**3. Functions of inhibitors of parasite lactate dehydrogenase (pLDH) as potential antimalarial agents**

The *plasmodium falciparum* lactate dehydrogenase enzyme (Pf LDH), has been considered a potential molecular target to antimalarials due to this parasite dependence on glycolysis for energy production by catalyzing the reduction of pyruvate to lactate. It has been a routine activity among drug designers for malarial infestation to embark on the screening of analogs to NADH(an essential cofactor) to pLDH.The continued search for new molecular targets for drug design is an endless search, since the introduction of the quinolones in malaria therapy. Chloroquine interacts specifically with PfLDH in the NADH binding pocket, occupying a position similar to that of the adenyl ring cofactor, hence acting as a competitive inhibitor for this critical glycolytic enzyme [5,6,7,8]. Analogs of NADH have been identified as new potential inhibitors to PfLDH[9]. Computational studies have been undertaken to recognize the potential binding of selected compounds to the pLDH active site. This was analyzed using Motegro Virtual Docker Software. The researchers selected fifty (50) compounds based on their similarity to NADH. The compounds with the best bonding energies included: itraconazole, atorvastatin and posaconazole. These were tested against P. falciparum , chloroquine resistant blood parasites. All these compounds proved to be active in two immunoenzymatic assays performed in parallel using monoclonals specific to pfLDH or a histidine rich protein 2 (HRP 2). The IC 50 values for each drug in both tests are similar; values were lowest for posaconazole (< 5µM) and were 40-and 100-fold less active than chloroquine. The compounds so tested reduced *P. berghi* parasitemia in treated mice, in comparison to untreated control. The drug itraconazole is the least active compound. Posaconazole is an inhibitor of ergosterol biosynthesis [10]. In this study, it was the most active drug against *P. falciparum*. It is also, the most effective compound against murine malaria caused by *P. berghei* and was the most promising agent in vitro and in vivo. Itraconazole is normally acquired as a tablet, causes a strong inhibition of P. falciparum growth in vitro and is partially active against *P. berghei*. The results of these trials according to the authors proved that molecular docking studies are important in the strategy for discovering new antimalarial drugs. This approach is more practical and less expensive than discovering novel compounds that require studies on human toxicology. The parasite enzyme, lactate dehydrogenase has recently received a great deal of attention, since it may constitute a valid therapeutic target for diseases such as malaria and cancer. Because the LDH enzymes found in *P.vivax*, *P. ovale* and *P.malariae*, all exhibit 90% identity to PfLDH; It would be desirable to have new anti-pLDH drugs particularly, ones that are effective against *P*. *falciparum*, the most virulent species of human malaria. Most invasive tumor phenotypes show a metabolic switch (Warburg effect) from oxidative phosporylation to an increased anerobic glycolysis by promoting an up-regulation of the human isoform-5 of lactate dehydrogenase (hLDH-5 or LDH-A), which is normally present in muscles and liver. Hence, inhibition of hLDH-5 may constitute an efficient way to interfere with tumor growth and invasiveness.

Functions of Dehydrogenases in Health and Disease 169

nations afflicted with malaria. The presence of pGluDH is known to represent parasite viability, and a rapid diagnostic test using pGluDH as antigen would have the ability to differentiate live and dead organisms. It is possible to note that a complete RDT with pGluDH as antigen has been developed in China. Glutamate dehydrogenases are ubiquitous enzymes that occupy an important branch point between carbon and nitrogen metabolisms. Both nicotinamide adenine dinucleotide[ (NAD)EC 1.4.1.2] and nicotinamide adenine dinucleotide phosphate (NADP) dependent GluDH [EC1.4.1.4] enzymes are present in plasmodia. The NAD-dependent GluDH is relatively unstable and not useful for diagnostic purposes. Glutamate dehydrogenase provides an oxidizable carbon source used in production of energy as well as a reduced electron carrier, NADH. Glutamate is a principal donor to other amino acids in subsequent transamination reactions. The multiple roles of glutamate in nitrogen balance, make it a gateway between free ammonia and the amino groups of most amino acids. The GluDH activity in *P. vivax*, *P.ovale* and *P. malariae* has been tested, but given the importance of GluDH as a branch point enzyme, every cell must have a high concentration of GluDH. It is well known that enzymes with high molecular weights like GluDH have many isoenzymes which allow strain differentiation (given the right monoclonal antibody).The host produces antibodies against the parasite

**6. New therapeutic approaches for treatment of plasmodium falciparum** 

The antimalarial treatment so far recommended for P. falciparum consists of drug combinations containing Artemisinin derivatives (ACT) known as artemisinin combination therapy with other antimalarials, including quinolone compounds such as Amodiaquine and Mefloquine. The mechanism of action of the quinolones involve the inhibition of hematin polymerization, thus intoxicating the parasite with the ferriprotoporphyrin groups generated by hemoglobin degradation. Other antimalarials used in the ACT therapy include-Pyrimethamine and proguanil, which inhibit the tetrahydrofolic acid cycle (tetrahydropterate reductase, limiting the formation of folic acid, an important cofactor in DNA biosynthesis. Despite the arsenal of drugs available for malaria treatment, the disease remains a worldwide public health problem. P. falciparum develops resistance under selected drug pressure. Plasmodium vivax is the most prevalent human malaria parasite world over and has been shown to be resistant to chloroquine, including in Brazil and other countries where malaria is endemic. Various efforts have been made to develop new drugs (antimalarials), but resistance to drugs has limited the search. The continued search for new molecular targets for drug design has broadened the therapeutic arsenal and strategies to

enzyme, indicating a low sequence identity.

fight drug resistance in human malarial infestation.

**uncomplicated malaria** 

**7. Three new parasite ldh (pan-pLDH) tests for diagnosis of** 

Since Charles Laveran first visualized the malaria parasite in 1880; the mainstay of malaria diagnosis has been the microscopic examination of blood smear. It is the main economic,
