Chapter 30 Prodrugs and Site-Specific Chemical Delivery Systems

Bodor, Nicholas; Kaminski, James J.

doi:10.1016/s0065-7743(08)61178-1

Cited by 44 publications

(11 citation statements)

References 102 publications

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“…However, the oral antimalarial ED 50 for T3 could not be determined because it was Ͼ10 mg͞kg (data not shown). Nevertheless, this design gave a platform from which we attempted to overcome the low bioavailability of these drugs when delivered orally by creating prodrugs with a hydrolyzable thioester bond that could be bioconverted to the active form in the blood (26,27). One compound (TM1) lacking this hydrolyzable thioester, is devoid of antimalarial activity.…”

Section: Discussionmentioning

confidence: 99%

Prodrugs of bisthiazolium salts are orally potent antimalarials

Vial

Wein

Farenc

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

105

151

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We created neutral antimalarial prodrugs that deliver bisthiazolium compounds with antimalarial activity in the nanomolar range. These drugs primarily affect early intraerythrocytic stages through rapid, nonreversible cytotoxicity. The compounds are suitable for both parenteral and oral use and plasma promotes rapid conversion of the prodrug into the drug. We demonstrate that very low doses offer protection in a murine model of malaria. The drugs show great potential for curing high parasitemia with short-course treatments. Oral administration of the TE3 prodrug completely cures Plasmodium cynomolgi infection in rhesus monkeys. The drugs specifically accumulate inside infected erythrocytes, block phosphatidylcholine biosynthesis, and interact with hemozoin. To our knowledge, this class of compounds represents one of the most potent antimalarials tested to date. These unique properties signal a promising future for this class of antimalarial.M alaria is a public health problem affecting Ͼ40% of the world's population. It causes up to 2 million deaths, mostly young children, in Africa, and Ͼ300 million clinical cases each year (1), with major consequent impact on economic productivity and livelihood (2). Currently, there are no licensed vaccines and the spread of drug-resistant parasites and insecticideresistant mosquitoes is an increasing problem. New antimalarial compounds, particularly those based on compounds structurally unrelated to existing antimalarial drugs with new mechanisms of action, are urgently needed (3-5).We have developed classes of antimalarial drugs targeting membrane biogenesis during intraerythrocytic Plasmodium falciparum development. We have focused on mono-and bisquaternary ammonium compounds for their potent antimalarial activity in vitro and in vivo (6, 7). These compounds mimic choline structure; they potently inhibit the low-affinity choline carrier related to phospholipid biosynthesis in eukaryotic cells and the high-affinity carrier involved in biosynthesis of the neurotransmitter acetylcholine in the CNS (8, 9). These compounds have exceptional in vitro and in vivo antimalarial properties devoid of mutagenic activity (10 -12).G25 [1,16-hexadecamethylenebis(N-methylpyrrolidinium) dibromide] and other drugs in this class possess a permanently charged cationic group (7, 13) that is essential for activity but detrimental to oral absorption. This action prejudiced development for the clinic. Oral administration is essential for treatment in dispensaries in endemic countries and for prophylactic or curative treatment for travelers. A targeting carrier system is unsuitable because, in the absence of carrier-mediated specific processes, quaternary ammonium compounds are intrinsically incapable of crossing bilayered cellular membranes. Designing drugs that mask the ionizable groups was therefore the most attractive solution. This was the rationale behind development of a chemically modified form of drug that is converted into an active ionized form by enzymes present in plasma. Here, we repo...

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Section: Discussionmentioning

confidence: 99%

Prodrugs of bisthiazolium salts are orally potent antimalarials

Vial

Wein

Farenc

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

105

151

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“…The issue of tautomerism, though important in the mechanism of spontaneous mutations of nucleic bases [26], was disregarded since previous works considering both uracil and F-uracil tautomers at * Beside copies of the structures here examined, an arrangement similar to HB6 of Ref. [9] and two structures with H bonds involving F were obtained: one, with E = −8.00 kcal/mol, had the monomers (oriented with antiparallel dipoles) interacting via the N 1 H 1 · · ·F and C 2 O 2 · · ·H 6 groups, while the other, with E = −6.50 kcal/mol, via N 3 H 3 · · ·F and C 4 O 4 · · ·H 6 .…”

Section: Hf Geometriesmentioning

confidence: 99%

Ab initio modeling of competitive drug–drug interactions: 5‐fluorouracil dimers in the gas phase and in solution

Alagona¹,

Ghio²,

Monti³

2001

Int J of Quantum Chemistry

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5-Fluorouracil (FU) is a halogen derivative of the uracil nucleoside widely used for treatment of solid tumors and in combination drug regimens for cancer chemotherapy. In drug delivery by biodegradable poly(ester-ether-ester)s, drug-drug interactions are competitive with respect to the drug-copolymer ones. The potential energy and free energy of association for a variety of FU-FU dimers (either H-bonded or stacked) were therefore studied in the gas phase to shed some light on their absolute and relative strength, because competition between these two kinds of interactions was recently proposed [McCarthy et al. Mol Phys 1997, 91, 513] and examined with a combination of methods [Hobza et al. J Phys Chem A 1998, 102, 6921] for uracil dimers. The effect of the computational level [Hartree-Fock/second order Møller-Plesset (HF/MP2) or B3LYP, including or not counterpoise corrections to the basis set superposition error] was examined as well as that of the use of polarization functions more diffuse than usual 6-31G * (0.25) more diffuse than usual. The MP2 level is necessary to describe stacking interactions, because B3LYP is inadequate for them, giving results very similar to the HF ones. The 6-31G * (0.25) basis set produces very favorable interaction energies, but it is prone to basis set superposition error (BSSE). The binding free energy is noticeably less favorable than the potential energy, due to the increase in vibrational entropy for the association process. There is a good linear relationship between S vib and the binding energy for the HF/6-31G * optimized structures. Estimates of the incidence of thermal corrections at the MP2 level were carried out on the MP2/3-21G and B3LYP/6-31G * structures, where possible. The solvation properties in chloroform or in water of the dimers kept rigid at their in vacuo geometries were examined in the polarizable continuum model framework.

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“…It has been found that prodrug approach here had some limitations. Prodrugs are pharmacologically not active (or may be weakly active) compounds that results from transient chemical modifications of biologically active species, so that they are metabolically transformed into effective drugs following administration [28][29][30][44][45][46][47]. Compared with the original structures, prodrug structures incorporate chemical modifications to get improvement in some deficient physiological properties, such as membrane permeability or water solubility or to overcome some other problems like rapid elimination, bad taste, a formulation difficulty etc.…”

Section: Eye-targeted Chemical Delivery Systems (Cdss) and Retrometabmentioning

confidence: 99%