Designing, synthesis and bioactivities of 4-[3-(4-hydroxyphenyl)-5-aryl-4,5-dihydro-pyrazol-1-yl]benzenesulfonamides

Figures & data

Figure 1. Chemical structures of some carbonic anhydrase inhibitors which are in clinical use.

Scheme 1. Synthesis of compounds 1–9.

Table 1. Cytotoxic activity of compounds 1–9 against human oral malignant and nonmalignant cells.

CC50 (μM)
	Human oral squamous cell carcinoma cell lines							Human oral normal cells								TS
Compounds	Ca9–22 (A)	SI	HSC-2	SI	HSC-3	SI	HSC-4	SI	Mean (B)	SD	Mean SI	HGF (C)	HPLF	HPC	Mean (D)	SD	(D/B)	(C/A)	PSE
1	82.0	1.4	94.7	1.2	81.0	1.5	83.7	1.4	85.3	6.3	1.4	133.3	59.7	161.0	118.0	52.4	1.4	1.6	1.6
2	57.0	1.7	95.3	1.0	67.3	1.4	70.3	1.4	72.5	16.3	1.4	99.3	42.3	150.0	97.2	53.9	1.3	1.7	1.9
3	53.3	2.0	95.3	1.1	71.0	1.5	88.3	1.2	77.0	18.8	1.4	107.7	39.3	167.3	104.8	64.0	1.4	2.0	1.9
4	39.7	2.2	81.7	1.1	57.0	1.5	61.0	1.4	59.8	17.3	1.6	89.0	29.3	144.3	87.6	57.5	1.5	2.2	2.6
5	44.3	1.7	82.3	0.9	76.0	1.0	54.0	1.4	64.2	18.0	1.3	63.0	34.7	131.0	76.2	49.5	1.2	1.4	2.0
6	61.7	1.4	84.7	1.0	78.0	1.1	62.3	1.4	71.7	11.5	1.2	64.7	33.0	155.0	84.2	63.3	1.2	1.0	1.7
7	55.7	1.4	85.0	0.9	70.3	1.1	61.7	1.3	68.2	12.7	1.2	52.0	34.3	149.3	78.6	61.9	1.2	0.9	1.7
8	39.3	1.7	76.0	0.9	63.3	1.0	63.7	1.0	60.6	15.3	1.2	42.0	30.0	126.7	66.2	52.7	1.1	1.1	1.9
9	99.3	1.2	67.0	1.8	87.3	1.4	93.7	1.3	86.8	14.1	1.4	165.7	26.7	173.3	121.9	82.6	1.4	1.7	1.7
5-FU	29.0	>34.5	13.0	>76.9	16.0	>62.5	13.0	>76.9	17.8	7.6	>62.7	>1000	>1000	>1000	>1000	>1000	>56.2	>34.5	>352.2

CC₅₀ values refer to the concentrations of the compounds in micromoles which reduce the viable cell number by 50%. Oral squamous cell carcinoma (OSCC) cell lines used are Ca9–22 (derived from gingiva), HSC-2, HSC-3, HSC-4 (derived from tongue). Normal oral cells used are human gingival fibroblasts (HGF), human periodontal ligament fibroblasts (HPLF), and human pulp cells (HPC). Tumor selectivity (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. SI: Selectivity Index; SD: Standart Deviation; 5-FU: 5-Fluorouracil; μM: Micromolar.

Table 2. Effects of compounds 1–9 on hCA IX and XII isoenzymes activity.

	Ki (nM)
Compounds	hCA IX	hCA XII	hCA XII/hCA IX
1	923	68.9	13.4
2	100	95	1.1
3	93.1	33.6	2.8
4	97.7	38.8	2.5
5	85.7	9.2	9.3
6	84.1	8.6	9.8
7	66.2	7.6	8.7
8	63.7	7.5	8.5
9	53.5	6.2	8.6
AAZ*	25	5.7	4.4

* Acetazolamide (AAZ) was used as a standard inhibitor for all CAs investigated here.