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Leprosy
Organic Compounds to Combat Neglected Tropical Diseases 131
recognized by a burst of inflammatory phenomena over preexisting lesions,
especially in borderline forms, with occasional ulceration. Very often these reactions
are associated with additional motor and sensory loss if not treated promptly [37].
Type 2 reactions, also known as erythema nodosum leprosum, are associated with
BL and LL forms of disease. They are characterized by an acute development of
fever, and tender, painful, erythematous subcutaneous nodules. Other organs may
be involved, including the eyes, nasal mucosa, nerves, joints, kidneys, testes [38].
These types of reactions are thought to result from an immune complex disorder
with the subsequent activation of complement cascade.
2. SYNTHETIC STUDIES ON ANTILEPROTIC COMPOUNDS
Although as there is no intention to describe all the mechanism of actions of any
specific drug, this chapter will cover selected important syntheses to date on
potential antileprotic compounds without being concerned with fully classifying
drugs by their targets in the human body.
The first breakthrough for treating leprosy occurred in the 1940s with the development
of the drug dapsone, which halted the progression of the disease. However, continuous
treatment is required, making it difficult for patients to follow [39].
Dapsone was first synthesized by Fromm and Wittmann in 1908 by means of
oxidation of 4,4’-dinitrophenyl sulfide to the corresponding sulfone in a solution
of potassium dichromate, glacial acetic acid, and sulfuric acid. The nitro groups
were reduced with tin and hydrochloric acid, and free base was obtained by
treatment with alkali (Scheme 1) [40].
Reagents and conditions: (i) K
2
Cr
2
O
7
, glacial AcOH, H
2
SO
4
; (ii) Sn/HCl.
Scheme 1: First synthesis of dapsone.
As early as 1954, clofazimine (Fig. 1) originally known B663, was synthesized by
a group of researchers as anti-tuberculosis lichen derived compound. The drug
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132 Organic Compounds to Combat Neglected Tropical Diseases de Lima and de Lima
proved ineffective against tuberculosis but in 1959 Chang demonstrated its
effectiveness against leprosy. After clinical trials the product was launched in
1969 as Lamprene (Novartis) [41].
The mechanism of action of clofazimine is believed to be by binding to the
guanine bases of bacterial DNA and also increasing activity of bacterial
phospholipase A2, leading to release and accumulation of toxic
lysophospholipids, and thus inhibition of bacterial proliferation [42, 43].
N
N
NH
Cl
N
Cl
Figure 1: Structure of clofazimine.
In 1956 studies reported the preparation of several compounds derivatives of 4,4’-
diaminodiphenylsulfoxide, thiosemicarbazide, and isonicotinylhydrazine for
investigation as possible antileprotic agents (Fig. 2) [44].
4,4'-Diaminodiphenylsulfoxide
H
2
N
S
N
H
NH
2
Thiosemicarbazide
Isonicotinylhydrazine
S
O
NH
2
H
2
N
N
N
H
O
NH
2
Figure 2: Carbogens investigated as antileprotic in 1950s.
The authors report the synthesis of a series of 4,4’-
diacylaminodiphenylsulfoxides, thiosemicarbazones and isonicotinylhydrazones
derivatives. These compounds were tested for bacteriostatic activity on
Mycobacterium tuberculosis var. hominis (strain H 37 Rv) in Dubos-Davis culture
medium. Thiosemicarbazones of vanililacetone and similar derivatives together
with p-hydroxyacetophenone and the next higher homologous ketones showed
tubercolostatic activity. In vivo tests in mice were also performed in order to
determine chemotherapeutic indexes.
Leprosy
Organic Compounds to Combat Neglected Tropical Diseases 133
In 1965 Zhuravlev and co-workers synthesized the antipsychotic trifluoperazine,
10-[3-(4-methyl-1-piperazinyl)-propyl]-2-(trifluoromethyl)-10H-phenothiazined
dihydrochloride (TFPH) (Fig. 3) employing either trifluoromethyl phenothiazine,
N-methyl-N’-(3-chloropropyl)piperazine and sodium hydroxide or 10-(3-
chloropropyl)-2-trifluoromethyl phenothiazine and N-methylpiperazine [45].
Later on, a study demonstrating anti-tubercular activity of TFPH [46] prompted an
investigation into inhibition of ATP synthesis in M. leprae [47]. It was observed
that TFPH reduced ATP levels of in vitro incubated M. leprae derived from
human leprosy cases. The authors concluded that the effects of TFPH on
M. leprae suggest a compound with broad spectrum of anti-mycobaterial activity.
However, it was noted that more detailed investigations were needed for their
application as clinical agent.
S
N
CF
3
N
N
CH
3
.2HCl
Figure 3: Structure of TFPH.
In the beginning of the 1970s a series of three articles named “Potential
Antileprotic Agents” were published to describe the synthesis of compounds
aimed to treat leprosy [48-50] (Fig. 4).
N
N
N
N
N
N
H
2
N
NH
2
R
NH
2
H
2
N
R
CH
3
Diarylsulfones
Pteridines
2,4-Diamino-5-methyl-6-alkylquinazolines
S
RH
2
N
O O
Figure 4: Series of compounds investigated in 1974.
The first article describes an effort to establish the structure-activity requirements
of diaryl sulfones relative to a mycobacterial model and evaluate them as growth
inhibitors of Mycobacterium species 607 [48]. In the subsequently paper initial
studies on the synthesis of pteridines designed to inhibit step II, reduction of
dihydrofolate to tetrahydrofolate in Mycobacterium sp. 607, were reported. The
compounds were effective inhibitors of the dihydrofolic reductase isolated from
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134 Organic Compounds to Combat Neglected Tropical Diseases de Lima and de Lima
the organism but failed to inhibit cell growth [49]. The last report continues to
explore structure-activity relationships in bicyclic pyrimidine systems and a series
of 2,4-diamino-5-methyl-6-alkylquinazolines were synthesized and tested as anti-
microbial agents. The results showed that these compounds were moderate to
strongly effective growth inhibitors (MIC of 1.8 nmol/mL for 6-n-propyl analog)
of Mycobacterium sp. 607 [50].
N-Alkylbenzylamines are known to present specific action against mycobacteria
[51]. Meindl and co-workers synthesized a series of benzylamines with various N-
alkyl chains and aryl substituent for evaluation on Mycobacterium tuberculosis H
37 Ra [52]. The synthesis involving reductive amination of the corresponding
substituted benzaldehydes is shown in Scheme 2.
Reagents and conditions: (i) R
1
NH
2
; (ii) LiAlH
4
or NaBH
4
; (iii) NH
2
OH; (iv) LiAlH
4
.
Scheme 2: Preparation of benzylamine derivatives (1984).
Evaluation of this class of compound in tuberculostatic, bacteriostatic and
bactericidal assays showed promising results and prompted the researchers to
analyze the structure-activity relationship in the class of benzylamines for
combination with dapsone or other antimycobacterial compounds in the therapy of
leprosy.
Hooper and co-workers published two important reviews on medicinal chemistry
of antileprotic drugs [53, 54]. These reviews discuss the chemistry of the drugs
used in therapy with special attention on the more recent developments and the
use of qualitative (SAR) and quantitative (QSAR) methods for the analysis of the
structure-activity relationships. The chemotherapy was divided in two main
Leprosy
Organic Compounds to Combat Neglected Tropical Diseases 135
groups, first-line and second-line. The first-line drugs comprise the dapsone,
rifampicin, and clofazimine, which are used as multi-drug treatment because of
the clinical aspects of the disease and patient compliance. These reviews also
summarize of the various synthetic routes to sulfones, iminophenazines, and
rifamycins, along with information about QSAR studies. The second-line therapy
group includes the thioamides, prothionamide and ethionamide, the
thiosemicarbazone, thiacetazone, and the thiourea, thiambutosine. References and
discussion of synthetic routes and structure-activity relationships are focused to
thioamides, thiosemicarbazones, and thioureas. This review also describes new
drugs and drug targets including, dihydrofolate redutase inhibitors,
aminoglycosides, -lactam antibiotics, quinolones, deoxyfructoserotonin,
tyrosinase inhibitors, and inhibitors of cell wall development
In 1994, WHO Study Group noted that the potential for finding new drugs is
greater because thousands of compounds were being screened for antitubercolosis
activity and some of these were likely to be effective against M. leprae [55]. A
typical treatment regimen consisting of rifampicin (600 mg) plus ofloxacin (400
mg) daily for 1 month was being evaluated for some types of leprosy. The WHO
recommended new efforts to develop very short-course regiments for specific
types of leprosy in certain countries. All this effort aimed to reduce duration of
therapy and allow easier compliance.
During this decade the synthesis of tetrazoles from D-mannofuranose and both
enantiomers of rhamnofuranose provided the first examples of tetrazole analogues
(Fig. 5) of furanose based carbohydrates. The bicyclic system was achieved by
intramolecular [1,3]-dipolar cycloaddition of azonitriles. These molecules were
believed to be potential mannosidase inhibitors and may interfere with
biosynthesis of cell walls of Mycobacteria providing a strategy for the treatment
of leprosy [56].
N
HO
OH
N
N
N
OH
N
HO
OH
N
N
N
OH
N
HO
OH
N
N
N
OH
H
H
H
OH
Figure 5: Tetrazoles with potential to treat leprosy.
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136 Organic Compounds to Combat Neglected Tropical Diseases de Lima and de Lima
One cannot forget the history of thalidomide (2-(2,6-dioxo-3-
piperidyl)isoindoline-1,3-dione) (Scheme 3) developed in Germany as a
barbiturate in the late 1950s. However, by 1962 its teratogenic properties were
discovered and its use severely limited. However, it was discovered that the drug
could be used to treat erythema nodosum leprosum (ENL) in leprosy.
Thalidomide was then approved by FDA for the treatment of ENL in 1998 under a
rigorous distribution and monitoring program [57]. In 1999, due to anti-
inflammatory and immunomodulating activities, researchers of Celgene
Corporation developed a concise two-steps synthesis of thalidomide based on the
use of L-glutamine as starting material instead of L-glutamic acid used earlier.
This improved synthetic route allowed preparation of multikilogram quantities
(Scheme 3) [57].
Scheme 3: Synthesis of thalidomide by Celgene Corporation.
Reagents and conditions: (i) L-glutamine, Na
2
CO
3
; 4N HCl(aq.); (ii) CDI,
DMAP.
Investigations in twenty first century on potential antileprotic compounds to treat
leprosy’s symptoms are replete of novel synthetic approaches.
In 2001, medicinal chemistry efforts on derivatives of the new classes of
phthalimidouracils and 5-phthalimidobarbituric acids were reported [58]. These
compounds were designed as analogues of thalidomide. 5-ethyl-1-phenyl-5-
(tetrafluorophtalimido)barbituric acid and 2-(2,4-difluorophenyl)-4,5,6,7-
tetrafluoro-1H-isoindole-1,3-(2H)-dione showed to be potent inhibitors of tumor
necrosis factor-α (TNF-α) production (Fig. 6).
N
O
O
NH
N
O
O
O
Et
Ph
N
O
O
F
F
Figure 6: TNF-α inhibitor analogues of thalidomide.
Leprosy
Organic Compounds to Combat Neglected Tropical Diseases 137
The importance of this work for leprosy patients is based on the association of
TNF-α production with skin and peripheral nerve pathology of leprosy reversal
reactions [59].
With respect to modulation of TNF-α, another relevant publication to point out is
an exemplar and careful study concerning the synthesis and immunological
activity of a series of new water-soluble thalidomide prodrugs [60] such as the
molecules showed in Fig. 7.
N
O
O
N
O
O
O
O
X
NH
R
R = H or CH
3
X = CH
2
, CHCH
3
, CHCH(CH
3
)
2
, CH
2
NHCOCH
2
.HCl
Figure 7: Water-soluble prodrugs of thali d o mide.
Grosset [61] referred to rifapentine, a rifamycin derivative and, the fluorquinolone
moxifloxacin (Fig. 8) as having highly potential antimicrobial activity and
therefore potential for much more effective drug treatment. Promising data has
also been presented for drug regiments against M. leprae.
NN
NH
O
F
O O
OH
N
N
N
OH
OH
OH
O
O
O
O
OH
O
NH
O
O
H
HO
Rifapentine
Moxifloxacin
Figure 8: Structures of the antimicrobial moxifloxacin and rifapentine.
Interested in exploring the active antiangiogenic pharmacophore of thalidomide
and its derivatives, Xiao reported the synthesis of these compounds by using
solid-phase synthesis [62]. The strategy involved the coupling of hydroxymethyl
polystyrene with phthalic anhydride to form the resin linked acid and reaction
with primary amines followed by acid or base treatment to form thalidomide and
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138 Organic Compounds to Combat Neglected Tropical Diseases de Lima and de Lima
its analogues (Schemes 4 and 5). The authors show that the procedure can be used
to synthesize a combinatorial library of thalidomide analogues.
In addition to publications related to thalidomide analogues it is worth to mention
a fine work dealing with a facile synthesis of azido-thalidomide analogue [63].
The workers used of cheap and readily available starting materials and reagents,
and only two steps required purification. Once more, researchers were searching
for the mechanism of action of thalidomide and related analogues by using azido
analogue of thalidomide, which then will be examined biologically for its
potential use as photoaffinity label. The synthetic route was devised to be
performed into two parts. The first involved the synthesis of the glutarimide
moiety. With this product in hands, it was submitted to condensation with 4-
nitrophthalic anhydride to give the 4-nitro-substituted thalidomide derivative.
Reduction of the nitro group produced the 4-amino-substituted analogue which
was treated with sodium nitrite in aqueous HCl at 0
o
C, followed by addition of
sodium azide, affording the 4-azido-substituted thalidomide analogue (Scheme 6).
Scheme 4: Solid-phase synthesis of thalidomide and R-(o carboxybenzamido)glutarimide.
Significant progress in the treatment of leprosy patients may be possible with the
discovery of new agents with antileprosy activity having different modes of action
than currently available drugs. With this in mind, Makarov [64] in the course of
their program to develop new anti-tuberculosis drugs using structure–activity
relationships, selected a set of original compounds with antibacterial activity in
vitro for the investigation of their antileprosy potential. They developed a facile
synthesis of 2-chloro-3-cyano-5-nitropyridine (1) and synthesized a series of 3-
Leprosy
Organic Compounds to Combat Neglected Tropical Diseases 139
cyano-2-dialkyldithiocarbamoyl-5-nitropyridine deri-vatives using 2-
hydroxynicotinic acid as starting material (Scheme 7).
They also reported the antileprosy activity of a previously prepared pyrimidine
derivatives showed in Fig. 9.
N
N
NO
2
S
R
S
N
R = OMe or NMe
2
(3)
Figure 9: Pyrimidine derivatives.
Reagents and conditions for Schemes 4 and 5: (i) TEA, DMAP, DMF, room temp., 18 h;(ii) DIC,
HOBT, R-aminoglutarimide, DMF, room temp, 18 h; (iii) 5% TFA/toluene, 4 h; (iv) 1%
KOH/CH
3
OH, room temp, 2 h. Note: PS = polystyrene resin; (v) DIC, HOBT, DMF, aniline, room
temp., 18 h; (vi) same step v (replace aniline with diethyl glutamate); (vii) 5% TFA/toluene, reflux
12 h; (viii) 1% KOH/CH
3
OH, reflux, 2 h. Note: PS + polystyrene resin.
Scheme 5: Solid-phase synthesis of thalidomide analogues.
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140 Organic Compounds to Combat Neglected Tropical Diseases de Lima and de Lima
Reagents and conditions: (i) CDI, 4-DMAP, THF, reflux; (ii) TFA, r. t.; (iii) 4-nitrophthalic
anhydride, AcOH, reflux; (iv) 10% Pd/ C , acet one; (v ) NaN O
2
, HCl, 0
o
C.
Scheme 6: Synthesis of azido photoaffinity analogue of thal i domide.
Reagents and conditions: (i) HNO
3
fum., H
2
SO
4
conc.; (ii) SO
2
Cl
2
, CCl
4
, DMF; (iii) NH
3
H
2
O; (iv)
POCl
3;
(v) NaSC(S)NR
1
R
2
, EtOH.
Scheme 7: Synthetic route for the preparation of some dialkyldithiocarbamates.
The authors tested the in vivo efficacy of these compounds against M. leprae in the
infected footpad model, and showed that the analogs 3-cyano-2-diethyldithio-
carbamoyl-5-nitropyridine (2, NR
1
R
2
= NEt
2
) and 6-methoxy(dimethylamino)-5-
nitro-4-tetrahydromethylendithio-carbamoyl-pyrimidines (3) reduced the number of
M. leprae by two orders of magnitude, comparable to the effect of dapsone. The co-
adminstration of compound 3-cyano-2-diethyldithiocarbamoyl-5-nitropyridine and
6-dimethylamino-5-nitro-4-tetrahydromethylendithio-carbamoyl-pyrimidine with
dapsone synergistically enhanced the activity. Additionally, these compounds were
well tolerated over the treatment period of 7.5 months.
Dithiocarbamate derivatives were also shown to suppress M. leprae proliferation
and specially 2 (NR
1
R
2
= NEt
2
) in a dose of 30 mg/kg exhibited high antileprosy
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