Inhibition studies of quinazoline-sulfonamide derivatives against the γ-CA (PgiCA) from the pathogenic bacterium, Porphyromonas gingivalis

Figures & data

Figure 1. Amino acid sequence alignment of the γ-CAs from Porphyromonas gingivalis (PgiCA), Vibrio cholerae (VhCA) and Brucella suis (bSuCA). The metal ion ligands are indicated in red. The multialignment was performed with the program Clustal W. The asterisk (*) indicates identity at all aligned positions; the symbol (:) relates to conserved substitutions, while (.) means that semi-conserved substitutions are observed.

Figure 2. Phylogenetic trees of the amino acid sequences of γ-CAs from different Gram-negative bacteria. The tree was constructed using the program PhyML 3.0. Legend: EcoCA, Escherichia coli; VchCA, Vibrio cholerae; SspCA, Sulfurihydrogenibium yellowstonense; SazCA, Sulfurihydrogenibium azorense; PgiCA, Porphyromonas gingivalis; bSuCA, Brucella suis; BpsCA, Burkholderia pseudomallei; ReuCA, Ralstonia eutropha.

Scheme 1. Synthesis of 3,5,6 and/or 8-substituted-2-thio-4-oxoquinazoline and 2-thio-4-thioxoquinazoline derivatives 3a–h and 4a–e.

Scheme 2. Synthesis of substituted sulfa derivative 7 and 2,3,5,6 and/or 8-substituted-4-oxoquinazoline derivatives 8a–h.

Scheme 3. Synthesis of 2,3,5,6 and/or 8-substituted-4-thioxoquinazoline derivatives 9a–e.

Table 1. Inhibition data of sulfonamides 8a–h, 9a–e and acetazolamide AAZ (as standard inhibitor) against human (h) isoforms hCA I, II (cytosolic) and bacterial enzyme PgiCA by a stopped-flow CO₂ hydrase assay18.

Compound		KI (nM)*		Selectivity ratios
	hCA I	hCA II	PgiCA	hCA I/PgiCA	hCAII/PgiCA
8a	105	1.3	218.5	0.5	0.006
8b	119	1.8	18.9	6.3	0.1
8c	86.5	1.7	3.5	24.7	0.5
8d	2078	208.4	248.7	8.4	0.8
8e	4761	233.8	359.9	13.2	0.6
8f	5432	208.9	344.6	15.8	0.6
8g	674	12.1	23.8	28.3	0.5
8h	3371	122.9	292.6	11.5	0.4
9a	4168	67.5	377.5	11.0	0.2
9b	793	78.26	30.7	25.8	2.5
9c	2162	114.2	38.4	56.4	3.0
9d	803	65.3	39.4	20.4	1.7
9e	4549	96.0	>425	>10	>0.2
AAZ	250	12	324	0.77	0.03

The selectivity ratios are also reported.

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

Maresca A, Vullo D, Scozzafava A, Supuran CT. Inhibition of the alpha- and beta- carbonic anhydrases from the gastric pathogen Helycobacter pylori with anions. J Enzyme Inhib Med Chem 2013;28:388–91

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