Synthesis, antiviral activity and structure–activity relationship of 1-(1-aryl-4,5-dihydro-1H-imidazoline)-3-chlorosulfonylureas and products of their cyclization

Figures & data

Figure 1. Previously reported antiviral compound16.

Figure 2. The scheme of synthesis of the investigated compounds.

Table 1. Parameters for drug-likeness estimation.

Compounds	Molecular mass	logP	HBD	HBA	No. of atoms	Molar refractivity	No. of rings	No. of rigid bonds	No. of rotatable bonds
3a	302.73	0.97	2	7	30	71.85	2	28	3
3b	316.76	1.46	2	7	33	76.28	2	31	3
3c	332.76	0.95	2	8	34	77.66	2	31	4
3d	332.76	0.95	2	8	34	77.66	2	31	4
3e	335.98	1.63	2	7	30	76.45	2	28	3
3f	337.18	1.63	2	7	30	76.45	2	28	3
4a	328.73	1.57	0	8	30	76.57	3	30	2
4b	342.75	2.06	0	8	33	80.99	3	33	2
4c	358.75	1.56	0	9	34	82.38	3	33	3
4d	358.75	1.56	0	9	34	82.38	3	33	3
4e	363.17	2.24	0	8	30	81.17	3	30	2
4f	363.17	2.24	0	8	30	81.17	3	30	2

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

Figure 3. ADMET properties of the studied compounds.

Table 2. Solubility and toxicity of the investigated compounds.

Compounds	logS	Mutagenicity	Tumorigenicity	Irritating effects	Reproductive effects
3a	−2.470	0.8	1.0	0.8	1.0
3b	−2.969	0.8	1.0	0.8	1.0
3c	−2.650	0.8	1.0	0.8	1.0
3d	−2.625	0.8	1.0	0.8	1.0
3e	−3.300	0.8	1.0	0.8	1.0
3f	−3.294	0.8	1.0	0.8	1.0
4a	−3.269	0.8	1.0	0.8	1.0
4b	−3.760	0.8	1.0	0.8	1.0
4c	−3.266	0.8	1.0	0.8	1.0
4d	−3.237	0.8	1.0	0.8	1.0
4e	−3.923	0.8	1.0	0.8	1.0
4f	−3.915	0.8	1.0	0.8	1.0

S – solubility [mol/dm³].

Table 3. Cytotoxicity of compounds 3d, 4a, 4b, 4c, 4d.

	Cell line/CC50 (µg/mL)*
Compounds	Vero
3d	840.93 ± 147.53
4a	809.50 ± 35.68
4b	819.77 ± 28.89
4c	90.80 ± 11.11
4d	650.07 ± 132.25
Acyclovir	>2000
Ribavirin	>2000

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

*Mean ± SD values come from three independent experiments.

Table 4. Antiviral activity of the compounds against HSV-1 and CVB3.

Compounds	Concentration [µg/mL]	HSV-1 [TCID50/mL]*	CVB3 [TCID50/mL]*
3d	625	4.69 ± 0.39	7.70 ± 0.24
	800	3.62 ± 0.87	6.25 ± 1.55
4a	500	4.09 ± 0.00	7.17 ± 0.00
	625	4.20 ± 0.24	8.17 ± 0.00
4b	500	4.82 ± 0.35	8.83 ± 0.00
	625	5.08 ± 0.67	8.83 ± 0.00
4c	31	6.38 ± 0.97	8.50 ± 0.00
	62	6.38 ± 0.97	5.34 ± 1.41
4d	250	4.89 ± 0.29	8.33 ± 0.00
	500	3.90 ± 0.16	8.50 ± 0.00
Acyclovir	2000	0	–
Ribavirin	2000	–	0
Control	0	6.38 ± 0.97	8.33 ± 0.32

Data represent the mean ± SD of at least 2–3 independent experiments. TCID₅₀ – 50% Tissue Culture Infectious Dose.

*The virus titres are shown in log.

Table 5. Molecular descriptors for structure–activity determination.

Compounds	Surface (Å^2)	PSA (Å^2)	Volume (Å^3)	Ovality	HOMO (eV)	LUMO (eV)	Polarizability
3d	552.8	101.1	253.5	1.67	−9.33	−2.27	30.79
4a	486.8	90.6	236.5	1.52	−9.63	−2.28	30.35
4b	503.0	90.6	251.6	1.57	−9.46	−2.25	32.10
4c	523.9	99.5	262.4	1.58	−9.62	−2.13	32.65
4d	526.5	99.5	263.9	1.58	−9.52	−2.32	32.65

Figure 4. HOMO (A, C) and LUMO (B, D) orbitals for 3d (A, B) and 4a (C, D).

Figure 5. The map of the electrostatic potential (ESP) onto a surface of the electron density for 3d (A) and 4a (B).

Saczewski F, Debowski T, Szmigiel J. Synthesis and transformations of 2-amino-1(4,5-dihydro-1H-imidazol-2-yl)benzimidazoles. A route to 2,3-dihydrobenzo[4,5]-imidazo[1,2-a][1,3,5]triazine ring system. Heterocycles 1998;48:1879–85

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