Type 2 antifolates in the chemotherapy of falciparum malaria

Delfino, Reinaldo T.; Santos-Filho, Osvaldo A.; Figueroa‐Villar, José Daniel

doi:10.1590/s0103-50532002000600003

Cited by 25 publications

(30 citation statements)

References 44 publications

(119 reference statements)

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“…Therefore, a hydrogen atom is suitable substituent of Y position because the unfavourable steric area of Y is closed to an important mutation position, Asn108, of quadruple mutant Pf DHFR. The obtained unfavourable steric contour coincides with the previous publications [3,5,9,10] that reported a steric clash between the Cl substituent of pyr and the side chain of Asn108. Figure 6 depicts electrostatic contour maps of CoMFA.…”

Section: Comfa Contour Analysissupporting

confidence: 90%

“…Inhibition of DNA synthesis through inhibition of Pf DHFR can be done by preventing dihydrofolate to forming tetrahydrofolate by using an antifolate such as pyrimethamine (pyr) and cycloguanil drugs. Pyr is an effective, sentitive and selective antifolate drug against the wild type Pf DHFR but its antimalarial action is slow [5]. Generally, pyr is used in combinations with other antifolates, such as Maloprim (pyr-dapsone) [6] and Fansidar (pyr-sulfadoxine) [7,8].…”

Section: Introductionmentioning

confidence: 99%

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Particular interaction between pyrimethamine derivatives and quadruple mutant type dihydrofolate reductase of Plasmodium falciparum: CoMFA and quantum chemical calculations studies

Maitarad

Saparpakorn

Hannongbua

et al. 2008

Journal of Enzyme Inhibition and Medicinal Chemistry

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Comparative molecular field analysis (CoMFA) was performed on twenty-three pyrimethamine (pyr) derivatives active against quadruple mutant type (Asn51Ile, Cys59Arg, Ser108Asn, Ile164Leu) dihydrofolate reductase of Plasmodium falcipaarum (Pf DHFR). The represented CoMFA models were evaluated based on the various three different probe atoms, C sp3 (þ1), O sp3 (21) and H (þ1), resulting in the best model with combined three types of probe atoms. The statistical results were r 2 cv ¼ 0.702, S press ¼ 0.608, r 2 nv ¼ 0.980, s ¼ 0.156, and r 2 test2set ¼ 0.698 which can explain steric contribution of about 50%. In addition, an understanding of particular interaction energy between inhibitor and surrounding residues in the binding pocket was performed by using MP2/6-31G(d,p) quantum chemical calculations. The obtained results clearly demonstrate that Asn108 is the cause of pyr resistance with the highest repulsive interaction energy. Therefore, CoMFA and particular interaction energy analyses can be useful for identifying the structural features of potent pyr derivatives active against quadruple mutant type Pf DHFR.

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Section: Comfa Contour Analysissupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Particular interaction between pyrimethamine derivatives and quadruple mutant type dihydrofolate reductase of Plasmodium falciparum: CoMFA and quantum chemical calculations studies

Maitarad

Saparpakorn

Hannongbua

et al. 2008

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…8 These drugs are divided in two groups: the first are the type I antifolates, which includes compounds that compete with para-amino-benzoic acid (PABA) and interrupt the synthesis of tetrahydrofolate; The type II antifolates act as antagonists in the enzymes dihydrofolate reductase (DHFR) and thymidylate synthase (TS). Two of the most important type II antifolates that act against DHFR are pyrimethamine and cycloguanil, which are now much less useful to treat malaria in South America.…”

Section: Introductionmentioning

confidence: 99%

A complete model of the Plasmodium falciparum bifunctional enzyme dihydrofolate reductase-thymidylate synthase: a model to design new antimalarials

França¹,

Medeiros²,

Santos³

et al. 2004

J. Braz. Chem. Soc.

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É proposto um modelo teórico para a pfDHFR-TS que inclui os 55 aminoácidos que não foram contemplados no modelo cristalográfico. O cálculo do potencial eletrostático sobre a superfície do modelo, revelou uma região contínua de potencial positivo conectando os dois sítios ativos, sugerindo um mecanismo otimizado de transporte de dihidrofolato.We propose a theoretical model for pfDHFR-TS, which includes the 55 aminoacid residues ignored in the crystallographic model. The electrostatic potential calculation on the model surface revealed a continuous positive potential region between the two active sites, suggesting an optimized mechanism for dihydrofolate transport. Keywords: malaria, homology modeling, DHFR-TS, optimized substrate transport, Plasmodium falciparum IntroductionMalaria is one of the most serious widespread parasitic diseases in humans. Nowadays, at least 300 million people are infected by malaria every year, with something in between 2 and 3 million deaths. To worsen the situation, the population that lives in endemic areas is about 2 billion people or 40% of the world population.1 It is possible that the rise in Earth temperature will eventually increase the endemic areas to include greater extensions of Europe and North America. In some parts of Africa, 10% of the deaths of children less than five years old are due to the direct effects of malaria. In fact, the actual epidemic of malaria makes it impossible to calculate the contribution of this disease to the mortality rate of children of this age due to other sickness. 2 The World Health Organization (WHO) estimates that 3,000 children under 5 years old die of malaria in Africa every day, 3 a situation that Mankind should not tolerate. In addition and frequently overlooked in the case of malaria caused by Plasmodium falciparum, there is considerable morbidity associated with this disease that manifests as chronic severe anemia in children and adults. In Brazil, the most important endemic areas of malaria are situated in Amazonian Region, where this disease is one of the major hindrances to the progress of the region, leading to 300,000 to 400,000 new reported cases every year. 4Malaria is a disease of the poorest regions of the planet, and because of this, the interest of the major pharmaceutical companies in the development of economically feasible chemotherapy is very low or does not exist. In fact, the strategies used against malaria, like chemotherapy and the use of insecticides, are often not accessible to the populations of the endemic areas due to economic and social reasons.One of the major obstacles to the control of malaria is the rapid spread of parasite resistance to the current available chemotherapy and of the mosquito vector to insecticides. This phenomenon has rendered other times wonderful antimalarials, such as chloroquine, completely useless in several regions.5-7 Also, it should be expected that resistance should eventually rise for any new drug that we develop in the future, thus making the search of new antimalarial chemother...

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“…The poorest populations often living in 107 and malaria [108][109][110][111] to the mix, the diseases kill several million each year, shorten lives and reduce productivity.…”

Section: Current and Future Developmentsmentioning

confidence: 99%

New approaches to the development of anti-protozoan drug candidates: a review of patents

Cunha

Ramalho

Mancini

et al. 2010

J. Braz. Chem. Soc.

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As doenças causadas por protozoários afetam hoje em dia uma grande parcela da população mundial, provocando muitas mortes e exercendo grande influência na qualidade de vida e no desenvolvimento de muitos países. Essas doenças afetam principalmente países pobres e por isso, a pesquisa e o desenvolvimento de novos fármacos são negligenciados. De fato, a maioria das drogas usadas no tratamento dessas doenças data de décadas passadas e apresentam muitas limitações, incluindo o aparecimento da resistência às drogas. Este artigo tem como foco os mais recentes desenvolvimentos publicados no campo de patentes, entre 2001-2008, com especial atenção a promissores compostos atuando contra tripanossomíase, leishmaniose, malária, toxoplasmose, amebíase, giardíase, balantidíase e pneumocistose.Protozoan infections are parasitic diseases that affect hundreds of millions of people worldwide, but have been largely neglected for drug development because they affect poor people in poor regions of the world. Most of the current drugs used to treat these diseases are decades old and have many limitations, including the emergence of drug resistance. This review will focus on the most recent developments, from 2001 to 2008, published in the field of patents and publications, paying particular attention to promising compounds acting against trypanosomiasis, leishmaniasis, malaria, toxoplasmosis, amebiasis, giardiasis, balantidiasis and pneumocystosis, their chemistry and biological evaluation, and to new chemical and pharmaceutical processes.

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Type 2 antifolates in the chemotherapy of falciparum malaria

Cited by 25 publications

References 44 publications

Particular interaction between pyrimethamine derivatives and quadruple mutant type dihydrofolate reductase of Plasmodium falciparum: CoMFA and quantum chemical calculations studies

Particular interaction between pyrimethamine derivatives and quadruple mutant type dihydrofolate reductase of Plasmodium falciparum: CoMFA and quantum chemical calculations studies

A complete model of the Plasmodium falciparum bifunctional enzyme dihydrofolate reductase-thymidylate synthase: a model to design new antimalarials

New approaches to the development of anti-protozoan drug candidates: a review of patents

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