Drug Discovery Today  Volume 22, Number 3  March 2017 REVIEWS

Reviews  POST SCREEN

New prodrugs against tuberculosis
Giorgia Mori, Laurent Roberto Chiarelli, Giovanna Riccardi and Maria
Rosalia Pasca
Department of Biology and Biotechnology Lazzaro Spallanzani, University of Pavia, via Ferrata 1, 27100 Pavia, Italy

The term prodrug was first introduced by Albert in 1958. Generally, prodrugs can be utilized for
improving active drug solubility and bioavailability, increasing drug permeability and absorption,
modifying the distribution profile, preventing fast metabolism and excretion, and reducing toxicity.
Previously, the prodrug approach was a final resort during the drug discovery process only after all other
approaches had been exhausted. However, this strategy is now considered during the early stages of the
drug development process. Most antitubercular agents are defined as prodrugs, including isoniazid and
ethionamide. Thus, the prodrug approach could provide novel targets for the rational design of more
effective treatments for tuberculosis (TB).

Introduction The implementation of a prodrug strategy has improved the

TB is a communicable infectious disease caused by the Mycobacte-
rium tuberculosis complex and is considered a priority disease for
drug development [1]. The recommended regimen for drug-sensi-
tive TB was established four decades ago and remains highly
effective [1]. Standard treatment comprises 2 months of treatment
with at least three first-line drugs, such as isoniazid (INH), rifampin
(RIF), and pyrazinamide (PZA), followed by 4 months of treatment
with at least INH and RIF. When the infection is unresponsive to
this initial treatment, second-line drugs come into play [2,3]. If
patients adhere to the full treatment, the therapy completely cures
drug-susceptible TB with less than an 8% chance of relapse [3]. By
contrast, the treatment regimen recommended for drug-resistant
TB (multidrug-resistant strains, MDR-TB) is toxic, poorly tolerated,
and lasts for up to 24 months, with treatment success rates of only
50% [1,4]. The emergence of incurable TB [extensively drug-
resistant (XDR-TB) and totally drug-resistant (TDR-TB) strains] has
resulted in the need for less toxic and radically shorter therapeutic
regimens. This will require the development of effective ways to
use currently available drugs and to progress several promising
new compounds from the bench to clinical studies [1,3].
Corresponding author: Pasca, M.R. (mariarosalia.pasca@unipv.it)
physicochemical, biopharmaceutical, and pharmacokinetic prop-
erties of pharmacologically active compounds, and it has been
estimated that approximately 10% of drugs marketed worldwide
can be classified as prodrugs [5].
The term prodrug was introduced in 1958 by Albert [6], and
included biologically inert compounds that are activated in vivo
by an enzymatic and/or chemical conversion to be transformed
in an active metabolite. Prodrugs can be divided into two main
classes: carrier-linked and bioprecursor prodrugs [7]. In the first
class, a bioreversible covalent linkage temporary binds the
active drug to a carrier (promoiety). Once in the body, the
carrier-linked prodrug undergoes biotransformation, releasing
the parent drug and the carrier. Ideally, the carrier should be
nonimmunogenic, easy to synthesize at a low cost, stable under
the conditions of prodrug administration, and biodegradable to
nonactive metabolites [7,8]. The bioprecursor class of prodrugs
results from a molecular modification of the active compound
itself. The bioprecursor is then transformed metabolically or
chemically to the active agent [7].
Prodrugs can be additionally classified into two types depending
on the site of conversion into the active metabolite: Type I prodrugs
are metabolized intracellularly (Type IA, at the cellular targets of

1359-6446/ 2016 Elsevier Ltd. All rights reserved.

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 REVIEWS
their therapeutic action and Type IB, by metabolic tissues), whereas
Type II prodrugs are metabolized extracellularly (Type IIA, in the
milieu of the gastrointestinal fluid; Type IIB, in the circulatory
system and/or other extracellular fluid compartments; and Type
IIC, near or inside therapeutic target/cells) [5]. Antimycobacterial
prodrugs can be further divided in two main groups depending on
their mechanism of activation: mycobacterial bioactivated and host
bioactivated.
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Interestingly, among currently available first- and second-line
agents, INH, PZA, and ethionamide (ETH) are prodrugs that exert
their effects via mycobacterial metabolic activation [2]. Among
these prodrugs, PZA is the most unconventional, being primarily
active against nongrowing persisters [9]. PZA enters bacilli through
passive diffusion and is converted to its active form, pyrazinoic
acid (POA), by pyrazinamidase (PZase)/nicotinamidase [911].
INH is used in combination with PZA during the first 2 months
of TB therapy and is activated by KatG, a multifunctional catalase
peroxidase that activates INH by peroxidation, resulting in active
intracellular INH-derived damaging species [12]. ETH is structur-
ally similar to INH, and S-oxygenation of the ETH thiourea moiety
is involved in the bioactivation of a hepatotoxic metabolite known
to retain full activity against TB [2,13,14]. ETH oxidation is medi-
ated by EthA, a monooxygenase that induces ETH sensitivity when
overexpressed in mycobacteria [13,14]. The principal positive
aspects of the mycobacterial bioactivated prodrug include in-
creased bioavailability and solubility, and decreased toxicity.
The main benefits of host-bioactivated drugs include: increased
bioavailability and therapeutic effectiveness; improved solubility,
chemical stability, and organoleptic properties; ameliorated ab-
sorption; increased organ/tissue-selective delivery of the active
agent; and decreased toxicity [15,16]. Such characteristics are
useful for optimizing the absorption, distribution, metabolism,
excretion, and unwanted toxicity (so-called ADMET properties)
of the active drug [15,16].
By contrast, the main limitations of both prodrug groups relate
to possible toxicity resulting from the production of unexpected
metabolites after bioactivation [16]. For instance, INH, ETH, and
other prodrugs activated by EthA (e.g., isoxyl and thiacetazone)
can be further metabolized by the host, resulting in hepatotoxicity
[17].
However, the main problem related to the use of mycobacte-
rial bioactivated prodrugs is the emergence of strains resistant to
prodrugs because of mutations in the gene encoding the activa-
tor. This is the case for INH and ETH [13]. The main mechanisms
of resistance to these two drugs are mutations in the genes katG
and ethA, which prevent the formation of the INH-NAD or ETH-
NAD adducts. For example, the KatG(S315T) mutation is found
in up to 94% of INH-resistant M. tuberculosis clinical isolates [13].
This problem is still unresolved, despite the fact that INH is
currently the most commonly used antitubercular drug. In ad-
dition, the issue of drug resistance could also occur in cases in
which (myco)bacterial bioactivation is expected, particularly if
the gene encoding the activator is not essential for bacterial
growth.
In terms of the emergence of new drugs required to fight TB,
many of the current anti-tubercular drug candidates currently in
preclinical trials are prodrugs. Thus, it is timely to discuss their
possible use in modern pharmacotherapy.
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Drug Discovery Today  Volume 22, Number 3  March 2017
From old to new prodrugs against TB
To specifically hit a single target with high affinity, an ideal
antitubercular agent should be neither reactive nor too small.
Nonetheless, many of the key antitubercular drugs are called
reactive dirty fragments [18]. INH, PZA, and ETH are reactive
small molecules that exert their antibacterial effects on different
targets upon bioactivation [18]. It is by investigating the mecha-
nisms of action of these compounds and those of their activators
that it is possible to discover new drug targets.
Mycobacterial bioactivated prodrugs
para-Aminosalicylic acid
para-Aminosalicylic acid (PAS) entered clinical practice as a bac-
teriostatic agent used in combination with streptomycin (STR) and
INH [19]. However, because of adverse gastrointestinal effects
associated with PAS treatment, it was replaced with the better-
tolerated ethambutol (EMB) [20]. Although widely used for over 60
years, the mechanism of action of PAS remained elusive; only
recently was it demonstrated that PAS is a prodrug activated by the
mycobacterial folate pathway, generating a hydroxyl dihydrofo-
late antimetabolite that inhibits the enzymatic activity of dihy-
drofolate reductase (DHFR) [18,21,22].
This evidence underlined the usefulness for drug development
of exploiting the intracellular enzyme catalysis of compounds [21].
Thanks to improved formulations of PAS and because of the global
spread of MDR and XDR M. tuberculosis strains, PAS has recently re-
entered antitubercular drug regimens as second-line agent [23].
Recently, a M. tuberculosis strain with a mutation in Rv2671
[encoding the 5-amino-6-ribitylamino-2,4(1H,3H)-pyrimidine-
dione 50 -phosphate (AROPP) reductase (RibD)] was found to be
resistant to DHFR inhibitors, including PAS [24]. These advances in
our understanding of the mechanism of action of PAS will enable
the development of novel strategies to revitalize this agent for use
in TB therapy [2325].
Antituberculars activated by EthA: ethionamide,
thiacetazone, isoxyl, 7947882, and 7904688
Among the recognized drug activators, EthA is likely to metabolize
the widest range of compounds. This enzyme, even though de-
fined as a Baeyer Villiger monooxygenase, has broad substrate
specificity, being able to oxidize different thiocarbamide com-
pounds [14,26]. EthA activates several compounds, which in turn
target different mycobacterial enzymes through mechanisms of
action that, in some cases, are still not clearly defined (Fig. 1). A
deeper investigation of these compounds could lead to new infor-
mation and to the identification of new potential drug targets. It is
well known that EthA converts ETH or prothionamide (PTH) via
oxidation to an imidoyl radical, forming a NAD-adduct that
inhibits the cellular target InhA (Fig. 1) [26]. In addition, thiace-
tazone (TAC) and isoxyl (ISO) are both prodrugs activated by EthA
and their mechanisms of action were recently characterized
[27,28]. These thioamides, initially used as second-line drugs, were
recently retracted because of their serious adverse effects and their
high frequency of drug-resistant mutants [28]. EthA oxidizes these
compounds to sulfenic acid forms, which covalently react with a
cysteine residue of the HadA subunit of the FAS II b-hydroxyacyl
ACP dehydratase complex, thus inhibiting the dehydration step of
the type II fatty acid synthase pathway (Fig. 1) [28]. It is likely that
EthA activates the Perchlozone1 analog of TAC, approved for
Drug Discovery Today  Volume 22, Number 3  March 2017 REVIEWS

N
InhA

NH
O H 7947882
N N
ADPR NH2 S NO2
O
ETH NAD+
N
H

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EthA N
PyrG
S NO2
O O O
H2N S

ISO H H
N N

S O
O

O TAC
HN
HN SH
N NH

O
HN
HN S
N NH S
Cys61 HadA

H H
N N

S
O S O

Cys61
HadA
Drug Discovery Today

FIGURE 1
The main mechanisms of EthA-mediated compound activation. The monooxygenase activates several thiol-containing compounds, which exert their toxic effects
through different targets and different mechanisms of action. Once activated, ethionamide (ETH) forms a covalent adduct with NAD+, which inhibits InhA.
Conversely, thiacetazone (TAC) and isoxyl (ISO) form covalent adducts with their target HadA upon activation, whereas thiophenecarboxamides act through
noncovalent inhibition of the CTP synthetase PyrG following EthA oxidation.

TABLE 1
Main prodrugs under development.
Compound Stage of development Mechanism of activation Refs
PA-824 (pretomanid) Phases II and III of clinical trial Ddn nitroreductase [31]a
Delamanid Phases III of clinical trial Ddn nitroreductase [35,36]a
PBTZ169 Last phase of preclinical trial DprE1 (target itself ) [3739]a
Lansoprazole Host bioactivation [43]
Thienopyrimidine TP053 Rv2466c [41,42]
Thiophenecarboxamide 7947882 EthA [30]
Carbamothioylcarboxamide 7904688 EthA [30]
a
http://www.newtbdrugs.org.

therapy for MDR-TB in Russia in 2012, with the same mechanism 7904688, were recently identified via phenotypic screening [30]
used for the activation of TAC and ISO [29]. (Table 1). The involvement of EthA in the activation of these
Two new further compounds activated by EthA, the thiophe- compounds was first suggested by genetic analysis of M. tuberculo-
necarboxamide 7947882 and the carbamothioylcarboxamide sis spontaneous resistant mutants and then demonstrated by

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 REVIEWS Drug Discovery Today  Volume 22, Number 3  March 2017

biochemical studies, leading to the validation of a new cellular
target, the CTP synthetase PyrG. However, the precise mechanism
of action of these compounds has been only partially defined. It
has been demonstrated that, for both compounds, EthA activation
occurs through oxidation of the sulfur atom. However, the active
metabolite was identified only for 7947882 (Fig. 1), whereas, for
7904688, only an inactive end-product was isolated, leading to the
hypothesis that the real active metabolite could be a highly reac-
Reviews  POST SCREEN
benzothiazinone PBTZ169 are currently in clinical trials (http://
www.newtbdrugs.org; Table 1). The dihydro-nitroimidazooxazole
derivative delamanid received conditional approval by the Euro-
pean Medicines Agency (EMA) for the treatment of MDR-TB in
November 2013.
Nitro compounds are usually activated in M. tuberculosis
through different enzymatic reactions, thus leading to different
mechanisms of action (Fig. 2). For instance, the bicyclic 4-nitroi-

tive intermediate [30]. Thus, the possibility that these activated
compounds hit additional targets, probably by forming covalent
adducts, cannot be excluded.
Nitro compounds: PA-824, delamanid, PBTZ169, and
TP53
Similarly to the reactive dirty fragment, nitro group-containing
compounds are usually not a preferred choice for drug discovery.
However, despite their potential mutagenic effects, several have
been demonstrated to be promising drug candidates [3134].
Compounds such as the nitroimidazoles and the benzothiazi-
nones showed great potential against M. tuberculosis infections,
such that two nitroimidazoles (PA-824 and delamanid) and the
midazoles PA-824 and delamanid are prodrugs activated by Ddn, a
deazaflavin-dependent nitroreductase [35] (Table 1). The reactive
intermediates, formed during the conversion to the main desnitro-
metabolites, are considered to have a vital role in the inhibition of
methoxy mycolic acid and ketomycolic acid production in repli-
cating bacilli [36], while the generation of reactive nitrogen species
is the main cause of the anaerobic activity of the compounds
(Fig. 2) [31,35].
Compared with nitroimidazoles, benzothiazinones (BTZs)
[37,38] are suicide inhibitors of the decaprenylphosphoryl-b-D-
ribose oxidoreductase DprE1, an essential enzyme involved in cell
wall biosynthesis. To fulfill their antitubercular activity, the nitro

Mycolic acid Nitrothienopyrimidines

synthesis Oxi
d
O O Rv2 ized
R2 n N R2 466
O N Dd S
c Reaction products
N+ N N S
R1 R1
O

N OH uce
d Toxic effects
Red 466c O2N
O
Rv2 S
SH
Respiratory SH N
poisoning
N N
Nitroimidazoles H
DprE1-Cys387

FAD SH

DprE1-Cys387
R
DP

FADH2 SH
X

O
DP

Benzothiazinones F3C
N
O S N
F3C +N O
N O
O O
S N O
O
N F3C
N
FAD S OH O
S N
O
DprE1-Cys387 N
FAD SH O O
DprE1-Cys387
Drug Discovery Today

FIGURE 2
Mechanisms of activation and action of nitro compounds. Ddn activates nitroimidazoles, which could exert their antitubercular activity against replicating and
nonreplicating bacilli through different intermediate metabolites of the reaction. Similarly, Rv2466c activates the nitrothiophenes, probably releasing toxic
intermediates. Conversely, the mechanism of benzothiazinone (BTZ) activation is very different; once oxidized by the target itself (DprE1), these compounds, being

522 www.drugdiscoverytoday.com
suicide inhibitors, bind the enzyme active site, covalently blocking its activity.
Drug Discovery Today  Volume 22, Number 3  March 2017
group of BTZs is enzymatically activated by the target itself [38].
DprE1 reduces the nitro group of the BTZs to nitroso to reoxidize
its flavin cofactor during the catalytic cycle, and the activated
moiety can readily react with a cysteine of the active site of the
enzyme, irreversibly blocking its activity (Fig. 2) [9]. PBTZ169 is the
most suitable BTZ derivative for clinical development [39] (Table 1),
being less cytotoxic than the hit BTZ, and showing better efficacy at
lower concentrations in a TB murine model. Moreover, PBTZ169
was less susceptible to inactivation by Mycobacterium smegmatis
NfnB nitroreductase, which confers BTZ resistance [39,40].
Among the newly discovered enzymatically activated nitro
compounds, one of the most promising is the thienopyrimidine
TP053, which is active against both replicating and nonreplicating
M. tuberculosis cells [41] (Table 1). TP053 is activated by Rv2466c, a
member of the thiol-disulfide oxidoreductase superfamily, and is
responsible for the reduction of the nitro group (Fig. 2). However,
although the mechanism of reduction of TP053 by Rv2466c has
been extensively investigated, its precise mode of action remains
enigmatic. Similarly to other nitro compounds, the generation of
toxic anion radicals or of other highly reactive compounds, such as
nitroso or hydroxylamine derivatives resulting from the reduction
the nitro moiety, has not yet been excluded [41,42].
Host bioactivated prodrugs: lansoprazole
Prodrugs can be activated by the host rather than by the myco-
bacteria, making their identification almost impossible with the
conventional phenotypic screening. This is the case for lansopra-
zole (LSP) [43] (Table 1). The antimycobacterial effects of this well-
known gastric proton-pump inhibitor emerged from a high-
throughput screen of a panel of US Food and Drug Administration
(FDA)-approved drugs using a host cell-based assay [43,44]. LSP is
converted in the host cell cytoplasm into lansoprazole sulfide,
which kills M. tuberculosis cells by inhibiting the b subunit of the
cytochrome bc1 complex, a well-known drug target. This new and
innovative screen, in addition to having provided a new lead with
well-defined pharmacological data available, has resulted in the
development of a novel tool to identify further new potential
antitubercular prodrugs [43].
Pyrazinamide: a mixed prodrug?
A similar host-mediated bioactivation was recently suggested for
PZA. Although it is generally assumed that the conversion of PZA to
POA mainly occurs inside mycobacterial cells [45], pharmacokinet-
ic studies demonstrated that the high concentration of POA in
plasma was host mediated. POA can then reach the infection site in
the lungs, thus contributing to the in vivo efficacy of PZA. This
finding contributes to explain the discrepancies between the in vitro
and in vivo efficacy of PZA, suggesting also the further development
of POA as an antitubercular drug. In fact, POA showed promising
oral bioavailability, particularly when co-administered with xan-
thine oxidase inhibitors, such as allopurinol, which increases POA
exposure [45]. Recently, several POA esters were developed to
maintain the stability of the prodrug in plasma, and all of these
showed some activity against PZA-resistant mycobacteria [46].
Overall, investigating the prodrug mechanism of activation
provides important insight into compound metabolism. This
could help in suggesting new strategies for the synthesis of effec-
tive antitubercular prodrug derivatives.
REVIEWS
New strategies for TB prodrugs
The beginning of 21st century has been a time of real progress in
the uses of the prodrug approach for drug development. Many
published journal articles, reviews, and patents describe the effec-
tiveness of prodrugs that are currently undergoing clinical trials
(reviewed in [8]).
The prodrug strategy is one of the most promising approaches to
enhance the therapeutic efficacy of pharmacologically active
agents by optimizing the ADMET properties of the parent drugs
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[5] and it represents a faster strategy than searching for an entirely
new therapeutically active agent with such suitable ADMET char-
acteristics [7]. This is also the case for the phosphate and ester
prodrug approaches (described below) used to improve host bioac-
tivated prodrugs.
Moreover, for prodrugs metabolized by mycobacterial enzymes,
the effectiveness of the molecules could be improved by increasing
the bioactivation rate, for instance by increasing the enzymatic
activity or the activator expression levels. Finally, the mycobacte-
rial bioactivation mechanisms of new prodrugs active against M.
tuberculosis were recently revealed as a result of phenotypic screen-
ings, such as thienopyrimidine compounds activated by Rv2466c
[41]. This classical strategy remains a useful method for identifying
by chance both new drug targets and new activators.
Here, we discuss examples of prodrug strategies applied to
develop new agents that are active against M. tuberculosis.
A phosphate prodrug approach: pVXc-486
One of the main obstacles to drug development is the lack of
solubility. Although the prodrug approach is often considered as
ones last hope, it is also a useful and versatile method for drug
development [47]. Among the different strategies utilized for
enhancing the solubility and bioavailability of parental drugs,
the phosphate-prodrug approach was successfully used for the
synthesis of the prodrug pVXc-486 [48]. pVXc-486 is the phos-
phate prodrug of VXc-486, and is an aminobenzimidazole that
targets the M. tuberculosis DNA gyrase. Both VXc-486 and its
phosphate prodrug pVXc-486 target the DNA gyrase ATPase
subunit B (GyrB) [48,49]. Interestingly, the M. tuberculosis isolates
resistant to moxifloxacin (MXF, targeting the DNA gyrase cata-
lytic subunit GyrA), were susceptible to VXc-486, indicating that
fluoroquinolone-resistant strains remain susceptible to antituber-
cular compounds targeting GyrB [48]. The efficacy and potency of
the phosphate prodrug pVXc-486 was demonstrated by directly
comparing pVXc-486 with VXc-486 in a dose-response study in in
vivo experiments. pVXc-486 is rapidly converted to VXc-486 after
oral administration, with its bioconversion likely to occur in the
intestinal lumen via epithelial/luminal phosphatases following
active uptake [48]. It was found that pVXc-486 had dose-depen-
dent bactericidal activity that was more potent than that of VXc-
486 and comparable to that of MXF [48]. Moreover, because TB
regimens comprise drug combinations, pVXc-486 was used with
standard-of-care drugs against M. tuberculosis drug-sensitive and
drug-resistant strains; for example, the combination of pVXc-486
with rifapentine (RFP), bedaquiline (BDQ), linezolid (LZD), and
PZA had significant positive effects in a murine model of TB.
Moreover, pVXc-486 improved the bactericidal activity of com-
bination regimens in models of drug-sensitive and drug-resistant
TB treatments in vivo. pVXc-486 could also be used in place of
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 REVIEWS
MXF, especially against MDR- and XDR-TB. Thus, these results
together suggest that further development of pVXc-486 is war-
ranted [48].
An ester prodrug approach: salycil-AMS
In addition to poor solubility, several antitubercular agents are
characterized by poor bioavailability, mainly because of their
low lipophilicity, which prevents their diffusion across the my-
cobacterial cell wall. This is the case for the [50 -O-(N-salicylsul-
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famoyl)adenosine] (salycil-AMS) compound, a potent inhibitor
of the MbtA enzyme involved in siderophore biosynthesis
[50,51], and for the acyclic nucleoside phosphonate inhibitors
(ANPs) of hypoxanthine-guanine phosphoribosyltransferase, a
key enzyme of the purine salvage pathway [52]. Among the
chemical bonds used to link the parental drug and carrier, esters
have proven to be promising because of their amenability to
hydrolysis both in vivo and in vitro [47]. The synthesis and
evaluation of a series of lipophilic ester prodrugs of salycil-
AMS led to a lower than expected improvement of its oral
bioavailability [51]. In this case, this approach was unsuccessful,
but provided useful information for further studies [51]. Pro-
drugs of ANPs also showed good antitubercular activity and
minimal cytotoxicity [52]. Thus, these first attempts provide
some evidence for the use of this prodrug strategy in drug
development.
ETH boosters
A well-characterized mechanism of mycobacterial bioactivation
could help to develop new methods to improve prodrug efficacy,
for example by increasing the rate of bioactivation. This is the case
for ETH boosters. In fact, the expression of the ETH activator EthA
is under the control of the EthR transcriptional repressor, which
then contributes to intrinsic ETH low activity. Recently, it was
demonstrated that EthR is a valuable target for boosting ETH
bioactivation, because small molecules were found to bind the
repressor, inhibiting its DNA-binding ability and, thus, abolish-
ing its function and increasing ETH activity [53,54]. Moreover,
some ETH boosters are also able to increase the activity of other
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Drug Discovery Today  Volume 22, Number 3  March 2017
EthA-activated compounds, such as the thiophenecarboxamide
7947882 (M.R. Pasca, unpublished, 2016).
Concluding remarks
Prodrugs are used to overcome pharmacokinetic and pharmaceu-
tical barriers to increase drug biological bioavailability, to deliver
the drug to a specific site in the body, to prolong drug action, to
minimize toxicity, and to protect the drug from presystemic
metabolism [49].
Several antitubercular compounds, such as PZA, INH and ETH,
are bioprecursor prodrugs that require activation by M. tuberculosis
enzymes to acquire bacterial toxicity. Other antitubercular agents,
such as LSP or PZA, undergo host-mediated bioactivation instead.
The major problem with these prodrugs is the difficulty in pre-
dicting their bioconversion rates and, thus, their pharmacological
or toxicological effects.
Different strategies have been proposed to overcome problems
such as poor patient compliance, lack of solubility, and poor
bioavailability. A phosphate prodrug approach has been used for
enhancing the solubility of the VXc-486 drug. This strategy gave rise
to the pVXc-486 prodrug, characterized by a better in vivo efficacy
against M. tuberculosis than the parental drug VXc-486. Membrane
permeability has a significant effect on drug efficacy and here the
prodrug strategy can be a valuable option for improving poorly
permeable drugs [49]. For lipophilic ester prodrugs of the salycil-
AMS compound, the prodrug approach was unsuccessful, but did
provide a useful benchmark to guide future studies. By contrast,
ETH boosters have been synthesized and utilized to successfully
improve the activity of EthA-activated compounds [53,54].
Overall, outstanding progress has been made in the field of TB
prodrug design; however, more studies are needed to offer a
winning alternative to improve TB drug ADMET properties with-
out losing the benefits of the drug molecule itself.
Acknowledgments
This work was supported by European Communitys Seventh
Framework Program (Grant 260872) and by the University of
Pavia, Italy (UniversitiamoTubercolosis: a re-emergent killer).
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