Carbonic anhydrase inhibitors. The nematode alpha-carbonic anhydrase of Caenorhabditis elegans CAH-4b is highly inhibited by 2-(hydrazinocarbonyl)-3-substituted-phenyl-1H-indole-5-sulfonamides.
A series of 2-(hydrazinocarbonyl)-3-substituted-phenyl-1H-indole-5-sulfonamides possessing various 2-, 3- or 4-substituted phenyl groups with methyl-, halogeno- and methoxy-functionalities, as well as the perfluorophenyl moiety, have been evaluated as inhibitors of an alpha-carbonic anhydrase (CA, EC 4.2.1.1) of the nematode model organism Caenorhabditis elegans (CAH-4b, or ceCA). The substitution pattern at the 3-phenyl ring highly influenced the ceCA inhibitory activity of these heterocyclic sulfonamides, with best inhibitors (K(I)s in the range of 6.0-13.4 nM) incorporating 3-methyl-, 4-methyl-, 2-/3-/4-fluoro-, 4-chloro- and 3-/4-bromo-phenyl such moieties. Some of these sulfonamides also showed a good selectivity profile for the inhibition of the nematode over the human isozymes CA I and II (selectivity ratios in the range of 1.78-4.95 for the inhibition of ceCA over hCA II). These data can be used for the design of possibly new antihelmintic drugs, since the genome of many parasitic nematodes encode for a multitude of orthologue CA isozymes to ceCA investigated here.
Güzel
Ozlen
O
Istanbul University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 34116 Beyazit, Istanbul, Turkey.
Innocenti
Alessio
A
Hall
Rebecca A
RA
Scozzafava
Andrea
A
Mühlschlegel
Fritz A
FA
Supuran
Claudiu T
CT
D000818:Animals; D017173:Caenorhabditis elegans / Q000201:enzymology*; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006834:Hydrazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007527:Isoenzymes; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
D002257:Carbonic Anhydrase Inhibitors; D006834:Hydrazines; D007211:Indoles; D007527:Isoenzymes; D013449:Sulfonamides; D002256:Carbonic Anhydrases