Synthesis, crystal structure, hirshfeld surface analysis, molecular docking and molecular dynamics studies of novel olanzapinium 2,5-dihydroxybenzoate as potential and active antipsychotic compound

Figures & data

Figure 1. Molecular structure of Olanzapinium 2,5-dihydroxybenzoate.

Figure 2. ¹H-NMR spectrum of Olanzapinium 2,5-dihydroxybenzoate in CDCl₃.

Figure 3. ¹³C-NMR spectrum of Olanzapinium 2,5-dihydroxybenzoate in CDCl₃+DMSO-d₆.

Figure 4. ORTEP representation of Olanzapinium 2,5-dihydroxybenzoate, showing the atom-numbering scheme. Displacement ellipsoids are drawn at the 30% probability level.

Table

Melting Point (mp):	110–112 °C
^1H NMR (300 MHz, CDCl3):	δ7.65 − 7.63 (m, 1H), 7.37 − 7.26 (m, 2H), 6.97 − 6.85 (m, 5H), 6.75 − 6.68 (m, 3H), 6.34 − 6.22 (m, 2H), 3.98 − 3.88 (m, 1H), 3.72 − 3.65 (m, 4H), 2.95 − 2.92 (m, 4H), 2.67 − 2.56 (m, 3H), 2.36 − 2.25 (m, 3H), 1.22 − 1.08 (m, 6H)
^13C NMR (75 MHz, CDCl3 + DMSO-d6)	δ 172.3, 156.7, 155.1, 153.5, 147.7, 143.6, 137.2, 127.8, 126.5, 123.8, 122.8, 121.0, 120.7, 118.3, 115.7, 115.1, 114.6, 77.6, 77.1, 76.7, 61.8, 52.0, 44.3, 42.7, 24.3, 14.2.

Table 1. Bond length (Å) of Olanzapinium 2,5-dihydroxybenzoate.

Atom	Bond length (Å)	Atom	Bond length (Å)
C1—C2	1.495 (5)	C16—N3	1.451 (4)
C1—H1A	0.9600	C16—H16A	0.9700
C1—H1B	0.9600	C16—H16B	0.9700
C1—H1C	0.9600	C17—N4	1.483 (4)
C2—C3	1.343 (4)	C17—H17A	0.9600
C2—S1	1.736 (3)	C17—H17B	0.9600
C3—C4	1.433 (4)	C17—H17C	0.9600
C3—H3	0.9300	N2—H2N	0.87 (3)
C4—C5	1.364 (4)	N4—H4N	0.89 (4)
C4—C12	1.475 (4)	C18—O1	1.251 (4)
C5—N2	1.389 (4)	C18—O2	1.261 (4)
C5—S1	1.730 (3)	C18—C19	1.497 (4)
C6—C7	1.383 (4)	C19—C20	1.394 (4)
C6—C11	1.401 (4)	C19—C24	1.395 (4)
C6—N2	1.429 (4)	C20—C21	1.373 (4)
C7—C8	1.378 (5)	C20—H20	0.9300
C7—H7	0.9300	C21—O4	1.374 (4)
C8—C9	1.371 (5)	C21—C22	1.379 (4)
C8—H8	0.9300	C22—C23	1.376 (4)
C9—C10	1.386 (5)	C22—H22	0.9300
C9—H9	0.9300	C23—C24	1.381 (4)
C10—C11	1.388 (4)	C23—H23	0.9300
C10—H10	0.9300	C24—O3	1.362 (4)
C11—N1	1.408 (4)	O3—H3O	0.89 (4)
C12—N1	1.287 (4)	O4—H4O	0.84 (4)
C12—N3	1.389 (4)	C25—C26	1.485 (5)
C13—N3	1.463 (4)	C25—H25A	0.9600
C13—C14	1.504 (4)	C25—H25B	0.9600
C13—H13A	0.9700	C25—H25C	0.9600
C13—H13B	0.9700	C26—O5	1.440 (4)
C14—N4	1.484 (4)	C26—C27	1.495 (5)
C14—H14A	0.9700	C26—H26	0.9800
C14—H14B	0.9700	C27—H27A	0.9600
C15—N4	1.484 (4)	C27—H27B	0.9600
C15—C16	1.504 (5)	C27—H27C	0.9600
C15—H15A	0.9700	O5—H5O	0.88 (4)
C15—H15B	0.9700

Table 2. Bond angles (in degree) of Olanzapinium 2,5-dihydroxybenzoate.

Atoms	Angle in degree	Atoms	Angle in degree
C2—C1—H1A	109.5	N4—C17—H17A	109.5
C2—C1—H1B	109.5	N4—C17—H17B	109.5
H1A—C1—H1B	109.5	H17A—C17—H17B	109.5
C2—C1—H1C	109.5	N4—C17—H17C	109.5
H1A—C1—H1C	109.5	H17A—C17—H17C	109.5
H1B—C1—H1C	109.5	H17B—C17—H17C	109.5
C3—C2—C1	130.5 (3)	C12—N1—C11	124.2 (3)
C3—C2—S1	110.4 (2)	C5—N2—C6	114.5 (2)
C1—C2—S1	119.1 (3)	C5—N2—H2N	113 (2)
C2—C3—C4	114.6 (3)	C6—N2—H2N	111 (2)
C2—C3—H3	122.7	C12—N3—C16	118.9 (3)
C4—C3—H3	122.7	C12—N3—C13	121.3 (2)
C5—C4—C3	111.5 (3)	C16—N3—C13	111.0 (2)
C5—C4—C12	120.9 (3)	C17—N4—C15	111.5 (3)
C3—C4—C12	127.6 (3)	C17—N4—C14	111.7 (3)
C4—C5—N2	126.8 (3)	C15—N4—C14	111.1 (2)
C4—C5—S1	111.5 (2)	C17—N4—H4N	111 (2)
N2—C5—S1	121.6 (2)	C15—N4—H4N	109 (2)
C7—C6—C11	120.1 (3)	C14—N4—H4N	103 (2)
C7—C6—N2	119.9 (3)	C5—S1—C2	91.97 (15)
C11—C6—N2	119.9 (3)	O1—C18—O2	123.9 (3)
C8—C7—C6	121.4 (3)	O1—C18—C19	118.6 (3)
C8—C7—H7	119.3	O2—C18—C19	117.4 (3)
C6—C7—H7	119.3	C20—C19—C24	118.7 (3)
C9—C8—C7	119.3 (3)	C20—C19—C18	121.3 (3)
C9—C8—H8	120.3	C24—C19—C18	120.0 (3)
C7—C8—H8	120.3	C21—C20—C19	121.1 (3)
C8—C9—C10	119.6 (3)	C21—C20—H20	119.4
C8—C9—H9	120.2	C19—C20—H20	119.4
C10—C9—H9	120.2	C20—C21—O4	117.8 (3)
C9—C10—C11	122.3 (3)	C20—C21—C22	119.5 (3)
C9—C10—H10	118.9	O4—C21—C22	122.7 (3)
C11—C10—H10	118.9	C23—C22—C21	120.3 (3)
C10—C11—C6	117.3 (3)	C23—C22—H22	119.9
C10—C11—N1	116.3 (3)	C21—C22—H22	119.9
C6—C11—N1	126.2 (3)	C22—C23—C24	120.7 (3)
N1—C12—N3	117.6 (3)	C22—C23—H23	119.7
N1—C12—C4	126.6 (3)	C24—C23—H23	119.7
N3—C12—C4	115.7 (3)	O3—C24—C23	119.2 (3)
N3—C13—C14	109.8 (3)	O3—C24—C19	121.1 (3)
N3—C13—H13A	109.7	C23—C24—C19	119.7 (3)
C14—C13—H13A	109.7	C24—O3—H3O	103 (3)
N3—C13—H13B	109.7	C21—O4—H4O	108 (3)
C14—C13—H13B	109.7	C26—C25—H25A	109.5
H13A—C13—H13B	108.2	C26—C25—H25B	109.5
N4—C14—C13	110.8 (3)	H25A—C25—H25B	109.5
N4—C14—H14A	109.5	C26—C25—H25C	109.5
C13—C14—H14A	109.5	H25A—C25—H25C	109.5
N4—C14—H14B	109.5	H25B—C25—H25C	109.5
C13—C14—H14B	109.5	O5—C26—C25	106.9 (3)
H14A—C14—H14B	108.1	O5—C26—C27	112.0 (3)
N4—C15—C16	112.1 (3)	C25—C26—C27	113.3 (4)
N4—C15—H15A	109.2	O5—C26—H26	108.2
C16—C15—H15A	109.2	C25—C26—H26	108.2
N4—C15—H15B	109.2	C27—C26—H26	108.2
C16—C15—H15B	109.2	C26—C27—H27A	109.5
H15A—C15—H15B	107.9	C26—C27—H27B	109.5
N3—C16—C15	109.9 (3)	H27A—C27—H27B	109.5
N3—C16—H16A	109.7	C26—C27—H27C	109.5
C15—C16—H16A	109.7	H27A—C27—H27C	109.5
N3—C16—H16B	109.7	H27B—C27—H27C	109.5
C15—C16—H16B	109.7	C26—O5—H5O	110 (2)
H16A—C16—H16B	108.2

Figure 5. Views of the Hirshfeld surfaces of title compound mapped with d_norm in two different orientations. The HS is plotted in the range −0.1500 to 1.4938 a.u.

Figure 6. Views of the shape-index diagram of title compound.

Figure 7. Protein 3 D structure of human potassium voltage-gated channel (KCNA) (PDB ID: 4BGC).

Figure 8. (A) The shape of the pore as seen at XY-axis. (B) The top view of the cavity.

Table 3. Molecular docking results.

Name	Ligand	Filename	MolDock dcore	Rerank score	MW
[03] Compound 1	Compound 1	[03] Compound1.mol2	−107.729	−83.2566	506.617
[01] Compound 1	Compound 1	[01] Compound1.mol2	−111.855	−83.1217	506.617
[02] Compound 1	Compound 1	[02] Compound1.mol2	−107.028	−81.9834	506.617
[00] Compound 1	Compound 1	[00] Compound1.mol2	−120.044	−79.2459	506.617
[04] Compound 1	Compound 1	[04] Compound1.mol2	−108.893	−60.6982	506.617

Figure 9. Molecular dynamics RMSD and RMSF of free human potassium voltage-gated channel (I, II); Human potassium voltage-gated channel with OLANZAPINIUM 2,5-DIHYDROXYBENZOATE.

Figure 10. Interaction diagram of human potassium voltage-gated channel complex with Olanzapinium 2,5-dihydroxybenzoate observed during the molecular dynamics simulation. (A) The protein-ligand interaction diagram.

Figure 10. (B) The residues that interact with the ligand in each trajectory frame. (C) Schematic diagram of ligand interaction with the amino acid residues of protein during MD simulation.

Figure 11. The ligand property trajectory of the human potassium voltage-gated channel complex with Olanzapinium 2,5-dihydroxybenzoate during the 100 ns simulation.

Figure 12. The most effective pose of compound Olanzapinium 2,5-dihydroxybenzoate with lowest re-rank score shows hydrogen bond interaction with a channel protein KCNA 1 (Residues in colour cyan, ligand in colour pink and hydrogen bond in black dots.)

Figure 13. Electrostatic interaction of compound Olanzapinium 2,5-dihydroxybenzoate with the channel protein KVNA 1.

Figure 14. Van der Waals interaction of compound Olanzapinium 2,5-dihydroxybenzoate with the channel protein KVNA 1.

Table 4. Predicted ADMET properties of the compound by AdmetSAR program.

Model	Result	Probability
Absorption
Blood–brain barrier	BBB-	0.8474
Human intestinal absorption	HIA+	0.8807
Caco-2 permeability	Caco2-	0.5852
P-glycoprotein substrate	Substrate	0.93
P-glycoprotein inhibitor	Non-inhibitor	0.7854
	Non-inhibitor	0.8543
Renal organic cation transporter	Non-inhibitor	0.6211
Distribution
Subcellular localization	Nucleus	0.4491
Metabolism
CYP450 2C9 substrate	Non-substrate	0.6695
CYP450 2D6 substrate	Non-substrate	0.7364
CYP450 3A4 substrate	Substrate	0.5738
CYP450 1A2 inhibitor	Non-inhibitor	0.7022
CYP450 2C9 inhibitor	Non-inhibitor	0.7599
CYP450 2D6 inhibitor	Non-inhibitor	0.8014
CYP450 2C19 inhibitor	Non-inhibitor	0.7163
CYP450 3A4 inhibitor	Non-inhibitor	0.8929
CYP inhibitory promiscuity	Low CYP inhibitory promiscuity	0.8445
Excretion and toxicity
Human ether-a-go-go-related Gene inhibition	Weak inhibitor	0.9763
	Non-inhibitor	0.5895
AMES toxicity	Non AMES toxic	0.6047
Carcinogens	Non-carcinogens	0.8607
Fish toxicity	High FHMT	0.9991
Tetrahymena pyriformis toxicity	High TPT	0.9449
Honey bee toxicity	Low HBT	0.7284
Biodegradation	Not ready biodegradable	0.9914
Acute oral toxicity	III	0.6079
Carcinogenicity (three-class)	Non-required	0.6409

Table 5. ADMET predicted profile – regression.

Model	Value	Unit
Absorption
Aqueous solubility	−3.1394	LogS
Caco-2 Permeability	0.8479	LogPapp, cm/s
Distribution, metabolism, excretion and toxicity
Rat Acute Toxicity	2.6271	LD50, mol/kg
Fish Toxicity	1.2842	pLC50, mg/L
Tetrahymena pyriformis toxicity	0.6645	pIGC50, µg/L