The Experts below are selected from a list of 243 Experts worldwide ranked by ideXlab platform
Yongyuth Yuthavong - One of the best experts on this subject based on the ideXlab platform.
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development of a lead inhibitor for the a16v s108t mutant of dihydrofolate reductase from the Cycloguanil resistant strain t9 94 of plasmodium falciparum
Journal of Medicinal Chemistry, 2000Co-Authors: Yongyuth Yuthavong, Tirayut Vilaivan, Netnapa Chareonsethakul, Sumalee Kamchonwongpaisan, Worachart Sirawaraporn, Rachel Quarrell, Gordon D O LoweAbstract:The Ala16Val+Ser108Thr (A16V+S108T) mutant of the Plasmodium falciparum dihydrofolate reductase (DHFR) is a key mutant responsible for Cycloguanil-resistant malaria due to steric interaction between Val-16 and one of the C-2 methyl groups of Cycloguanil. 4,6-Diamino-1,2-dihydrotriazines have been prepared, in which both methyl groups of Cycloguanil are replaced by H or by H and an alkyl or phenyl group, and their inhibition constants against wild-type and mutant DHFR determined. The S108T mutation is considered to decrease Cycloguanil binding further through the effect on the orientation of the p-chlorophenyl group. By moving the p-chloro-substituent to the m-position in the chlorophenyl group, the activity against the A16V+S108T mutant enzyme is improved, and this effect is reinforced by the p-chloro substituent in the 3,4-dichlorophenyl group. A lead compound has been found with inhibitory activity similar to that of Cycloguanil against the wild-type DHFR and about 120-fold more effective than cycloguan...
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Development of a lead inhibitor for the A16V+S108T mutant of dihydrofolate reductase from the Cycloguanil-resistant strain (T9/94) of Plasmodium falciparum
Journal of Medicinal Chemistry, 2000Co-Authors: Yongyuth Yuthavong, Tirayut Vilaivan, Netnapa Chareonsethakul, Sumalee Kamchonwongpaisan, Worachart Sirawaraporn, Rachel Quarrell, Gordon D O LoweAbstract:The Ala16Val+Ser108Thr (A16V+S108T) mutant of the Plasmodium falciparum dihydrofolate reductase (DHFR) is a key mutant responsible for Cycloguanil-resistant malaria due to steric interaction between Val-16 and one of the C-2 methyl groups of Cycloguanil. 4,6-Diamino-1,2-dihydrotriazines have been prepared, in which both methyl groups of Cycloguanil are replaced by H or by H and an alkyl or phenyl group, and their inhibition constants against wild-type and mutant DHFR determined. The S108T mutation is considered to decrease Cycloguanil binding further through the effect on the orientation of the p-chlorophenyl group. By moving the p-chloro-substituent to the m-position in the chlorophenyl group, the activity against the A16V+S108T mutant enzyme is improved, and this effect is reinforced by the p-chloro substituent in the 3,4-dichlorophenyl group. A lead compound has been found with inhibitory activity similar to that of Cycloguanil against the wild-type DHFR and about 120-fold more effective than cycloguan...
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interaction of pyrimethamine Cycloguanil wr99210 and their analogues with plasmodium falciparum dihydrofolate reductase structural basis of antifolate resistance
Bioorganic & Medicinal Chemistry, 2000Co-Authors: Giulio Rastelli, Tirayut Vilaivan, Sumalee Kamchonwongpaisan, Worachart Sirawaraporn, Rachel Quarrell, Pornthep Sompornpisut, Gordon Lowe, Yodhathai Thebtaranonth, Yongyuth YuthavongAbstract:Abstract The nature of the interactions between Plasmodium falciparum dihydrofolate reductase (pfDHFR) and antimalarial antifolates, i.e., pyrimethamine (Pyr), Cycloguanil (Cyc) and WR99210 including some of their analogues, was investigated by molecular modeling in conjunction with the determination of the inhibition constants ( K i ). A three-dimensional structural model of pfDHFR was constructed using multiple sequence alignment and homology modeling procedures, followed by extensive molecular dynamics calculations. Mutations at amino acid residues 16 and 108 known to be associated with antifolate resistance were introduced into the structure, and the interactions of the inhibitors with the enzymes were assessed by docking and molecular dynamics for both wild-type and mutant DHFRs. The K i values of a number of analogues tested support the validity of the model. A ‘steric constraint’ hypothesis is proposed to explain the structural basis of the antifolate resistance.
Alan F Cowman - One of the best experts on this subject based on the ideXlab platform.
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point mutations in the dihydrofolate reductase and dihydropteroate synthetase genes and in vitro susceptibility to pyrimethamine and Cycloguanil of plasmodium falciparum isolates from papua new guinea
American Journal of Tropical Medicine and Hygiene, 1996Co-Authors: John C Reeder, K.h. Rieckmann, B Genton, Kerry Lorry, Bruce D Wines, Alan F CowmanAbstract:Plasmodium falciparum isolates from 24 Papua New Guinean patients with symptomatic malaria were tested for susceptibility to pyrimethamine and Cycloguanil. Thirteen isolates were sensitive to both agents and the remainder exhibited varying degrees of resistance. No isolates were found to be resistant to one agent yet sensitive to the other and a positive correlation suggesting cross-resistance was found. Parasite DNA extracted from the patients' stained blood slides was amplified and sequenced to examine point mutations in the dihydrofolate reductase (DHFR) and dihydropteroate synthetase genes (DHPS) associated with antifolate resistance. All resistant isolates possessed mutations in the DHFR gene at codon 108, the majority changing from Ser to Asn, but one isolate from Ser to Thr, a change not previously reported in field isolates. A second mutation of the DHFR gene at Cys-59 to Arg was present in isolates with higher level resistance, but not exclusively so. Sequencing the DHPS gene, as a predictor of sulfadoxine resistance, revealed only one example that was different from DHPS alleles of sensitive isolates.
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amino acids in the dihydrofolate reductase thymidylate synthase gene of plasmodium falciparum involved in Cycloguanil resistance differ from those involved in pyrimethamine resistance
Proceedings of the National Academy of Sciences of the United States of America, 1990Co-Authors: Simon J Foote, Denise Galatis, Alan F CowmanAbstract:Abstract Cycloguanil, the active metabolite of the antimalarial drug proguanil, is an inhibitor of dihydrofolate reductase as is another antimalarial, pyrimethamine. Its use has been limited by the rapid development of resistance by parasites around the world. We have determined the Cycloguanil- and pyrimethamine-sensitivity status of 10 isolates of Plasmodium falciparum and have sequenced in all these isolates the dihydrofolate reductase (DHFR; 5,6,7,8-tetrahydrofolate: NADP+ oxidoreductase, EC 1.5.1.3) portion of the DHFR-thymidylate synthase (TS; 5,10-methylenetetrahydrofolate: dUMP C-methyltransferase, EC 2.1.1.45) gene. Instead of the known serine-to-asparagine change at position 108 that is important in pyrimethamine resistance, a serine-to-threonine change at the same position is found in Cycloguanil-resistant isolates along with an alanine-to-valine change at position 16. We conclude that pyrimethamine and Cycloguanil resistance most commonly involve alternative mutations at the same site. However, we also have identified a parasite with a unique set of changes that results in resistance to both drugs.
K.h. Rieckmann - One of the best experts on this subject based on the ideXlab platform.
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in vitro activities of the biguanide ps 15 and its metabolite wr99210 against Cycloguanil resistant plasmodium falciparum isolates from thailand
Antimicrobial Agents and Chemotherapy, 1997Co-Authors: Michael D Edstein, G D Shanks, S Bahr, Barbara M Kotecka, K.h. RieckmannAbstract:The in vitro activities of the new biguanide PS-15 and its putative active metabolite, WR99210, were determined against seven different isolates or clones of Plasmodium falciparum. The mean 50% inhibitory concentrations of PS-15 and WR99210 were 1,015 and 0.06 ng/ml, respectively. WR99210 was up to 363 times more potent than Cycloguanil, the active metabolite of proguanil, against Cycloguanil-resistant parasites. The pronounced activity of WR99210 against multidrug-resistant P. falciparum indicates that further studies are required to determine the value of the prodrug, PS-15, as an antimalarial agent.
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ex vivo antimalarial activity of proguanil combined with dapsone against Cycloguanil resistant plasmodium falciparum isolates
Acta Tropica, 1997Co-Authors: Michael D Edstein, G D Shanks, K.h. RieckmannAbstract:The ex vivo antimalarial activity of plasma samples obtained from 20 healthy Caucasian volunteers following daily proguanil (200 mg) plus dapsone (8 mg) for malaria chemoprophylaxis inhibited five Cycloguanil-resistant Thai isolates of Plasmodium falciparum. All volunteers were phenotyped as extensive metabolisers (EMs) of proguanil. Three of the five isolates were obtained from Thai soldiers who had failed malaria prophylaxis on daily proguanil (200 mg) plus dapsone (4.0 or 12.5 mg). The Thai soldiers were also classified as EMs, but had relatively lower plasma Cycloguanil concentrations compared to values reported in the literature for Caucasians and black Kenyans. Although the high level of parasite resistance to Cycloguanil was the most likely explanation for the Thai soldiers failing prophylaxis on proguanil plus dapsone, their low Cycloguanil concentrations may have also contributed to their lack of protection. However, in areas where parasites are more susceptible to Cycloguanil, such as in certain regions of Africa, proguanil plus dapsone may still be an effective chemoprophylactic drug combination. (C) 1997 Elsevier Science B.V.
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effects of folic and folinic acids on the activities of Cycloguanil and wr99210 against plasmodium falciparum in erythrocytic culture
Annals of Tropical Medicine and Parasitology, 1997Co-Authors: Kristen K. Seymour, K.h. Rieckmann, Richard I. ChristophersonAbstract:The in-vitro effects of folinic acid on the antimalarial activities of the triazine antifolates, Cycloguanil and WR99210, were compared with those of their parent biguanides, proguanil and PS-15, a...
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point mutations in the dihydrofolate reductase and dihydropteroate synthetase genes and in vitro susceptibility to pyrimethamine and Cycloguanil of plasmodium falciparum isolates from papua new guinea
American Journal of Tropical Medicine and Hygiene, 1996Co-Authors: John C Reeder, K.h. Rieckmann, B Genton, Kerry Lorry, Bruce D Wines, Alan F CowmanAbstract:Plasmodium falciparum isolates from 24 Papua New Guinean patients with symptomatic malaria were tested for susceptibility to pyrimethamine and Cycloguanil. Thirteen isolates were sensitive to both agents and the remainder exhibited varying degrees of resistance. No isolates were found to be resistant to one agent yet sensitive to the other and a positive correlation suggesting cross-resistance was found. Parasite DNA extracted from the patients' stained blood slides was amplified and sequenced to examine point mutations in the dihydrofolate reductase (DHFR) and dihydropteroate synthetase genes (DHPS) associated with antifolate resistance. All resistant isolates possessed mutations in the DHFR gene at codon 108, the majority changing from Ser to Asn, but one isolate from Ser to Thr, a change not previously reported in field isolates. A second mutation of the DHFR gene at Cys-59 to Arg was present in isolates with higher level resistance, but not exclusively so. Sequencing the DHPS gene, as a predictor of sulfadoxine resistance, revealed only one example that was different from DHPS alleles of sensitive isolates.
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a statistical analysis of the antimalarial activity of proguanil and Cycloguanil in human volunteers
Annals of Tropical Medicine and Parasitology, 1994Co-Authors: M.d. Edstein, G D Shanks, K.h. RieckmannAbstract:Proguanil, an orally administered antimalarial drug, was given to 36 individuals (200 mg daily for 3 days). The antimalarial activity in plasma samples collected after the drug administration was then determined by bioassay. Concentrations of proguanil and Cycloguanil (the principal active metabolite) in these samples were also measured by high performance liquid chromatography. A regression analysis was then performed on these variables to determine if the antimalarial activity of the samples was due to proguanil alone or to proguanil and Cycloguanil together. The analysis indicated that Cycloguanil is the main determinant of antimalarial activity after proguanil administration and that the activity of Cycloguanil is not influenced by the presence of proguanil.
Le J Bras - One of the best experts on this subject based on the ideXlab platform.
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increased incidence of Cycloguanil resistance in malaria cases entering france from africa determined as point mutations in the parasites dihydrofolate reductase genes
Annals of Tropical Medicine and Parasitology, 1999Co-Authors: R Durand, J P Di Piazza, C Longuet, Y. Secardin, J. Clain, Le J BrasAbstract:The incidence of Cycloguanil resistance in 501 Plasmodium falciparum isolates from individuals entering France from Africa was estimated by a method based on PCR-restriction-fragment-length polymorphisms. None of the subjects had taken antifol prophylaxis. Annual incidence of the resistance, detected as a point mutation at codon 108 in the parasite's dihydrofolate-reductase gene, increased from 19.8% in 1995 to 43.6% in 1997 (P<0.001). The proportion of isolates found to be susceptible (i.e. wild-type) among travellers returning from the African countries known as Group 2 in France (i.e. Burkina Faso, Cote d'Ivoire, Gambia, Ghana, Guinea, Liberia, Madagascar, Mali, Mauritania, Niger, Senegal, Sierra Leone, Tchad and Togo) was reasonably high (62.9%) and much higher than in the other subjects returning from other identifiable countries in Africa (35.3%). The antimalarial prophylaxis recommended in France to those travelling to Group-2 countries, chloroquine-proguanil, therefore still seems reasonable, alth...
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resistance a la chloroquine et au Cycloguanil de plasmodium falciparum chez des patients arrivant en france apres un voyage en afrique sans chimioprophylaxie
Bulletin De La Societe De Pathologie Exotique, 1998Co-Authors: Le J Bras, Bruno Pradines, J P Di Piazza, R Durand, N Godineau, O Bouchaud, R Roue, B Marchou, G Martet, C LonguetAbstract:La sensibilite a la chloroquine et au Cycloguanil a ete etudiee sur des isolats de Plasmodium falciparum, preleves chez des patients en provenance d'Afrique tropicale n'ayant pas recu de medicament par un test isotopique in vitro ou par la mise en evidence de la mutation 5108N de la dihydrofolate reductase (DHFR). Une chimioresistance a la chloroquine ou au Cycloguanil est constatee pour pres de la moitie des isolats. Les taux les plus eleves de chimioresistance sont observes dans les pays d'Afrique ou la transmission du paludisme est permanente. La frequence globale de la resistance conjointe a la chloroquine et aux antifoliniques se situe a 28 % en 1995-97. Un ajustement des recommandations chimioprophylactiques pour les pays d'Afrique francophone est propose.
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sensibilite in vitro de plasmodium falciparum aux antifoliniques trimethoprime pyrimethamine Cycloguanil etude sur 29 souches africaines
Bulletin De La Societe De Pathologie Exotique, 1997Co-Authors: L K Basco, Le J BrasAbstract:La sensibilite in vitro a trois inhibiteurs de la dihydrofolate reductase (pyrimethamine, Cycloguanil, trimethoprime) a ete etudiee sur 29 souches et isolats africains de Plasmodium falciparum par le semi-microtest isotopique. Le trimethoprime est moins actif que la pyrimethamine ou le Cycloguanil et son activite est correlee a celle de deux autres inhibiteurs, ce qui suggere la resistance croisee in vitro parmi les inhibiteurs de la dihydrofolate reductase.
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in vitro activity of Cycloguanil against african isolates of plasmodium falciparum
Antimicrobial Agents and Chemotherapy, 1993Co-Authors: L K Basco, O Ramiliarisoa, P Ringwald, J C Doury, Le J BrasAbstract:The in vitro activity of Cycloguanil was assessed against 86 African isolates of Plasmodium falciparum by a semi-micro assay system. A bimodal distribution of susceptibility patterns was observed, with 44% of the isolates being Cycloguanil susceptible. Cycloguanil alone retains a high activity against the intraerythrocytic forms of some isolates and, together with its activity against the hepatic stages, may be useful for chemoprophylaxis when combined with chloroquine.
Jose Daniel Figueroavillar - One of the best experts on this subject based on the ideXlab platform.
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homology modeling of wild type and pyrimethamine Cycloguanil cross resistant mutant type plasmodium falciparum dihydrofolate reductase a model for antimalarial chemotherapy resistance
Biophysical Chemistry, 2001Co-Authors: Osvaldo A Santosfilho, Ricardo Bicca De Alencastro, Jose Daniel FigueroavillarAbstract:Abstract We propose a low-resolution model for both the wild type and the pyrimethamine (Pyr)/Cycloguanil (Cyc) cross-resistant mutant type Plasmodium falciparum DHFR (PfDHFR), based on homology modeling using chicken liver DHFR as a template. The built models contain five α-helices, eight β-sheets, eight tight turns and several loops. The Ramachandran plot for the models shows 95.3 and 100% of the amino acid residues in the favorable regions for the whole enzymes and for the active sites, respectively. Furthermore, we made a preliminary analysis of the complexes Pyr/Cyc-wild DHFR and Pyr/Cyc-mutant DHFR in order to explain the probable mechanism of resistance. Our results show that the steric factor may be the main structural cause of P. falciparum resistance toward antifolate drugs.
