Carbonic anhydrase inhibitors. Synthesis, and molecular structure of novel series N-substituted N′-(2-arylmethylthio-4-chloro-5-methylbenzenesulfonyl)guanidines and their inhibition of human cytosolic isozymes I and II and the transmembrane tumor-associat

• Series of novel guanidines containing primary sulfonamide residue was synthesized.
• The inhibitory activity against hCA I, II, IX and XII was investigated.
• Thirteen compounds were stronger hCA IX inhibitors than clinically used sulfonamides.
• Selectivity ratios CA IX versus CA II (≤26) was higher than reference (≤0.8).
• Some compounds suppress growth of tumor cells in vitro.

A series of novel N-substituted N′-(2-arylmethylthio-4-chloro-5-methylbenzenesulfonyl)guanidines 9–41 have been synthesized and investigated as inhibitors of four isoforms of zinc enzyme carbonic anhydrase (CA.EC 4.2.1.1), that is the cytosolic CA I and II, and cancer-associated isozymes CA IX and XII. Against the human CA I investigated compounds showed KI in the range of 87–6506 nM, toward hCA II ranging from 7.8 to 4500 nM, against hCA IX in the range of 4.7–416 nM and against hCA XII at range of 0.96–540 nM. Compounds 10, 12–14, 16, 18–20, 24–26, 31 and 32 exhibited a powerful inhibitory potency toward hCA IX (KI = 4.7–21 nM) in comparison to the reference sulfonamides AAZ, MZA, EZA, DCP and IND (KI = 24–50 nM). Compound 14 was the most potent inhibitor of hCA I (KI = 87 nM), hCA IX (KI = 4.7 nM) and hCA XII (KI = 0.96 nM), while 26 was the most effective inhibitor of hCA II (KI = 7.8 nM). The most promising compound 32 exerted the highest selectivity ratios toward hCA IX versus hCA I (hCA I/hCA IX = 261) and hCA II (hCA II/hCA IX = 26). The in vitro antitumor activity of compounds 10, 13, 14, 21, 22, 25, 32, 38 and 41 was evaluated at the US National Cancer Institute (NCI) against a panel of 60 human tumor cell lines. The most active antitumor agents 21 and 25, inhibiting 32–35 human tumor cell lines with GI50 in the range of 2.1–5.0 μM also showed relatively high inhibitory activity toward hCA IX and XII with KI from 18 to 40 nM.

A series of novel N-substituted N′-(2-arylmethylthio-4-chloro-5-methylbenzenesulfonyl)guanidines have been synthesized. Some of them exhibited a powerful carbonic anhydrase CAI, CAII, CAIX and CAXII inhibitory potency as well as anticancer activity.Figure optionsDownload as PowerPoint slide