0.017905 | −0.02838 | C12 | 0.150724 | 0.146506 | C12 | 0.248658 | 0.036082 |
C10 | 0.06879 | 0.280332 | C13 | 0.042069 | 0.047266 | C13 | −0.0052 | 0.299978 |
C11 | 0.072491 | 0.126125 | O2 | 0.043892 | −0.00795 | O2 | 0.06509 | 0.008517 |
C11 | 0.082042 | 0.279733 | C11 | 0.100165 | 0.242535 | |||
C10 | 0.070804 | 0.106261 | C10 | 0.087702 | 0.132955 | |||
C14 | 0.034749 | −0.00463 | ||||||
C15 | 0.01249 | −0.0003 |
Compound | In Vitro Cytotoxicity IC50 (µM) * | |||
---|---|---|---|---|
HCT 116 | HepG2 | MCF-7 | WI38 | |
3b | 9.18 ± 0.6 | 6.13 ± 0.3 | 7.86 ± 0.4 | 13.95 ± 0.9 |
4 | 19.42 ± 1.5 | 15.33 ± 1.3 | 25.95 ± 2.1 | 71.64 ± 3.9 |
5 | >100 | 73.5 ± 4.0 | >100 | 54.16 |
Sunitinib | 17.91 ± 1.3 | 8.38 ± 0.5 | 24.06 ± 2.0 | 55.63 ± 3.3 |
Parameters | 3b | 4 | 5 | |
---|---|---|---|---|
Compound | ||||
Molecular properties | ||||
Molecular weight | 282.343 | 310.397 | 338.451 | |
LogP | 2.769 | 3.18404 | 4.22824 | |
H-acceptor | 3 | 3 | 3 | |
H-donors | 3 | 2 | 1 | |
Surface area | 123.363 | 136.303 | 149.352 | |
Absorption | ||||
Water solubility (log mol/L) | −3.585 | −3.885 | −4.325 | |
Intestinal absorption (human) | 94.208% | 95.068% | 95.904% | |
Skin permeability | −2.736 | −3.166 | −2.919 | |
Distribution | ||||
BBB permeability | 0.198 | 0.68 | 0.052 | |
Metabolism | ||||
CYP2D6 substrate CYP3A4 substrate | No No | No Yes | No Yes | |
Excretion | ||||
Total clearance (log mL/min/kg) | −0.12 | 0.099 | 0.234 | |
Renal OCT2 substrate | No | Yes | Yes | |
Toxicity | ||||
Max. tolerated dose (human) (log mg/kg/day) | 0.257 | −0.031 | −0.137 | |
Oral rate acute toxicity (LD50) (mol/kg) | 1.56 | 2.341 | 2.811 | |
Oral rate chronic toxicity (LOAEL) (log mg/kg_bw/day) | 0.549 | 1.297 | 1.435 | |
Hepatotoxicity | No | No | No | |
Skin sensitization | No | No | No |
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Lahmidi, S.; Bakheit, A.H.; Essassi, E.M.; Mague, J.T.; Alanazi, M.M. X-ray Crystal Structure, Hirshfeld Surface Analysis, DFT, and Anticancer Effect of 3-Hydroxy-4-phenyl-1,5-benzodiazepin-2-one Derivatives. Crystals 2023, 13, 1693. https://doi.org/10.3390/cryst13121693
Lahmidi S, Bakheit AH, Essassi EM, Mague JT, Alanazi MM. X-ray Crystal Structure, Hirshfeld Surface Analysis, DFT, and Anticancer Effect of 3-Hydroxy-4-phenyl-1,5-benzodiazepin-2-one Derivatives. Crystals. 2023; 13(12):1693. https://doi.org/10.3390/cryst13121693
Chicago/Turabian StyleLahmidi, Sanae, Ahmad H. Bakheit, El Mokhtar Essassi, Joel T. Mague, and Mohammed M. Alanazi. 2023. "X-ray Crystal Structure, Hirshfeld Surface Analysis, DFT, and Anticancer Effect of 3-Hydroxy-4-phenyl-1,5-benzodiazepin-2-one Derivatives" Crystals 13, no. 12: 1693. https://doi.org/10.3390/cryst13121693
APA StyleLahmidi, S., Bakheit, A. H., Essassi, E. M., Mague, J. T., & Alanazi, M. M. (2023). X-ray Crystal Structure, Hirshfeld Surface Analysis, DFT, and Anticancer Effect of 3-Hydroxy-4-phenyl-1,5-benzodiazepin-2-one Derivatives. Crystals, 13(12), 1693. https://doi.org/10.3390/cryst13121693