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Review
. 2007 Mar 19;13(3):616-77.
doi: 10.3390/molecules13030616.

Prodrugs for the treatment of neglected diseases

Man Chin Chung  1 , Elizabeth Igne Ferreira, Jean Leandro Santos, Jeanine Giarolla, Daniela Gonçales Rando, Adélia Emília Almeida, Priscila Longhin Bosquesi, Renato Farina Menegon, Lorena Blau
Affiliations
Review

Prodrugs for the treatment of neglected diseases

Man Chin Chung et al. Molecules. .

Abstract

Recently, World Health Organization (WHO) and Medicins San Frontieres (MSF) proposed a classification of diseases as global, neglected and extremely neglected. Global diseases, such as cancer, cardiovascular and mental (CNS) diseases represent the targets of the majority of the R&D efforts of pharmaceutical companies. Neglected diseases affect millions of people in the world yet existing drug therapy is limited and often inappropriate. Furthermore, extremely neglected diseases affect people living under miserable conditions who barely have access to the bare necessities for survival. Most of these diseases are excluded from the goals of the R&D programs in the pharmaceutical industry and therefore fall outside the pharmaceutical market. About 14 million people,mainly in developing countries, die each year from infectious diseases. From 1975 to 1999,1393 new drugs were approved yet only 1% were for the treatment of neglected diseases[3]. These numbers have not changed until now, so in those countries there is an urgent need for the design and synthesis of new drugs and in this area the prodrug approach is a very interesting field. It provides, among other effects, activity improvements and toxicity decreases for current and new drugs, improving market availability. It is worth noting that it is essential in drug design to save time and money, and prodrug approaches can be considered of high interest in this respect. The present review covers 20 years of research on the design of prodrugs for the treatment of neglected and extremely neglected diseases such as Chagas' disease (American trypanosomiasis), sleeping sickness (African trypanosomiasis), malaria, sickle cell disease, tuberculosis, leishmaniasis and schistosomiasis.

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Figures

Figure 1
Figure 1
Chemical structure of the mutual prodrug of nitrofurazone and primaquine and its conversion to the parent drugs by cruzipain.
Figure 2
Figure 2
Chemical structures of dipeptide prodrugs of primaquine.
Figure 3
Figure 3
Chemical structures of nitrofurazone and its prodrug hydroxymethyl nitrofurazone.
Figure 4
Figure 4
Chemical structures of α-ketoisocaproate, NIPOx and Et-NIPOx.
Figure 5
Figure 5
ADEPT approach for African trypanosomiasis.
Figure 6
Figure 6
Chemical structures of DB75 and its prodrug DB289.
Figure 7
Figure 7
Diester prodrug of glutathione derivative with antileishmaniasis activity.
Figure 8
Figure 8
Thermolytic activation of CpG ODN fma1555
Figure 9
Figure 9
Thermolytic activation of Pro-D35.
Figure 10
Figure 10
Chemical structure of the prodrugs CMD-P and SD-P.
Figure 11
Figure 11
Chemical structures of buparvaquone and its prodrugs.
Figure 12
Figure 12
The conversion of buparvaquone-oxime into buparvaquone by enzymatic oxidation and release of NO.
Figure 13
Figure 13
Oxidized polysaccharides applied at the development of prodrugs.
Figure 14
Figure 14
Chemical structures of bisthiazolium salt prodrugs.
Figure 15
Figure 15
Chemical structures of fosmidomycin and FR900098.
Figure 16
Figure 16
Chemical structures of FR900098 ester prodrugs.
Figure 17
Figure 17
Chemical structures of artemisinin, dihydroartemisinin and artesunate sodium salt.
Figure 18
Figure 18
FeII-catalysed degradation of endoperoxide prodrugs.
Figure 19
Figure 19
Chemical structures of M5 and 4-aminoquinoline derivative prodrugs.
Figure 20
Figure 20
Metabolism of primaquine.
Figure 21
Figure 21
Chemical structures of (A) alanylleucylprimaquine and (B) alanylleucylalanylleucylprimaquine.
Figure 22
Figure 22
Chemical structures of (A) d-valylleucyllysylprimaquine, (B) d-alanylleucyl-lysylprimaquine and (C) valylleucyllysylprimaquine.
Figure 23
Figure 23
Chemical structures of imidazolin-4-one derivatives of primaquine.
Figure 24
Figure 24
Pro-prodrug series of primaquine analogue (R=C5H11 or C7H15), and the regeneration of parent drug.
Figure 25
Figure 25
Primaquine-statine pro-prodrugs.
Figure 26
Figure 26
Chemical structures of proguanil, cycloguanil, WR99210, phenoxypropoxy-biguanides prodrugs and their active metabolites.
Figure 27
Figure 27
Chemical structures of compound FTI-2148 and its methyl ester prodrug FTI-2153.
Figure 28
Figure 28
Chemical structures of PQD, PQD-A4 and PQD-BE.
Figure 29
Figure 29
Chemical structures of compound M64 and its prodrugs.
Figure 30
Figure 30
CD-CS approach. Conversion of 5-fluorocytosine (5-FC) into 5-fluorouracil (5-FU) by cytosine deaminase (CD).
Figure 31
Figure 31
Structures and hydrolysis of prodrugs of oxamniquine.
Figure 32
Figure 32
Chemical structure of the dextran-methylcarboxylate prodrug of oxamniquine.
Figure 33
Figure 33
Chemical structures of some antimycobacterial agents.
Figure 34
Figure 34
Activation pathway of the bioprecursors for tuberculosis and targets of the active compounds.
Figure 35
Figure 35
Chemical structures of the mutual prodrugs (PAS = para-aminosalicylic acid; INH = isoniazid; EB = ethambutol).
Figure 36
Figure 36
Chemical structures of nitroimidazole prodrugs.
Figure 37
Figure 37
Ester prodrugs of zidovudine.
Figure 38
Figure 38
Ester prodrugs of stavudine.
Figure 39
Figure 39
Prodrugs of lamivudine.
Figure 40
Figure 40
Schematic representation of the polymeric prodrugs and the product of enzymatic hydrolysis activity. A and B, norfloxacin linked through amide bond and C and D, norfloxacin linked through an α bond.
Figure 41
Figure 41
Micelles of PEG-PAS covalently linked to drugs. A. isoniazide; B: pyrazinamide.
Figure 42
Figure 42
Chitosan-Isoniazid hemisuccinate.
Figure 43
Figure 43
Chemical structures of oxazolidinone derivatives.
Figure 44
Figure 44
Metabolic hydrolysis of Pivanex®.
Figure 45
Figure 45
Metabolic hydrolysis of AN-10.
Figure 46
Figure 46
Neutral (1) and acid (2) derivatives of butyric acid.
Figure 47
Figure 47
Some aldehyde derivatives with potent antisickling effect.
Figure 48
Figure 48
Hydroxyurea oxidation to nitric oxide (NO).
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