Synthesis and biological evaluation of fluoropyrazolesulfonylurea and thiourea derivatives as possible antidiabetic agents

Figures & data

Scheme 1: Synthesis of compounds 2–39.

Table 1. Molecular properties calculation*.

	Lipinski’s parameters
Compound	miLogP†	MW‡	nON¶	nOHNH§	nviolations‖	TPSA#	% ABS*	nrotb†	volume‡	Solubility¶	Druglikeness§	Drug-Score||
2	4.93	474.36	5	2	0	75.77	82.86	4	351.23	−5.60	3.84	0.42
3	4.57	409.49	5	2	0	75.77	82.86	4	349.90	−5.11	3.82	0.53
4	4.67	472.34	5	2	0	77.99	82.10	4	345.02	−5.95	2.16	0.42
5	4.31	407.47	5	2	0	77.99	82.10	4	343.69	−5.46	2.47	0.53
6	6.65	593.48	7	2	2	90.87	77.65	6	455.14	−7.22	5.90	0.16
7	6.29	528.61	7	2	2	90.87	77.65	6	453.81	−6.73	5.96	0.20
8	5.10	504.54	8	2	2	104.01	73.17	6	418.82	−6.07	7.27	0.28
9	4.67	515.57	8	2	1	103.76	73.20	6	433.10	−5.61	7.99	0.30
10	7.33	627.92	7	2	2	90.87	77.65	6	468.67	−7.95	8.06	0.14
11	6.96	563.05	7	2	2	90.87	77.65	6	467.35	−7.46	8.12	0.16
12	5.77	538.99	8	2	2	104.01	73.17	6	432.36	−6.80	9.43	0.21
13	5.35	550.01	8	2	2	103.76	73.20	6	446.63	−6.35	10.13	0.23
14	6.86	599.53	7	2	2	90.87	77.65	6	473.72	−7.28	3.03	0.16
15	6.50	534.66	7	2	2	90.87	77.65	6	472.40	−6.80	3.10	0.20
16	5.30	510.59	8	2	2	104.01	73.17	6	437.41	−6.13	4.42	0.28
17	4.88	521.62	8	2	1	103.76	73.20	6	451.68	−5.68	5.10	0.30
18	6.55	609.55	6	2	2	73.80	83.54	8	464.02	−7.22	5.90	0.16
19	5.00	520.61	7	2	1	86.94	79.00	8	427.70	−6.15	4.19	0.25
20	4.57	531.64	7	2	1	86.69	79.09	8	441.97	−5.70	4.83	0.27
21	7.23	643.99	6	2	2	73.80	83.54	8	477.55	−8.04	4.71	0.10
22	6.87	579.12	6	2	2	73.80	83.54	8	476.23	−7.55	4.74	0.12
23	5.68	555.06	7	2	2	86.94	79.00	8	441.23	−6.89	6.17	0.15
24	5.25	566.08	7	2	2	86.69	79.09	8	455.51	−6.43	6.82	0.16
25	7.40	615.59	6	2	2	73.80	83.54	8	482.60	−7.37	-1.46	0.09
26	5.84	526.66	7	2	2	86.94	79.00	8	446.28	−6.22	0.06	0.19
27	5.49	547.48	6	2	2	73.80	83.54	7	409.17	−5.80	4.36	0.32
28	3.94	458.54	7	2	0	86.94	79.00	7	372.85	−4.64	5.82	0.57
29	3.51	469.57	7	2	0	86.69	79.09	7	387.13	−4.19	6.48	0.61
30	6.93	589.56	6	2	2	73.80	83.54	10	459.57	−6.64	2.65	0.17
31	6.57	524.69	6	2	2	73.80	83.54	10	458.25	−6.14	2.71	0.21
32	4.95	511.65	7	2	1	86.69	79.09	10	437.53	−5.03	4.76	0.33
33	6.86	649.57	7	0	2	82.42	80.56	6	490.47	−7.98	5.63	0.17
34	7.54	684.01	7	0	2	82.42	80.56	6	504.00	−8.71	5.47	0.15
35	7.18	619.14	7	0	2	82.42	80.56	6	502.68	−8.22	5.52	0.18
36	7.07	655.62	7	0	2	82.42	80.56	6	509.05	−7.70	-0.51	0.12
37	6.71	590.75	7	0	2	82.42	80.56	6	507.73	−7.21	-0.47	0.14
38	8.97	644.80	6	0	2	67.04	85.87	7	552.18	−8.99	5.05	0.15
39	9.20	679.24	6	0	2	67.04	85.87	7	565.72	−9.72	5.20	0.14
Phenformin**	0.43	205.26	5	6	1	97.78	75.27	6	198.34	−0.97	3.93	0.35
3,5-Dimethylpyrazole††	0.762	96.13	2	1	0	28.68	99.10	0	97.99	−0.93	1.78	0.55

Calculated absorption (% ABS), polar surface area (PSA), LogS, Lipinski’s parameters, drug-likeness and drug score of the compounds 2–39.

* mipc – Molinspiration Property Calculator.

† Molinspiration (miLogP2.2 – November 2005).

‡ Molecular weight.

¶ Number of hydrogen-bond acceptors (O and N atoms).

§ Number of hydrogen-bond donors (OH and NH groups).

||Number of rule of 5 violations.

# Topological polar surface area.

* Percentage of absorption: % ABS = 109 − (0.345 × TPSA).

† Number of rotatable bonds.

‡ Molecular volume.

¶ Solubility prediction (LogS).

|| Fragment-based drug-likeness.

# Drug score combines drug-likeness, cLogP, logS, molecular weight and toxicity risks in one handy value.

** Positive control antidiabetic agent.

†† Positive control hypoglycemic agent.

Table 2. Antidiabetic activity of pyrazole derivatives.

Compd.	Reduction in plasma glucose level, %	p
2	7	<0.01*
3	6	<0.01*
4	8	<0.01*
5	9	<0.01*
6	16	<0.01*
7	19	<0.01*
10	18	<0.01*
11	20	<0.01*
14	21	<0.01*
15	23	<0.01*
18	<1	0.05
21	<1	0.05
22	2.5	0.05
25	3	0.05
27	4	0.05
30	2	0.05
31	1.5	0.05
33	7.5	0.01*
34	8	0.01*
35	9	0.01*
36	8	0.01*
37	10	0.01*
38	9.5	0.01*
39	7	0.01*
Phenformin	10	<0.01*
3,5-Dimethylpyrazole	4	<0.05*

*Statistically significant.