Synthesis and antiviral activity of 1-(1,3-disubstitutedimidazolidyn-2-ylidene)-3-ethoxycarbonylmethylurea derivatives

Figures & data

Scheme 1. The scheme of synthesis of the investigated compounds.

Table 1. Parameters for drug-likeness estimation.

Compound	Molar mass	log P	HBD	HBA	Number of atoms	Molar refractivity	Rings	Rigid bonds	Rotatable bonds	Drug-likeness score
3a	444.504	2.91	1	9	55	118.17	3	49	8	−5.66
3b	474.530	2.89	1	10	59	123.99	3	52	9	−6.25
3c	474.530	2.89	1	10	59	123.99	3	52	9	−7.90
3d	472.557	3.88	1	9	61	127.02	3	55	8	−6.58
3e	478.949	3.57	1	9	55	122.77	3	49	8	−6.14
3f	464.923	3.09	1	9	52	118.35	3	46	8	1.64
3g	494.949	3.07	1	10	56	124.16	3	49	9	1.07
3h	494.949	3.07	1	10	56	124.16	3	49	9	−0.58
3i	492.976	4.06	1	9	58	127.20	3	52	8	0.75
3j	499.368	3.75	1	9	52	122.95	3	46	8	0.82

HBD – number of hydrogen bond donors; HBA – number of hydrogen bond acceptors.

Figure 1. Evaluation of ADMET properties of the studied compounds.

Figure 2. HOMO (A, C) and LUMO (B, D) orbitals for 3c (A, B) and 3g (C, D).

Table 2. ADMET parameters of the studied compounds.

		Toxicity risk
Compounds	log S	Mutagenic	Tumorigenic	Irritant	Reproductive effective	Drug score
3a	−4.08	1.0	1.0	1.0	1.0	0.35
3b	−4.07	1.0	1.0	1.0	1.0	0.33
3c	−4.02	1.0	1.0	1.0	1.0	0.33
3d	−4.99	1.0	1.0	0.6	1.0	0.18
3e	−4.76	1.0	1.0	1.0	1.0	0.29
3f	−4.32	1.0	1.0	1.0	1.0	0.58
3g	−4.31	1.0	1.0	1.0	1.0	0.53
3h	−4.26	1.0	1.0	1.0	1.0	0.41
3i	−5.23	1.0	1.0	0.6	1.0	0.26
3j	−4.99	1.0	1.0	1.0	1.0	0.44

S – solubility.

Table 6. Molecular descriptors for structure–activity determination.

Comp.	Surface (Å^2)	PSA (Å^2)	Volume (Å^3)	Ovality	HOMO (eV)	LUMO (eV)	Polarizability
3a	703.1	144.3	386.4	1.84	−8.97	−1.03	44.74
3b	686.1	125.1	407.6	1.85	−9.49	−0.93	47.37
3c	721.3	155.9	406.0	1.83	−8.96	−0.91	47.49
3d	768.2	121.1	410.6	1.85	−9.41	−0.90	48.58
3e	743.4	119.3	392.9	1.79	−9.03	−1.12	46.82
3f	669.6	133.3	377.9	1.78	−9.14	−1.20	44.90
3g	748.4	121.1	395.4	1.83	−9.07	−0.99	47.52
3h	714.4	150.9	406.7	1.85	−9.17	−1.22	47.53
3i	763.6	118.5	408.9	1.85	−9.52	−1.09	48.77
3j	710.3	134.7	396.2	1.86	−9.52	−2.02	48.33

Table 3. Cytotoxicity of compounds 3a–3g.

	Cell line/CC50 (µg/mL)^a
Compounds	Vero
3a	479.00 ± 54.74
3b	759.10 ± 7.21
3c	480.13 ± 61.11
3d	125.00 ± 0.00
3e	196.97 ± 37.90
3f	107.97 ± 8.90
3g	250.00 ± 0.00
acyclovir	>2000

^aMean ± S.D. values come from three independent experiments.

CC₅₀ is the cytotoxic concentration required to reduce the number of viable cells by 50%.

Table 4. Antiviral activity of the compounds against HSV-1.

Compounds	MNCC [µg/mL]^a	TCID50/mL^b
3a	125	6.50 ± 0.32
	250	6.33 ± 0.36
3b	250	6.67 ± 0.37
	500	6.00 ± 0.45
3c	125	6.33 ± 0.36
	250	5.00 ± 0.45
3d	31	6.67 ± 0.37
	62	6.67 ± 0.37
3e	62	6.50 ± 0.32
	125	6.50 ± 0.32
3f	31	7.00 ± 0.45
	62	6.67 ± 0.37
3g	62	6.67 ± 0.37
	125	6.50 ± 0.32
Acyclovir	2000	0
Control	0	6.50 ± 0.32

^aMNCC – Maximum non-cytotoxic concentration.

^bThe virus titers are shown in log.

Table 5. Antiviral activity of the compounds against CVB3.

Compounds	MNCC [µg/mL]^a	TCID50/mL^b
3a	125	7.15 ± 0.07
	250	7.08 ± 0.60
3b	250	7.15 ± 0.07
	500	7.08 ± 0.60
3c	125	7.15 ± 0.07
	250	7.08 ± 0.60
3d	31	7.16 ± 1.00
	62	7.08 ± 0.60
3e	62	7.44 ± 0.49
	125	6.57 ± 1.72
3f	31	7.16 ± 1.00
	62	7.15 ± 0.07
3g	62	6.25 ± 0.34
	125	5.92 ± 0.81
Ribavirin	2000	0
Control	0	7.26 ± 0.86

^aMNCC – Maximum non-cytotoxic concentration.

^bThe virus titers are shown in log.

Figure 3. The map of the electrostatic potential (ESP) onto a surface of the electron density for 3c (a) and 3g (b).