Malária: Dos velhos fármacos aos novos alvos moleculares

Abstract

Malaria is a parasite disease that most affects humans with a global impact, without an effective treatment. According to the World Health Organization (WHO), the absence of a new therapeutic alternative, soon all strains will be resistant to current drugs. This study reports historical aspects, biological life cycle, current drugs, molecular targets able to therapeutic intervention and recent pharmacological receptors. This review concludes with a brief discussion of the prospects and difficulties contributing for advance for new antimalarials development. Keywords RESUMOMalária é a doença parasitária que mais acomete o homem. Segundo a Organização Mundial de Saúde (OMS), o aparecimento de cepas de Plasmodium resistentes a artemisinina tornam a busca de novos alvos e compostos com ação antimalárica extremamente necessária. Neste estudo relatamos aspectos históricos, ciclo biológico, atuais fármacos, alvos moleculares passíveis de intervenção terapêutica e recentes receptores farmacológicos. Esta revisão conclui com uma breve discussão das perspectivas e dificuldades contribuindo para o avanço no desenvolvimento de novos antimaláricos. Palavras-chave:PfHT, PfATPase, modelagem molecular, desenvolvimento de fármacos.

Antiprotozoal agents: How have they changed over a decade?

“…[ 48 ] Structure‐activity studies show that the inclusion of chlorine in the aromatic ring improves antimalarial activity, as is the case with chlorproguanil ( 21 ). [ 82,83 ] Cycloguanil ( 22 ) has the same mechanism of action as pyrimethamine ( 19 ), but with lower potency [ 16,82 ]…”

“…This interruption caused by 23 occurs through the inhibition of the enzyme dihydropterate synthase, causing the formation of dihydrofolic acid to be interrupted in one of the stages of folic acid synthesis. [47,48,83] F I G U R E 3 Artemisinin and analogs…”

“…[48] Structure-activity studies show that the inclusion of chlorine in the aromatic ring improves antimalarial activity, as is the case with chlorproguanil ( 21). [82,83] Cycloguanil (22) has the same mechanism of action as pyrimethamine (19), but with lower potency [16,82] Sulfadoxine (23), a sulfonamide, has a mechanism of action that is related to the biosynthesis of tetrahydrofolate, an important cofactor in the synthesis of nucleic acids and amino acids that is not produced when the folic acid pathway is interrupted, thus preventing the parasite's survival. This interruption caused by 23 occurs through the inhibition of the enzyme dihydropterate synthase, causing the formation of dihydrofolic acid to be interrupted in one of the stages of folic acid synthesis.…”

Success Case of the Application of Virtual High Throughput Screening Against Molecular Antimalarial Targets

“…The untreated malaria can evolve to pulmonary edema, renal complications, obstructive jaundice, causing the death of infected individual. 2 According to the World Health Organization (WHO), about three billion people are exposed to the risk of having malaria, of these, 216 million are affected by the disease and 655,000 die from it. In Brazil, the most important species are P. vivax, responsible for 90% of the cases, and P. falciparum, responsible for the most serious cases and for the mortality increase.…”

Structure-based drug design studies of the interactions ofent-kaurane diterpenes derived from Wedelia paludosa with the Plasmodium falciparumsarco/endoplasmic reticulum Ca2+-ATPase PfATP6

“…The exhaustiveness was set to 8 to improve the docking search. Finally, DS Visualizer v.4.0 (Accelrys Software Inc, USA) was used to show the docking results of the binding conformations ( Leite et al 2013) .…”