Antimalarial drugs chloroquine

Initially approved in the 1930s as antimalarial drug, quinacrine (2) became one of the first potential substitutes to quinine. The total synthesis of quinacrine would be achieved in 1931 by German scientists at Bayer,and it would be subsequently marketed as Mepacrine or Atebrine. However, quinacrine would soon be replaced by another synthetic and more efficient antimalarial drug, chloroquine (3). 

Like dapsone, the antimalarial drugs chloroquine, hydroxychloroquine, and quinacrine are useful in some noninfectious skin diseases, although the mechanism of their therapeutic effect is unknown. Their pharmacology is discussed in Chapter 53. 

Pioneer in this class which was discovered as a by-product of the antimalarial drug, chloroquine. 

Zurita J.L., A. Jos, A. del Peso, M. Salguero, M. Lopez-Artiguez, and G. Repetto (2005). Ecotoxicological evaluation of the antimalarial drug chloroquine. Aquatic Toxicology 75 97-107. 

Some nontaxoid MDR reversal compounds may share common structure features with the above-mentioned MDR reversal taxoids. For example, Chibale et al. attached hydrophobic moities to the antimalarial drugs chloroquine and primaquine, and they found that chloroquine derivatives are superior to primaquine derivatives against MDR in vitro and in vivo when coinjected with paclitaxel. Unexpectedly, they observed that those chloroquines fit very well to two baccatin Ill-based MDR reversal compounds in silico. " ... 

Aromoline was screened for in vitro antimalarial properties using a multi-drug resistant (Kl) strain of Plasmodium falciparum. The screen detected the inhibition of incorporation of [3H]-hypoxanthine into P. falciparum, and aromoline was characterized by IC 0.67 pg/ml (with 95% confidence intervals of 0.53 - 0.85). The standard antimalarial drug chloroquine diphosphate exhibits IC 0.14 pg/ml (with 95% confidence intervals of 0.12 - 0.16)[177]. 

Menting, J.G., Tilley, L., Deady, L.W., et al. (1997) The antimalarial drug, chloroquine, interacts with lactate dehydrogenase from Plasmodium falciparum. Mol. Biochem. Parasitol. 88, 215-224. 

The uncoating process has been shown to be carried out by virus-specific enzymes, synthesized at the direction of viral mRNA. The mRNA in turn has used a portion of the viral DNA as the template. Experimentally, at least, protein synthesis inhibitors can inhibit the production of these uncoating enzymes. However, due to a lack of significant specificity, the compounds were of no clinical value. The antimalarial drug chloroquine is the only agent of any consequence found to have any inhibiting effect on the uncoating of a virus, namely, Newcastle disease virus. 

About 6000 chemical entities can be used, in various pharmaceutical formulations, to treat human or animal diseases all attempts towards their classification represent arbitrary procedures. The first reason for that is that not a single drag has ever been encountered which exhibits only one biological activity. The antimalarial drug chloroquine is also active on some inflammatory processes, the anxiolytic benzodiazepines possess antiepileptic properties, etc. On the other hand, the scientific communities have different needs a chemical classification may sometimes be very useful to medicinal chemists but strictly of no interest to a social security employee. Conversely pharmacologists and physicians will probably prefer the physiological classification. 

Describe the pharmacodynamic and pharmacokinetic properties of the major antimalarial drugs (chloroquine, mefloquine, quinine, primaquine, and the antifolate agents). 

Stereoselectivity has been reported in the pharmacokinetic properties of some of the chiral antimalarial drugs (chloroquine, hydroxychloroquine, halofantrine, and mefloquine Tables 1 and 3). Each of these drugs possesses low hepatic extraction ratios, large Vd and ranging from one day to months. Plasma protein binding has been reported to range from about 50% (chloroquine and hydroxychloroquine. Table 3) to over 99% (halofantrine [19]). Chloroquine and its hydroxylated congener. 

Table 2 shows the effect of each purine inhibitor on incorporation of ( H) hypoxanthine into nucleic acids (acid-insoluble PCA fraction) of malaria infected erythrocytes. Two clinically proven antimalarial drugs, chloroquine (7-chloro-4-(4 -diethylamino-methyl-butylamino)-quinoline) and mefloquine (a-(2-piperidyl)-2, 8-bis (trifluoro-methyl)-4-quinolinemethenol hydrochloride), were included for comparison. Hadacidin, bredinin and mycophenolic acid all produced significant (p <. 005) decreases in nucleic acid synthesis by PRBC as measured by incorporation of ( H) hypoxanthine. Alanosine had no demonstrable effect. 

Lu et al. [31] described the synthesis, and in-vitro and in-vivo antimalarial evaluations of certain ester modified Neocryptolepine (5-methyl-5H-indolo[2,3-b]quinoline) derivatives. Modification was carried out by introducing ester group at C-2 and C-9 position of Neocryptolepine core. All the tested compounds showed higher activity than the well-known antimalarial drug Chloroquine. 

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