title: Carbonic anhydrase inhibitors: inhibition of Plasmodium falciparum carbonic anhydrase with aromatic/heterocyclic sulfonamides-in vitro and in vivo studies.
abstract: A library of aromatic/heterocyclic sulfonamides possessing a large diversity of scaffolds has been assayed for inhibition of the carbonic anhydrase (CA, EC 4.2.1.1) from the malaria parasite Plasmodium falciparum (pfCA). Low micromolar and submicromolar in vitro inhibitors were detected, whereas several compounds showed ex vivo anti-P. falciparum activity, in cell cultures. One derivative, that is, 4-(3,4-dichlorophenylureido)thioureido-benzenesulfonamide was an effective in vitro pfCA inhibitor (K(I) of 0.18 microM), inhibited the ex vivo growth of P. falciparum with an IC(50) of 1 microM, and was also effective as an antimalarial agent in mice infected with P. berghei, an animal model of human malaria infection, with an ID(50) of 10 mg/kg (chloroquine as standard showed an ID(50) of 5 mg/kg). By inhibiting the first step of pyrimidine nucleotide biosyntheses, that is, the CA-mediated carbamoylphosphate biosynthesis, sulfonamide inhibitors of the protozoan CAs may have potential for the development of novel therapies of human malaria.
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, 1873 Rama 4 Road, Pathumwan, Bangkok 10330, Thailand. fmedjkk@md2.md.chula.ac.th
authors.forename: Jerapan
authors.initials: J
authors.lastname: Krungkrai
authors.forename: Sudaratana R
authors.initials: SR
authors.lastname: Krungkrai
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000494:pharmacology; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D002256:Carbonic Anhydrases / Q000737:chemistry* / Q000378:metabolism; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008288:Malaria / Q000188:drug therapy; D051379:Mice; D010962:Plasmodium berghei / Q000378:metabolism; D010963:Plasmodium falciparum; D011743:Pyrimidines / Q000737:chemistry; D013449:Sulfonamides / Q000737:chemistry*
chemical_list: D000962:Antimalarials; D002257:Carbonic Anhydrase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; D002256:Carbonic Anhydrases