Synthesis and biological evaluation of novel 8-substituted quinoline-2-carboxamides as carbonic anhydrase inhibitors

Figures & data

Figure 1. Structures of some clinically used sulfonamides.

Figure 2. The “Tail approach” method for the design of novel CA inhibitors in this work.

Scheme 1. General synthetic route for the synthesis of 8-substituted quinoline-linked sulfonamide derivatives (5a–h). Reagents and conditions: (i) SeO₂, 1,4-dioxane, 110 °C, 12 h, (ii) H₂O₂, Formic acid, 0 °C, 12 h, (iii) Sulfanilamide, HATU, DIPEA, DMF, 0 °C-rt, 12–15 h, and (iv) R-X, K₂CO₃, Acetone, r.t., 12–15 h.

Table 1. CA inhibition data with the synthesised compounds 5a–5h and acetazolamide as standard drug, by a stopped flow CO₂ hydrase assay.

KI (nM)^a
Compound	R	hCA I	hCA II	hCA IV	hCA IX
5a	4-Nitrobenzyl	640.7	88.4	691.5	>10,000
5b	2-Bromobenzyl	444.4	85.7	3927	>10,000
5c	Benzyl	5290	8342	6410	>10,000
5d	3,5-Dimethylbenzyl	8126	8759	6757	>10,000
5e	3-Chlorobenzyl	6470	5175	806.7	>10,000
5f	2,5-Difluorobenzyl	6561	956.7	786.9	>10,000
5g	Prop-2-yn-1-yl	6914	5111	657.2	>10,000
5h	Methyl	61.9	33.0	1749	>10,000
AAZ	–	250	12.1	74	25.8

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