Malaria parasite carbonic anhydrase:inhibition of aromatic/heterocyclic sulfonamides and its therapeutic potential  

作　　者：Sudaratana R Krungkrai Jerapan Krungkrai 

机构地区：[1]Unit of Biochemistry,Department of Medical Science.Faculty of Science,Rangsit University [2]Department of Biochemistry,Faculty of Medicine,Chulalongkorn University

出　　处：《Asian Pacific Journal of Tropical Biomedicine》2011年第3期233-242,共10页亚太热带生物医学杂志（英文版）

基　　金：Supported by a grant from UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases(No.900142,930143,960103,970074,990490);the National Science and Technology Development Agency of Thailand(Career Development Award ID no.01-38-007);the Thailand Research Fund(BasicResearch Grants ID No.BRG/13/2543.BRG4580020.BRG 4880006)

摘　　要：Plasmodium falciparum(P.falciparum) is responsible for the majority of life-threatening cases of human malaria,causing 1.5-2.7 million annual deaths.The global emergence of drug-resistant malaria parasites necessitates identification and characterisation of novel drug targets and their potential inhibitors.We identified the carbonic anhydrase(CA) genes in P.falciparum.The pfGA gene encodes an α-carbonic anhydrase,a Zn^(2+)-metalloenzme,possessing catalytic properties distinct from that of the human host CA enzyme.The amino acid sequence of the pfCA enzyme is different from the analogous protozoan and human enzymes.A library of aromatic/heterocyclic sulfonamides possessing a large diversity of scaffolds were found to be very good inhibitors for the malarial enzyme at moderate-low micromolar and submicromolar inhibitions.The structure of the groups substituting the aromatic-ureido-or aromatic-azomethine fragment of the molecule and the length of the parent sulfonamide were critical parameters for the inhibitory properties of the sulfonamides.One derivative,that is,4-(3,4-dichlorophenylureido)thioureidobcnzcnesulfonamide(compound 10) was the most effective in vitro Plasmodium falciparum CA inhibitor,and was also the most effective antimalarial compound on the in vitro P.falciparum growth inhibition.The compound 10 was also effective in vivo antimalarial agent in mice infected with Plasmodium berghei,an animal model of drug testing for human malaria infection. It is therefore concluded that the sulphonamide inhibitors targeting the parasite CA may have potential for the development of novel therapies against human malaria.Plasmodium falciparum(P.falciparum) is responsible for the majority of life-threatening cases of human malaria,causing 1.5-2.7 million annual deaths.The global emergence of drug-resistant malaria parasites necessitates identification and characterisation of novel drug targets and their potential inhibitors.We identified the carbonic anhydrase(CA) genes in P.falciparum.The pfGA gene encodes an α-carbonic anhydrase,a Zn^(2+)-metalloenzme,possessing catalytic properties distinct from that of the human host CA enzyme.The amino acid sequence of the pfCA enzyme is different from the analogous protozoan and human enzymes.A library of aromatic/heterocyclic sulfonamides possessing a large diversity of scaffolds were found to be very good inhibitors for the malarial enzyme at moderate-low micromolar and submicromolar inhibitions.The structure of the groups substituting the aromatic-ureido-or aromatic-azomethine fragment of the molecule and the length of the parent sulfonamide were critical parameters for the inhibitory properties of the sulfonamides.One derivative,that is,4-(3,4-dichlorophenylureido)thioureidobcnzcnesulfonamide(compound 10) was the most effective in vitro Plasmodium falciparum CA inhibitor,and was also the most effective antimalarial compound on the in vitro P.falciparum growth inhibition.The compound 10 was also effective in vivo antimalarial agent in mice infected with Plasmodium berghei,an animal model of drug testing for human malaria infection. It is therefore concluded that the sulphonamide inhibitors targeting the parasite CA may have potential for the development of novel therapies against human malaria.

关 键 词：Malaria PLASMODIUM FALCIPARUM Carbonic ANHYDRASE Carbonic ANHYDRASE inhibitor Aromalic/heterocyclic SULFONAMIDES ANTIMALARIAL agents Drug target Parasitic disease 

分 类 号：R531.3[医药卫生—内科学]