Anti-obesity carbonic anhydrase inhibitors: challenges and opportunities

Figures & data

Figure 1. Role of mitochondrial and cytosolic CA isoforms in fatty acid biosynthesis: the transfer of acetyl groups from the mitochondrion to the cytosol (in the form of citrate) is required for the provision of substrate for de novo lipogenesis via malonyl-coenzyme A as key intermediate. Steps involving bicarbonate, both for the reaction catalysed by pyruvate carboxylase (PC) and acetyl-coenzyme A carboxylase (ACC) require the presence of CA isozymes: CA VA/VB in the mitochondrion and CA II in the cytosol.

Figure 2. Sulphonamide/sulfamate CAIs in clinical use: acetazolamide (AAZ), zonisamide (ZNS) and topiramate (TPM).

Table 1. CA inhibition data with selected drugs/investigational compounds against human (h) isoforms hCA I, II, VA and VB^13,51,52.

	KI (nM)
Drug/Cmpnd	hCA I	hCA II	hCA VA	hCA VB	Ref
AAZ	250	12	63	54	13
ZNS	56	35	20	6033	52
TPM	250	10	63	30	51

Figure 3. (A) hCA II complexed with superimposed topiramate (PDB 3HKU) in green, and zonisamide (PDB not deposited, available from the authors⁵²) in magenta. The Zn(II) is shown as a grey sphere that is bound to the protein ligands His94, His96 and His119. The hydrophobic half of the active site is coloured in red, the hydrophilic one in blue. His64, the proton shuttle residue, in green. Active site ribbon view of hCA II in adduct with B) TPM and C) ZNS. H-bonds are represented as black dashed lines. Active site ribbon view of hCA II in adduct with B) topiramate and C) zonisamide. H-bonds are represented as black dashed lines.

Figure 4. Phenol and NP based phenols screened as hCA VA/VB inhibitors.

Figure 5. NPs screened as hCA VA/VB inhibitors.

Table 2. Structures of compounds 24–33 screened for the inhibition of hCA I, II and VA.

Compound		KI (μM)
		hCA I	hCA II	hCA VA
24		4.98	90.60	7.50
25		5.18	>100	3.80
26		3.44	85.40	7.38
27		8.27	>100	8.36
28		3.75	>100	7.83
29		6.09	>100	4.52
30		8.81	18.90	9.07
31		5.06	3.71	43.10
32		6.82	>100	9.69
33		4.89	>100	44.00

The traditional names of the compounds are: 24: β-thujaplicin; 25: 2-hydroxyisobutyric acid; 26: 4-isopropylbenzoic acid; 27: methyl geranate; 28: 3-phenylpropyl benzoate; 29: 3Z-nonenoic acid; 30: Z-geranic acid; 31: 2-methylhexanoic acid; 32: ferulic acid; 33: 5-methylfuran-2-carboxylic acid.

Figure 6. hCA VA inhibitors 34–38 identified by VS techniques, and acipimox 39, identified by classical screening procedures.

Table 3. Benzenesulfonamides and 1,3,4-thiadiazole-sulphonamides acting as low nanomolar hCA VA and VB inhibitors⁶⁹.

	40-43		44
			KI (nM)
Compound	n	X	hCA VA	hCA VB
40	0	–	7.2	7.0
41	0	Cl	7.7	8.6
42	1	–	9.1	7.2
43	2	–	10.2	8.0
44	–	–	8.4	6.1

Figure 7. Sulfamides 45 and sulfamates 46–48 reported as hCA VA/VB inhibitors.

Figure 8. Aromatic/heterocyclic sufonamides 49 and 50 incorporating 10-camphorsulfonyl tails. In derivatives 49, n = 0, 1 and 2. Triazole-sulphonamides 51 incorporate X, Y Z groups of the type H, F, Me, OMe, CF₃, SO₂NH₂.

Figure 9. Chemical structures of Semaglutide (A), and Tirzepatide (B), recently approved anti-obesity agents.

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