Synthesis, central nervous system activity and structure–activity relationship of N-substituted derivatives of 1-arylimidazolidyn-2-ylideneurea and products of their cyclization

Figures & data

Figure 1. Structural formulas of bezitramide, fentanyl and petidine. Pharmacophoric features according to the Beckett’s model are shown in bold2^,12.

Figure 2. Non-classical opioid receptor pharmacophore models. B, base; Ar, aromatic; H, hydrophobic region; HA, hydrogen bond acceptor2^,12.

Figure 3. Previously reported antinociceptive and serotoninergic compounds. Series A–E and partially F exert their antinociceptive activity through the opioid system. Series G and some of compounds from series F have antinociceptive activity of unknown mechanism2^,8–12.

Figure 4. Pharmacophore model for the 5HT₂ receptor2^,10^,12.

Scheme 1. Synthesis of the investigated compounds.

Table 1. Parameters for drug-likeness estimation.

Compound	Molar mass	AlogP98	HBD	HBA	Number of atoms	Molar refractivity	Rings	Rigid bonds	Rotatable bonds	Druglikeness score
3a	276.291	0.718	2	7	36	73.38	2	32	5	1.82
3b	310.736	1.382	2	7	36	77.98	2	32	5	1.00
3c	310.736	1.382	2	7	36	77.98	2	32	5	1.36
3d	345.181	2.047	2	7	36	82.58	2	32	5	1.76
3e	306.317	0.702	2	8	40	79.19	2	35	6	−0.58
4a	261.28	−0.135	4	7	34	69.48	2	31	4	7.21
4b	295.725	0.529	4	7	34	74.08	2	31	4	6.43
4c	295.725	0.529	4	7	34	74.08	2	31	4	6.77
4d	330.17	1.194	4	7	34	78.68	2	31	4	7.14
4e	291.306	−0.152	4	8	38	75.29	2	34	5	4.85
5a	316.312	1.669	0	8	39	82.70	3	36	5	−0.58
5b	350.757	2.333	0	8	39	87.30	3	36	5	−1.44
5c	350.757	2.333	0	8	39	87.30	3	36	5	−1.06
5d	385.202	2.998	0	8	39	91.91	3	36	5	−0.64
5e	346.338	1.652	0	9	43	88.52	3	41	6	−2.92
6a	287.274	0.467	2	8	34	74.20	3	33	3	5.88
6b	321.719	1.131	2	8	34	78.80	3	33	3	5.04
6c	321.719	1.131	2	8	34	78.80	3	33	3	5.40
6d	356.164	1.796	2	8	34	83.40	3	33	3	5.81
6e	317.3	0.45	2	9	38	80.10	3	36	4	3.45

HBD, a number of hydrogen bond donors; HBA, a number of hydrogen bond acceptors.

Figure 5. The plot of ADMET properties of the investigated compounds.

Table 2. ADMET parameters of the studied compounds.

		Toxicity risk
Compound	logS	Mutagenic	Tumorigenic	Irritant	Reproductive effective	Drug score
3a	−2.635	1.0	1.0	1.0	1.0	0.86
3b	−1.811	1.0	1.0	1.0	1.0	0.85
3c	−2.628	1.0	1.0	1.0	1.0	0.78
3d	−3.47	1.0	1.0	1.0	1.0	0.72
3e	−1.951	1.0	1.0	1.0	1.0	0.62
4a	−1.031	1.0	1.0	1.0	1.0	0.93
4b	−2.029	1.0	1.0	1.0	1.0	0.88
4c	−2.023	1.0	1.0	1.0	1.0	0.88
4d	−3.038	1.0	1.0	1.0	1.0	0.8
4e	−1.353	1.0	1.0	1.0	1.0	0.92
5a	−3.452	1.0	1.0	0.6	1.0	0.36
5b	−4.092	1.0	1.0	0.6	1.0	0.29
5c	−4.084	1.0	1.0	0.6	1.0	0.30
5d	−4.747	1.0	1.0	0.6	1.0	0.28
5e	−3.39	1.0	1.0	0.6	1.0	0.27
6a	−2.793	1.0	1.0	0.6	1.0	0.55
6b	−3.615	1.0	1.0	0.6	1.0	0.51
6c	−3.607	1.0	1.0	0.6	1.0	0.51
6d	−4.449	1.0	1.0	0.6	1.0	0.46
6e	−2.928	1.0	1.0	0.6	1.0	0.53

S, solubility.

Table 3. The effect of the new compounds on the PTZ-induced clonic seizures, tonic convulsions and death of mice.

Treatment	Clonic seizures (number of mice reacting convulsions/ animals tested)	Tonic convulsions (number of mice reacting convulsions/ animals tested)	Mortality (number of dead mice/animals tested)
Control (PTZ  110 mg/kg)	9/10	8/10	8/10
3b	9/10	6/10	6/10
3c	9/10	8/10	7/10
3e	9/10	7/10	7/10
5a	7/10	6/10	5/10
5e	9/10	8/10	8/10
Control (PTZ 110 mg/kg)	8/10	7/10	7/10
4c	9/10	7/10	5/10
6d	9/10	9/10	9/10

The compounds at the dose equivalent 0.1 ED₅₀ were injected 60 min before injection of PTZ. There was no significant difference between the groups (p > 0.05 for all compounds and effects, as compared with control group, Fisher’s exact test).

Figure 6. The influence of compounds from series 3 and 5 compounds on the spontaneous motor activity of mice. One-way ANOVA showed significant changes in locomotor activity of mice [F_(11,87) = 4.657; p < 0.0001]. The post-hoc Dunnett’s test confirmed a significant reduction in motility of mice after the administration of series 3 compounds at the dose of 0.1 ED₅₀: (3b) (p < 0.01), and (3c, 3e) ED₅₀ (p < 0.05) and series 5 compounds: (5a) at the dose of 0.1 ED₅₀ (p < 0.001) and (5e) at the doses of 0.1 and 0.05 ED₅₀ (p < 0.01).

Figure 7. The influence of compounds from series 3 and 5 on the nociceptive reactions studied in the acetic acid (0.6%)-induced writhing test. One-way ANOVA showed significant changes in the number of writhing episodes of mice (F_(5,42) = 2.766, p < 0.05). Post-hoc Dunnett’s test confirmed a significant reduction in the writhing episodes of mice after the administration of compound 3b at the dose of 0.1 ED₅₀ (p < 0.05) and compounds: 5a at the doses of 0.1 and 0.05 ED₅₀ (p < 0.05) and 5e at the doses of 0.1 and 0.05 ED₅₀ (p < 0.0 and p < 0.01, respectively).

Figure 8. The influence of naloxone, 5 mg/kg, s.c. on antinociceptive activity of series 5 (compounds 5a and 5e), evaluated in the acetic acid (0.6%)-induced writhing test. One-way ANOVA showed significant changes in the number of writhing episodes of mice after the administration of compounds 5a and 5e and coadministration of these compounds with naloxone (F_(4,31) = 4.073, p < 0.01). Post-hoc Dunnett’s test showed a significant reduction in the writhing episodes of mice after the administration of the compounds 5a and 5e at the dose of 0.1 ED₅₀ (p < 0.05 and p < 0.001, respectively). Pretreatment with naloxone did not affect the numer of writhing episodes as compared to respective compounds tested.

Figure 9. The influence of series 3 and 5 compounds on the head twitch responses (HTR) evoked by 5-hydroxy-L-tryptophan (L-5-HTP, 230 mg/kg). One-way ANOVA showed significant changes in the number of HTR [F_(5,42) = 2.460; p < 0.05]. Post-hoc Dunnett’s test confirmed a significant reduction in HTR of mice after the administration of compound (3e) at the dose of 0.1 ED₅₀ (p < 0.05).

Figure 10. The influence of compounds 3c, 5a and 5e used at the doses of 0.1 and 0.05 ED₅₀ on the body temperature of mice. Post-hoc Bonferroni test confirmed a significant decrease in the body temperature of mice after the administration of compound 5a at the dose of 0.1 ED₅₀ from 30 to 120 min (p < 0.001, p < 0.01, p < 0.01, p < 0.05), (5e) at the dose of 0.1 ED₅₀ from 30 to 90 min (p < 0.001, p < 0.001, p < 0.01) and at the dose of 0.05 ED₅₀ from 30 to 90 min (p < 0.001 in 30 min, and p < 0.05 from 60 to 180 min), and compound 3c at the dose of 0.1 ED₅₀ from 60 to 90 min (p < 0.05) of observation.

Figure 11. The influence of compound 4c (used at the doses of 0.1 and 0.05 ED₅₀) on the body temperature of mice. Two-way ANOVA revealed significant effects for both doses [F_(2,146) = 45.70; p < 0.0001] and time [(F_(5,146) = 3.18; p < 0.01], as well as a statically significant dose x time [F_(10,146) = 3.02; p < 0.01]. Post-hoc Bonferroni test confirmed a significant decrease in the body temperature of mice after the administration of compound 4c at the dose of 0.1 ED₅₀ from 120 to 150 min (p < 0.01).

Figure 12. The molecular structures of 3b – (A), 4c – (B), 5e – (C), and 6d – (D).

Figure 13. The map of the electrostatic potential (ESP) onto a surface of the electron density for 3b – A, 4c – B, 5e – C and 6d – D.

Table 4. Parameters for structure–activity relationship studies.

Compound	HOMO, eV	LUMO, eV	HOMO-LUMO gap	PSA	Molar volume	Polarizability
3a	−8.90	−0.31	−8.59	83.83	210.0	29.09
3b	−8.75	−0.03	−8.72	83.83	219.3	30.91
3c	−8.87	−0.37	−8.50	83.83	219.3	30.91
3d	−8.98	−0.65	−8.33	83.83	228.6	32.73
3e	−8.56	−0.04	−8.52	92.76	231.7	31.39
4a	−8.70	−0.01	−8.70	101.44	185.0	27.54
4b	−8.85	−0.29	−8.56	101.44	194.4	29.37
4c	−8.82	−0.34	−8.48	101.44	194.4	29.37
4d	−8.93	−0.60	−8.33	101.44	203.7	31.19
4e	−8.52	−0.02	−8.51	110.37	206.8	29.85
5a	−9.31	−0.30	−9.00	82.213	223.10	32.78
5b	−9.53	−0.56	−8.97	82.213	232.4	87.30
5c	−9.36	−0.55	−8.80	82.213	232.4	87.30
5d	−10.05	−0.74	−9.32	82.213	241.6	36.43
5e	−8.92	−0.27	−8.65	91.143	244.7	35.09
6a	−9.25	−0.24	−9.02	99.823	182.1	29.41
6b	−9.42	−0.44	−8.98	99.823	191.4	31.23
6c	−9.31	−0.50	−8.81	99.823	191.4	31.23
6d	−10.01	−0.69	−9.32	99.823	200.7	33.06
6e	−8.87	−0.20	−8.67	108.753	203.8	31.27

HOMO, highest occupied molecular orbital; LUMO, lowest unoccupied molecular orbital; PSA, polar surface area.

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