Metronidazole-coumarin conjugates and 3-cyano-7-hydroxy-coumarin act as isoform-selective carbonic anhydrase inhibitors

Figures & data

Table 1.  Inhibition of human (h) CA isoforms hCA I-hCA XIV with compounds 1a, 1b, 2 and the sulfonamide standard CAI acetazolamide AAZ, by a stopped flow, CO₂ hydrase technique¹⁹.

Compound	KI (µM)
	1a	1b	2	AAZ
hCA I	>200	>200	104	0.25
hCA II	>200	>200	>200	0.012
hCA IV	>200	>200	>200	0.074
hCA VA	0.84	2.63	2.27	0.063
hCA VB	0.38	0.43	1.87	0.054
hCA VI	0.46	0.47	0.37	0.011
hCA VII	0.42	0.80	2.98	0.0025
hCA IX	0.37	0.40	0.24	0.025
hCA XII	0.39	53	7.11	0.0057
hCA XIII	>200	>200	5.34	0.017
hCA XIV	0.93	0.82	6.25	0.041

*Means from three determinations. Errors were in the range of ± 10 % of the reported values. All CA isoforms were recombinant ones obtained as reported earlier¹.

Scheme 1.  Preparation of metronidazole-coumarin conjugates by reaction of metronidazole 1 with 7-hydroxy (A) and 6-hydroxy-coumarin (B).

Scheme 2.  Rationale for investigating 3-cyano-7-hydroxy-coumarin 2 as a dual CA/MCT inhibitor. The coumarin 2 may be hydrolyzed through the CA esterase activity to a derivative of α-cyano-4-hydroxycinnamic acid (3, R=H), a known MCT inhibitor^5,18.

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