New Prodrugs of the Antiprotozoal Drug Pentamidine

ArticleinChemMedChem 6(12):2233-42 · December 2011with65 Reads
DOI: 10.1002/cmdc.201100422 · Source: PubMed
Pentamidine is an effective antimicrobial agent that is approved for the treatment of African trypanosomiasis but suffers from poor oral bioavailability and central nervous system (CNS) penetration. This work deals with the development and systematic characterisation of new prodrugs of pentamidine. For this reason, numerous prodrugs that use different prodrug principles were synthesised and examined in vitro and in vivo. Another objective of the study was the determination of permeability of the different pentamidine prodrugs. While some of the prodrug principles applied in this study are known, such as the conversion of the amidine functions into amidoximes or the O-alkylation of amidoximes with a carboxymethyl residue, others were developed more recently and are described here for the first time. These newly developed methods aim to increase the affinity of the prodrug for the transporters and mediate an active uptake via carrier systems by conjugation of amidoximes with compounds that improve the overall solubility of the prodrug. The different principles chosen resulted in several pentamidine prodrugs with various advantages. The objective of this investigation was the systematic characterisation and evaluation of eight pentamidine prodrugs in order to identify the most appropriate strategy to improve the properties of the parent drug. For this reason, all prodrugs were examined with respect to their solubility, stability, enzymatic activation, distribution, CNS delivery, and oral bioavailability. The results of this work have allowed reliable conclusions to be drawn regarding the best prodrug principle for the antiprotozoal drug pentamidine.
    • "Keeping the existing anti-HAT drugs in mind, efforts have been also been directed toward the development of prodrugs of pentamidine and eflornithine. Several prodrugs of pentamidine were tested in silico, in vitro, and in vivo to finally choose N,N 0 -bis(succinyloxy)pentamidine with the best characteristics in terms of solubility, activation, permeability, oral bioavailability , and ultimately its ability to cross the BBB (Kotthaus et al., 2011). On the other hand, another study which looked at mono-, di-, and trisubstituted derivatives of eflornithine found that none of the prodrugs were able to deliver eflornithine into the plasma owing to not being absorbed into the gastrointestinal tract or not being metabolized into eflornithine (Cloete et al., 2011). "
    [Show abstract] [Hide abstract] ABSTRACT: Human African trypanosomiasis (HAT or sleeping sickness) is a potentially fatal disease caused by the parasite, Trypanosoma brucei sp. The parasites are transmitted by the bite of insect vectors belonging to the genus Glossina (tsetse flies) and display a life cycle strategy that is equally spread between human and insect hosts. T.b. gambiense is found in western and central Africa whereas, T.b. rhodesiense is found in eastern and southern Africa. The disease has two clinical stages: a blood stage after the bite of an infected tsetse fly, followed by a central nervous system (CNS) stage where the parasite penetrates the brain; causing death if left untreated. The blood-brain barrier (BBB) makes the CNS stage difficult to treat because it prevents 98% of all known compounds from entering the brain, including some anti-HAT drugs. Those that do enter the brain are toxic compounds in their own right and have serious side effects. There are only a few drugs available to treat HAT and those that do are stage specific. This review summarizes the incidence, diagnosis, and treatment of HAT and provides a close examination of the BBB transport of anti-HAT drugs and an overview of the latest drugs in development.
    Article · Oct 2014
    • "furamidine, DB820 and DB829, Figs 1 and 3) replacing the alkyl chain in the pentamidine. As discussed in the section 'Design and synthesis', various pro-drugs of diamidines have been designed to improve oral bioavailability, by masking the positive charge of the amidine moiety using hydroxy, alkyloxy, acetoxy and amino acids (Clement and Raether, 1985; Boykin et al. 1996; Ismail et al. 2003; Kotthaus et al. 2011). Biotransformation of pafuramidine (Fig. 3), the methoxy pro-drug of furamidine, to the active furamidine is complex, involving multiple steps of sequential oxidative O-demethylation and reductive N-dehydroxylation reactions that are catalysed by cytochrome P450 enzymes and the cytochrome b5/NADH b5 reductase system, respectively (Saulter et al. 2005; Wang et al. 2006, 2007). "
    [Show abstract] [Hide abstract] ABSTRACT: SUMMARY Parasitic protozoa comprise diverse aetiological agents responsible for important diseases in humans and animals including sleeping sickness, Chagas disease, leishmaniasis, malaria, toxoplasmosis and others. They are major causes of mortality and morbidity in tropical and subtropical countries, and are also responsible for important economic losses. However, up to now, for most of these parasitic diseases, effective vaccines are lacking and the approved chemotherapeutic compounds present high toxicity, increasing resistance, limited efficacy and require long periods of treatment. Many of these parasitic illnesses predominantly affect low-income populations of developing countries for which new pharmaceutical alternatives are urgently needed. Thus, very low research funding is available. Amidine-containing compounds such as pentamidine are DNA minor groove binders with a broad spectrum of activities against human and veterinary pathogens. Due to their promising microbicidal activity but their rather poor bioavailability and high toxicity, many analogues and derivatives, including pro-drugs, have been synthesized and screened in vitro and in vivo in order to improve their selectivity and pharmacological properties. This review summarizes the knowledge on amidines and analogues with respect to their synthesis, pharmacological profile, mechanistic and biological effects upon a range of intracellular protozoan parasites. The bulk of these data may contribute to the future design and structure optimization of new aromatic dicationic compounds as novel antiparasitic drug candidates.
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  • [Show abstract] [Hide abstract] ABSTRACT: New 3-amidinophenylalanine-derived matriptase inhibitors were developed and tested against the related trypsin-like serine proteases matriptase-2, thrombin and factor Xa. The strongest matriptase inhibition was found for compounds containing an N-terminal 2′,4′-dichloro- or 2′,4′-dimethoxy-biphenyl-3-sulfonyl group. The combination with a C-terminal piperidyl-cyclohexylurea residue provided the first monobasic matriptase inhibitor with a Ki value < 3 nM and excellent selectivity over thrombin. The X-ray structure of a representative analogue in complex with thrombin superimposed with matriptase provides information regarding the selectivity profile observed in this study.
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