Synthesis, characterisation, biological evaluation and in silico studies of sulphonamide Schiff bases

Figures & data

Scheme 1. General synthetic procedure for target analogues (1–8).

Table 1. K_I values of hCA I, II and AChE with derivatives 1–8, AAZ and TAC as standard inhibitors.

Compounds	hCA I		hCA II		AChE
	KI (nM)	R^2	KI (nM)	R^2	KI (nM)	R^2
1	59.7 ± 0.1	0.9993	16.4 ± 0.7	0.9995	24.3 ± 1.0	0.9995
2	66.5 ± 0.9	0.9991	13.8 ± 0.1	0.9999	21.00 ± 0.9	0.9994
3	80.5 ± 1.5	0.9991	26.3 ± 0.09	0.9999	34.9 ± 1.4	0.9996
4	40.1 ± 0.6	0.9988	79.3 ± 0.2	0.9999	27.9 ± 1.3	0.9994
5	52.1 ± 0.7	0.9992	19.8 ± 1.2	0.9993	61.2 ± 4.0	0.9993
6	100.6 ± 1.9	0.9984	29.1 ± 0.3	0.9999	25.7 ± 1.0	0.9995
7	62.32 ± 1.3	0.9981	10.1 ± 0.03	0.9999	77.0 ± 9.3	0.9984
8	32.1 ± 0.4	0.9991	61.9 ± 0.2	0.9999	31.4 ± 1.2	0.9996
AAZ^a	436.2 ± 12.2	0.9982	93.5 ± 1.2	0.9996	–	–
TAC^b	–	–	–	–	109.75 ± 2.39	0.9999

^aAcetazolamide. ^bTacrine.

Table 2. Selectivity index values for K_I values of the compounds 1–8.

Compounds	KI (hCA II/hCA I)	KI (AAZ^a/hCA I)	KI (AAZ^a/hCA II)	KI (TAC^b/AChE)
1	0.27	7.31	5.72	4.52
2	0.21	6.55	6.77	5.23
3	0.33	5.42	3.55	3.14
4	1.98	10.89	1.18	3.93
5	0.38	8.37	4.72	1.79
6	0.29	4.34	3.22	4.28
7	0.16	7.00	9.22	1.42
8	1.93	13.57	1.51	3.50

^aAcetazolamide.

^bTacrine.

Table 3. The radical scavenging and metal reduction activity of synthesised compounds (1–8).

Compounds	DPPH^a [0.05 mg/mL]	ABTS^a [0.2 mg/mL]	Fe^3+ reducing ability^b [0.2 mg/mL]	Cu^2+ reducing ability^b [0.2 mg/mL]
1	18.7 ± 1.5	18.4 ± 2.0	0.15 ± 0.03	0.22 ± 0.02
2	8.2 ± 0.4	15.1 ± 1.4	0.27 ± 0.02	0.26 ± 0.04
3	5.9 ± 0.4	7.3 ± 0.6	0.11 ± 0.01	0.28 ± 0.04
4	12.7 ± 0.9	14.7 ± 0.9	0.33 ± 0.02	0.24 ± 0.05
5	1.9 ± 0.09	76.8 ± 8.1	0.33 ± 0.03	0.99 ± 0.07
6	9.2 ± 0.6	77.7 ± 7.9	0.47 ± 0.06	0.93 ± 0.07
7	4.2 ± 0.4	74.5 ± 6.4	0.39 ± 0.04	1.15 ± 0.08
8	3.2 ± 0.6	78.4 ± 7.7	0.33 ± 0.07	0.80 ± 0.05
BHT^c	47.0 ± 5.2	98.9 ± 9.1	0.67 ± 0.01	2.00 ± 0.11
BHA^c	21.7 ± 1.9	79.5 ± 6.1	1.23 ± 0.20	2.28 ± 0.13
Trolox^c	57.8 ± 6.8	94.4 ± 9.0	1.27 ± 0.12	1.81 ± 0.05

Data are mean ± standard deviation (n = 3). BHA: butylated hydroxyanisole; BHT: butylated hydroxytoluene.

^aThe percent (%) of ABTS and DPPH radical scavenging activity.

^bThe values were expressed as absorbance. High absorbance indicates high metal ions (Fe³⁺ and Cu²⁺) reducing ability.

^cStandard antioxidant.

Table 4. ADMET–related parameters of the derivatives (1–8).

Principal descriptors	1	2	3	4	5	6	7	8	Standard range
QPlogPw	13.47	13.46	13.47	13.46	14.84	14.83	14.83	14.82	4 to 45
QPlogPo/w	1.50	1.43	1.50	1.43	1.26	1.16	1.36	1.24	−2.0 to 6.5
QPlogS	−3.45	−3.35	−3.46	−3.36	−3.33	−3.17	−3.42	−3.26	−6.5 to 1.5
QPlogKp	−3.38	−3.39	−3.39	−3.40	−3.43	−3.44	−3.42	−3.43	−8.0 to −1.0
QPlogBB	−1.42	−1.43	−1.42	−1.44	−1.41	−1.43	−1.40	−1.42	−3.0 to 1.2
QPlogKhsa	−0.36	−0.38	−0.36	−0.38	−0.39	−0.40	−0.39	−0.40	−1.5 to 1.5
QPlogHERG	−5.63	−5.60	−5.64	−5.61	−5.56	−5.53	−5.55	−5.52	<−5
HOA	75.69	75.13	75.66	75.09	74.33	73.60	75.03	74.22	<25 poor, great >500
PSA	95.15	95.19	95.20	95.23	98.30	98.31	97.98	98.06	7 to 200
Rule of Five	0	0	0	0	0	0	0	0	max. 4
Rule of Three	0	0	0	0	0	0	0	0	max. 3

Various computational pharmacodynamic and pharmacokinetic parameters of synthesised compounds in this research were predicted such as water/gas partition coefficient (QPlogPw), octanol/water partition coefficient (QPlogPo/w), aqueous solubility (QPlogS), skin permeability (QPlogKp), brain/blood partition coefficient (QPlogBB), prediction of binding to human serum albumin (QPlogKhsa), IC₅₀ value for blockage of HERG K⁺ channels (QPlogHERG), human oral absorption (HOA), van der Waals surface area of polar nitrogen and oxygen atoms (PSA), number of violations of Lipinski’s rule of five and number of violations of Jorgensen’s rule of three.

Figure 1. Interaction of the ligands with the key amino acids within the active site of hCA I (PDB ID: 4WUP). (A) Docking pose of the native ligand 3UF (4-[(2-hydroxyethyl)sulfanyl]benzenesulfonamide, PubChem CID: 4269754). (B) Docking pose of compound 8 (4-((3-chloro-2-hydroxybenzyl)amino)benzenesulfonamide).

Figure 2. Interaction of the ligands with the key amino acids within the active site of hCA II (PDB ID: 4HT0). (A) Docking pose of the native ligand V50 (4-[(4,6-dimethylpyrimidin-2-yl)thio]-2,3,5,6-tetrafluorobenzenesulfonamide, PubChem CID: 71299336). (B) Docking pose of compound 7 (4-((3-bromo-2-hydroxybenzyl)amino)benzenesulfonamide).

Figure 3. Interaction of the ligands with the key amino acids within the active site of AChE (PDB ID: 4EY7). (A) Docking pose of the native ligand E20 (1-benzyl-4-[(5,6-dimethoxy-1-indanon-2-yl)methyl]piperidine, PubChem CID: 1150567). (B) Docking pose of compound 2 (3-((3-chloro-2-hydroxybenzylidene)amino)benzenesulfonamide).