Sulfonamides incorporating fluorine and 1,3,5-triazine moieties are effective inhibitors of three β-class carbonic anhydrases from Mycobacterium tuberculosis

Figures & data

Scheme 1. Preparation of sulfonamides 3–7 by reaction of the difluoro-triazinyl-benzene sulfonamides 1, 2 with nucleophiles (R₁H, R₂H) in presence of diisopropylethylamine (DIPEA), in DMF.

Table 1. Inhibition data of mycobacterial β-CA isoforms mtCA 1–3 with sulfonamides 1–7 reported here, and the standard sulfonamide inhibitors acetazolamide (AAZ), benzolamide (BZA) and dichlorophenamide (DCP) by a stopped flow CO₂ hydrase assay27.

				KI^a
No	n	R1	R2	hCA I (nM)	hCA II (nM)	mtCA 1 (μM)	mtCA 2 (μM)	mtCA 3 (μM)
1	0	F	F	88	4.9	0.55	>0.01	0.15
2	2	F	F	203	7.1	0.042	0.0086	0.0021
3	0	NH(CH2)2OH	F	238	5.5	0.35	>0.01	0.21
4	0	NHCH3	F	90	5.4	0.58	0.0096	0.022
5	2	NHCH2COOMe	F	81.5	5.6	0.46	>0.01	0.13
6	2	NHCH2COOH	F	250	5.0	0.61	0.0081	>1
7	0	NHCH3	NHCH3	83^b	23^b	0.57	>0.01	0.21
AAZ	–	–	–	250	12	0.481	0.009	0.104
BZA				15	9	0.81	0.46	0.34
DCP				1200	38	0.87	2.01	0.611

^aMean from three different assays, by a stopped flow technique (errors were in the range of ±5–10% of the reported values).

^bFrom work by Suarez Covarrubias et al.1.

Ilies MA, Vullo D, Pastorek J, et al. Carbonic anhydrase inhibitors. Inhibition of tumor-associated isozyme IX by halogenosulfanilamide and halogenophenylaminobenzolamide derivatives. J Med Chem 2003;46:2187–96

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Suarez Covarrubias A, Larsson AM, Hogbom M, et al. Structure and function of carbonic anhydrases from Mycobacterium tuberculosis. J Biol Chem 2005;280:18782–9

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