Synthesis and bioactivity studies of 1-aryl-3-(2-hydroxyethylthio)-1-propanones

Figures & data

Scheme 1. Synthesis of the compounds EU1–EU9.

Table 1. Experimental data of the compounds EU1–EU9.

Compound	Aryl	B1–B9	2-Mercaptoethanol	Reaction time	Yield
Code		(mmol)	(mmol)	(minute)	(%)
EU1	C6H5	0.39	0.39	2640	82.38
EU2	4-CH3C6H4	0.37	0.37	5785	70.49
EU3	4-H3OC6H4	0.35	0.35	5785	71.75
EU4	4-FC6H4	0.36	0.36	2750	89.39
EU5	4-ClC6H4	0.34	0.34	4640	81.78
EU6	4-BrC6H4	0.30	0.30	1325	82.39
EU7	C4H3S(2-yl)	0.38	0.38	2595	88.81
EU8	C4H3O(2-yl)	0.41	0.41	4650	67.11
EU9	4-O2NC6H4	0.33	0.33	3150	19.16

EU1–EU9 compounds were synthesized by using B1–B9 as starting compounds. Reactions were carried out in phosphate buffer solution (5 mL, pH = 7.4, 37 °C). Compounds were purified by column chromatography [Silicagel 60 (70–230 mesh) Ethylacetate:Hexane (8:2)].

Table 2. Spectral data of the compounds EU1–EU9.

EU1	^1H NMR (400 MHz, CDCl3, ppm) δ = 7.87–7.85 (m, 2H), 7.49–7.46 (m, 1H), 7.38–7.34 (m, 2H), 3.72–3.68 (m, 2H), 3.50 (brs, OH, 1H), 3.21–3.16 (m, 2H), 2.88–2.82 (m, 2H), 2.70–2.66 (m, 2H). ^13C NMR (100 MHz, CDCl3, ppm) δ = 198.8, 136.6, 133.6, 128.9, 128.2, 61.2, 39.2, 35.5, 26.2. HRMS (ESI–MS): calcd. for C11H14O2S [M + H]^+ 211.0748; found 211.0793.
EU2	^1H NMR (400 MHz, CDCl3, ppm) δ = 7.79 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H), 3.73 (m, 2H), 3.20 (t, J = 6.9 Hz, 2H), 3.16 (s, OH, 1H), 2.88 (t, J = 6.9 Hz, 2H), 2.71 (t, J = 6.9 Hz, 2H), 2.34 (s, 3H). ^13C NMR (100 MHz, CDCl3, ppm) δ = 198.3, 144.4, 134.2, 129.6, 128.4, 61.1, 39.0, 35.6, 26.3, 21.9. HRMS (ESI–MS): calcd. for C12H16O2S [M + H]^+ 225.0905; found 225.0949.
EU3	^1H NMR (400 MHz, CDCl3, ppm) δ =7.77 (d, J = 8.8 Hz, 2H), 6.78 (d, J = 8.8 Hz, 2H), 3.70 (s, 3H), 3.65 (t, J = 6.7 Hz, 2H), 3.56 (s, OH, 1H), 3.08 (t, J = 6.7 Hz, 2H), 2.78 (t, J = 6.7 Hz, 2H), 2.63 (t, J = 6.7 Hz, 2H). ^13C NMR (100 MHz, CDCl3, ppm) δ = 197.3, 163.8, 130.5, 129.6, 114.0, 61.2, 55.6, 38.7, 35.4, 26.4. HRMS (ESI–MS): calcd. for C12H16O3S [M + H]^+ 241.0854; found 241.0898.
EU4	^1H NMR (400 MHz, CDCl3, ppm) δ =7.91 (dd, J = 8.0, 5.7 Hz, 2H), 7.06 (t, J = 8.0 Hz, 2H), 3.72 (q, J = 6.5 Hz, 2H), 3.20 (t, J = 6.5 Hz, 2H), 3.13 (bs, OH, 1H), 2.87 (t, J = 6.5 Hz, 2H), 2.70 (t, J = 6.5 Hz, 2H). ^13C NMR (100 MHz, CDCl3, ppm) δ = 197.1, 166.0 (^1J = 255 Hz), 133.1 (^4J = 3 Hz), 130.9 (^3J = 9 Hz), 116.0 (^2J = 21 Hz), 61.0, 39.0, 35.6, 26.1. HRMS (ESI–MS): calcd. for C11H13FO2S [M + H]^+ 229.0654; found 229.0699.
EU5	^1H NMR (400 MHz, CDCl3, ppm) δ = 7.83 (d, J = 8.8 Hz, 2H), 7.37 (d, J = 8.8 Hz, 2H), 3.73 (t, J = 6.5 Hz, 2H), 3.21 (t, J = 6.5 Hz, 2H), 2.98 (s, OH, 1H), 2.88 (t, J = 6.5 Hz, 2H), 2.72 (t, J = 6.5 Hz, 2H). ^13C NMR (100 MHz, CDCl3, ppm) δ = 197.4, 140.0, 135.0, 129.7, 129.2, 61.0, 39.1, 35.7, 26.1. HRMS (ESI–MS): calcd. for C11H13ClO2S [M + H]^+ 245.0325; found 245.0403.
EU6	^1H NMR (400 MHz, CDCl3, ppm) δ = 7.82 (d, J = 8.6 Hz, 2H), 7.62 (d, J = 8.6 Hz, 2H), 3.78 (q, J = 6.4 Hz, 2H), 3.26 (t, J = 6.4 Hz, 2H), 2.95 (t, J = 6.4 Hz, 2H), 2.78 (t, J = 6.4 Hz, 2H). ^13C NMR (100 MHz, CDCl3, ppm) δ = 197.4, 132.3, 131.7, 129.8, 126.6, 60.7, 39.1, 36.0, 25.9. HRMS (ESI-MS): calcd. for C11H13BrO2S [M + H]^+ 288.9820; found 288.9898.
EU7	^1H NMR (400 MHz, CDCl3, ppm) δ = 7.68 (dd, J = 3.6, 1.1 Hz, 1H), 7.60 (dd, J = 4.8, 1.1 Hz, 1H), 7.08 (dd, J = 4.8, 3.6 Hz, 1H), 3.71 (m, 2H), 3.18–3.15 (m, 2H), 2.89–2.85 (m, 2H), 2.72–2.68 (m, 2H). ^13C NMR (100 MHz, CDCl3, ppm) δ = 191.6, 143.9, 134.4, 132.6, 128.5, 61.1, 39.7, 35.6, 26.3. HRMS (ESI–MS): calcd. for C9H12O2S2 [M + H]^+ 217.0312; found 217.0356.
EU8	^1H NMR (400 MHz, CDCl3, ppm) δ = 7.57 (br s, 1H), 7.20 (d, J = 3.7 Hz, 1H), 6.52 (dd, J = 3.7, 1.8 Hz, 1H), 3.74 (t, J = 6.0 Hz, 2H), 3.13–3.08 (m, 2H), 2.90–2.84 (m, 2H), 2.74–2.70 (m, 2H). ^13C NMR (100 MHz, CDCl3, ppm) δ = 187.7, 152.6, 147.0, 117.8, 112.7, 60.9, 38.8, 35.6, 25.9. HRMS (ESI–MS): calcd. for C9H12O3S [M + H]^+ 201.0541; found 201.0580.
EU9	^1H NMR (400 MHz, CDCl3, ppm) δ = 8.32 (d, J = 9.0 Hz, 2H), 8.11 (d, J = 9.0 Hz, 2H), 3.79 (t, J = 6.3 Hz, 2H), 3.34 (t, J = 6.3 Hz, 2H), 2.97 (t, J = 6.3 Hz, 2H), 2.79 (t, J = 6.3 Hz, 2H). ^13C NMR (100 MHz, CDCl3, ppm) δ = 197.0, 141.1, 129.8, 129.3, 124.2, 60.9, 39.8, 35.9, 25.8. HRMS (ESI–MS): calcd. for C11H13NO4S [M + H]^+ 256.0599; found 256.0644.

Table 3. Cytotoxic activities of the compounds EU1–EU9.

	CC50 (μM)
	Human OSCC cell lines				Human oral normal cells
	HSC-2	HSC-3	HSC-4	HL-60	HGF	HPC	HPLF	TS
EU1	>400	>400	>400	>400	>400	>400	>400	> <1.0
EU2	>400	>400	>400	340 ± 58	>400	>400	331 ± 32	> <1.0
EU3	>400	>400	>400	338 ± 38	>400	>400	>400	> <1.0
EU4	>400	>400	>400	>400	>400	>400	>400	> <1.0
EU5	337 ± 4	292 ± 8	380 ± 6	167 ± 17	328 ± 5	>400	317 ± 12	>1.2
EU6	336 ± 16	302 ± 40	>400	158 ± 15	322 ± 13	>400	321 ± 21	>1.2
EU7	>400	320 ± 20	>400	>400	>400	>400	>400	> <1.1
EU8	377 ± 16	363 ± 30	>400	>400	325 ± 41	>400	>400	> <0.97
EU9	49 ± 6	50 ± 8	68 ± 2	15 ± 1	72 ± 2	39 ± 2.0	64 ± 16	1.3
5-FU	4.9 ± 0.91	47 ± 7.2	2.5 ± 0.25	10 ± 1.1	>100	>100	>100	>6.2
Melphalan	6.2 ± 0.32	19 ± 0.58	36 ± 1.7	1.0 ± 0.04	96 ± 6.4	83 ± 4.5	80 ± 0.58	5.5

CC₅₀ values refer to the concentrations of the compounds in micromoles which reduce the viable cell number by 50%. Tumor-specific (TS) value is calculated by dividing the mean CC₅₀ value of each compound against normal cells to mean CC₅₀ value against OSCC. CC₅₀ value was determined from the growth curves plotted at different concentrations of each compounds in triplicate wells. Human oral squamous cell carcinoma cell lines (HSC-2, HSC-3, HSC-4), human promyelocytic leukemic cell line (HL-60), human oral normal mesenchymal cells (gingival fibroblast (HGF), pulp cells (HPC), periodontal ligament fibroblast (HPLF). TS: tumour selectivity; mM: micromolar.

Figure 1. Effect of the compound EU9 on HSC-2 cancer cells and HGF normal cells after. 24 h. (NS means no stimulation (control)).

Table 4. Inhibition percentages of hCA I and II by the compounds EU1–EU9.

	% Inhibition (10^−5 M)
Compound	hCA I	hCA II
EU1	27	26
EU2	26	26
EU3	25	27
EU4	24	25
EU5	24	26
EU6	23	25
EU7	26	25
EU8	27	25
EU9	30	25
Acetazolamide	87	91