Coumarin or benzoxazinone based novel carbonic anhydrase inhibitors: synthesis, molecular docking and anticonvulsant studies

Figures & data

Table 1. Structures of 2a–j and 3d–i (these compounds were available from previous studies).

Compounds	R1	R2	R3	n
2a	–CH3	–	–	–
2b	–(CH2)3CH3	–	–	–
2c	–	–H	–CH3	–
2d	–	–H	– (CH2)3CH3	–
2e	–	–H	Benzyl	–
2f	–	–H	3,4,5-Trimethoxybenzyl	–
2i	–	–	–	4
2j	–	–	–	5
3d	–	–OH	–CH3	–
3e	–	–OH	–CH3–CH = CH2	–
3f	–	–OH	–(CH2)3CH3	–
3g	–	–OH	Benzyl	–
3h	–	–OH	3-Methylbenzyl	–
3i	–	–OH	3,4,5-Trimethoxybenzyl	–

Scheme 1. Synthesis of 6,8-dimethyl coumarin bearing imidazolium and benzimidazolium salts (1a–i).

Scheme 2. Synthesis of 7-hydroxy coumarin bearing benzimidazolium salts (2g, h).

Scheme 3. Synthesis of 7,8-dihydroxy coumarin bearing imidazolium and benzimidazolium salts (3a–c, j).

Scheme 4. Synthesis of benzoxazinone bearing imidazolium and benzimidazolium salts (4a–i).

Table 2. IC₅₀ values of synthesized and previously reported compounds against hCA I and II inhibition.

Compounds	hCA I (µM)	hCA II (µM)
1a	11.76	17.17
1b	16.41	23.00
1c	10.11	14.52
1d	12.80	15.52
1e	7.79	9.91
1f	5.34	6.01
1g	15.62	19.67
1h	12.57	16.90
1i	9.46	8.92
2a51	264.00	327.00
2b51	218.00	188.00
2c51	138.00	137.00
2d51	147.00	221.00
2e51	153.00	154.00
2f51	79.00	88.00
2g	11.76	17.17
2h	16.41	23.00
2i51	81.00	94.00
2j51	99.00	89.00
3a	10.98	56.82
3b	11.72	26.81
3c	9.48	36.98
3d52	28.55	49.40
3e52	49.32	51.45
3f52	48.06	29.70
3g52	25.63	40.01
3h52	22.09	28.90
3i52	33.10	20.33
3j	4.99	6.01
4a	8.99	14.34
4b	18.09	20.16
4c	9.06	11.20
4d	15.49	22.92
4e	6.86	10.73
4f	14.71	24.28
4g	9.90	18.42
4h	7.61	9.88
4i	6.49	8.15
Acetazolamide57	3.30	2.40

Table 3. ScMet and neurotoxicity screening data in mice dosed ip with the compounds.

	ScMet				Toxicity
	½ h		4 h		½ h		4 h
	mg/kg		mg/kg		mg/kg		mg/kg
Compounds	30	100	30	100	30	100	30	100
1a	*	*	*	*	*	*	*	*
1b	0/1	0/1	0/1	*	0/1	0/1	0/1	*
1c	0/1	*	0/1	0/1	0/1	*	0/1	0/1
1d	0/1	0/1	0/1	0/1	0/1	0/1	0/1	0/1
1e	0/1	*	*	*	0/1	*	*	*
1f	0/1	0/1	*	0/1	0/1	0/1	*	0/1
1g	1/1	1/1	0/1	1/1	0/1	0/1	1/1	1/1
1h	0/1	0/1	0/1	0/1	0/1	0/1	0/1	0/1
1i	1/1	1/1	1/1	*	0/1	0/1	0/1	*
2a	*	*	0/1	*	*	*	0/1	*
2b	0/1	*	*	*	0/1	*	*	*
2c	0/1	1/1	0/1	*	0/1	0/1	0/1	0/1
2d	0/1	1/1	0/1	0/1	0/1	0/1	0/1	1/1
2e	1/1	1/1	*	*	0/1	0/1	*	*
2f	1/1	1/1	0/1	1/1	0/1	0/1	0/1	0/1
2g	0/1	0/1	0/1	0/1	0/1	0/1	0/1	0/1
2h	0/1	1/1	0/1	0/1	0/1	1/1	0/1	0/1
2i	0/1	1/1	1/1	*	0/1	1/1	0/1	*
2j	0/1	*	0/1	1/1	0/1	0/1	0/1	0/1
3a	0/1	1/1	0/1	1/1	0/1	0/1	0/1	0/1
3b	0/1	*	0/1	0/1	0/1	*	0/1	0/1
3c	0/1	0/1	0/1	0/1	0/1	0/1	0/1	0/1
3d	1/1	*	0/1	0/1	0/1	*	0/1	0/1
3e	0/1	1/1	0/1	1/1	0/1	0/1	0/1	0/1
3f	0/1	*	0/1	1/1	0/1	*	1/1	1/1
3g	1/1	1/1	1/1	1/1	0/1	0/1	0/1	0/1
3h	1/1	*	0/1	0/1	0/1	*	0/1	0/1
3i	1/1	1/1	1/1	1/1	0/1	0/1	0/1	0/1
3j	0/1	0/1	0/1	1/1	0/1	0/1	0/1	0/1
4a	0/1	*	0/1	0/1	0/1	*	0/1	0/1
4b	0/1	0/1	0/1	0/1	0/1	0/1	0/1	0/1
4c	0/1	1/1	0/1	0/1	0/1	0/1	0/1	0/1
4d	1/1	1/1	1/1	*	0/1	0/1	0/1	0/1
4e	*	*	1/1	*	*	*	0/1	*
4f	1/1	1/1	0/1	0/1	0/1	0/1	0/1	0/1
4g	1/1	1/1	1/1	0/1	0/1	0/1	0/1	0/1
4h	0/1	0/1	0/1	1/1	0/1	0/1	0/1	0/1
4i	1/1	1/1	1/1	1/1	0/1	0/1	0/1	0/1

Compounds were administered to mice intraperitoneally at 30 and 100 mg/kg; seizure protection and neurotoxicity were measured 0.5 and 4 h after administration. ScMet: Subcutaneous metrazole test (number of animals protected/ number of animals tested). Toxicity: Rotarod test (number of animals exhibiting toxicity/number of animals tested). 0/1: no activity or toxicity at dose level. 1/1: noticeable activity or toxicity at dose level (activity given in bold). *Animal death.

Table 4. MES screening data of 1i, 2f, 3g and 3j in mice dosed ip.

	MES
	½ h		4 h
Compounds	30 mg/kg	100 mg/kg	30 mg/kg	100 mg/kg
1i	1/1	1/1	1/1	1/1
2f	0/1	1/1	0/1	1/1
3g	0/1	1/1	0/1	1/1
3j	1/1	1/1	1/1	1/1
4i	1/1	1/1	1/1	1/1

Compounds were administered to mice intraperitoneally at 30 and 100 mg/kg; seizure protection was measured 0.5 and 4 h after administration. MES: Maximal electroshock test (number of animals protected/number of animals tested). 0/1: no activity at dose level. 1/1: noticeable activity at dose level (given in bold).

Figure 1. Docking of compound 3j within the hCA II active site. (A) Discovery Studio 4.0 Client images and (B) ADT images.

Figure 2. Docking of compound 1i within the hCA II active site. (A) Discovery Studio 4.0 Client images and (B) ADT images.

Table 5. Molecular docking binding scores and binding interactions of compounds 1i, 2a, 3g and 3j within the hCA II active site.

Compounds	Docking score (kcal/mol)	H-bonds	Close van der Waals contacts
3g	−5.9	–	Lys170, Phe231, Glu239
2a	−4.2	–	Lys170, Gly171
3j	−9.7	–	Gln92, Leu198, Val121, Phe 131, Pro202, Thr199, Zn262
1i	−9.5	–	Gln92, Leu198, Val121, Phe131, Asn67, Leu60, Asn62, Gly171

Residues participating in hydrogen bonds and close van der Waals contacts (<4 Å) with the inhibitors are shown.

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