Enaminone-based carboxylic acids as novel non-classical carbonic anhydrases inhibitors: design, synthesis and in vitro biological assessment

Figures & data

Figure 1. Structures of certain sulphonamide-based CAIs in clinical use and in clinical trials.

Figure 2. Structures for some reported carboxylic acid derivatives as non-classical CA inhibitors.

Figure 3. Design for herein reported carboxylic acid derivatives 5a–q, 7a–b and 12a–c.

Scheme 1. Synthesis of benzoic acids-bearing enaminones 5a–q and 3/4-((3-oxo-3-phenylpropyl)amino)benzoic acids 7a–b.

Scheme 2. Synthesis of hippuric acids-bearing enaminones 12a–c.

Figure 4. The existence of ortho-substituted carboxylic acids enaminones 5a–e in Z-form and the existence of meta- and para-substituted carboxylic acids enaminones 5f–k and 5l–q in E/Z-forms (1:1) in DMSO.

Figure 5. ¹H NMR of enaminone 5i showing the presence of Z-form [Z H_a (d), Z H_b (dd), E NH (d)] and E-form [E H_a (d), E H_b (overlapped dd), E NH (d)] in DMSO as a representative example for enaminones 5f–k and 5l–q.

Figure 6. The presence of meta- and para-substituted carboxylic enaminones 5f–k and 5l–q in Z/E-forms in DMSO and in D₂O/DMSO (¹H NMR).

Figure 7. ¹H NMR of enaminone 12b which showed the existence of Z- and E-form in DMSO as a representative example for 12a–c.

Table 1. hCA I, II, IX and XII inhibition results from the carboxylic acid derivatives 5a–q, 7a–b and 12a–c and acetazolamide (AAZ) as a reference CA inhibitor.

Cmpd.	COOH	Ar	KI (μM)^a
			hCA I	hCA II	hCA IX	hCA XII
5a	ortho	-C6H5	>100	39.4	10.6	6.4
5b	ortho	−4-F-C6H4	>100	24.3	13.2	4.3
5c	ortho	−4-Cl-C6H4	>100	32.7	17.7	12.5
5d	ortho	−4-NO2-C6H4	>100	26.9	14.1	7.8
5e	ortho	−2-Naph	>100	49.0	19.3	15.7
5f	meta	-C6H5	>100	72.8	15.9	9.5
5g	meta	−4-F-C6H4	>100	68.2	9.6	10.3
5h	meta	−4-Cl-C6H4	>100	77.1	19.2	8.6
5i	meta	−4-Br-C6H4	>100	81.4	32.5	13.9
5j	meta	−4-NO2-C6H4	>100	80.7	24.7	8.9
5k	meta	−2-Naph	>100	92.3	11.4	9.7
5l	para	-C6H5	75.3	9.8	1.2	0.97
5m	para	−4-F-C6H4	68.8	8.7	0.92	1.1
5n	para	−4-Cl-C6H4	81.5	13.5	3.4	4.6
5o	para	−4-Br-C6H4	>100	15.3	5.6	6.2
5p	para	−4-NO2-C6H4	95.6	12.6	4.1	0.85
5q	para	−2-Naph	79.4	7.4	0.76	1.5
7a	meta	-C6H5	>100	64.3	23.7	7.4
7b	para	-C6H5	63.8	16.7	8.3	9.1
12a	–	-C6H5	>100	>100	>100	>100
12b	–	−4-Br-C6H4	>100	>100	>100	>100
12c	–	−2-Naph	>100	>100	>100	>100
AAZ	–	–	0.250	0.012	0.025	0.006

^aMean from 3 different assays (errors were in the range of ± 5–10% of the reported values).