European Journal of Medicinal Chemistry 49 (2012) 1e23

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European Journal of Medicinal Chemistry

journal homepage: http://www.elsevier.com/locate/ejmech

Invited review

Recent advances in antitubercular natural products

Abraham García a, *, Virgilio Bocanegra-García c, Jose Prisco Palma-Nicolás b, Gildardo Rivera c, *
a
Facultad de Ciencias Químicas, Universidad Autónoma de Nuevo León, Monterrey, Nuevo León, Mexico
b
Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Coyoacan, DF, Mexico
c
Centro de Biotecnología Genómica, Instituto Politécnico Nacional, Reynosa, Tamaulipas, Mexico

a r t i c l e i n f o a b s t r a c t

Article history: Currently, one third of the world’s population is infected with Mycobacterium tuberculosis and 8.9e9.9
Received 20 September 2011 million new and relapse cases of tuberculosis are reported every year. The emergence of new cases,
Received in revised form the increased incidence of multi-drug resistant strains of M. tuberculosis, and the adverse effects of first-
9 December 2011
and second-line antituberculosis drugs have led to renewed research interest in natural products in the
Accepted 20 December 2011
Available online 9 January 2012
hope of discovering new antitubercular leads. Interestingly, hundreds of natural products, possessing
novel, uncommon, and known structural architectures, have been reported to exhibit activity towards
non-resistant and multi-drug resistant strains of M. tuberculosis. The present review covers literature
Keywords:
Natural products
published during the last five years about those naturally occurring compounds with reported growth
Terpene inhibitory activity in vitro towards sensitive and resistant M. tuberculosis strains. Compounds with
Alkaloid antitubercular properties at minimal inhibitory concentrations (MICs) of less than 50 mg/mL or 60 mM
Polyketide were selected and grouped according to their source of origin (plants, bacteria, fungi, marine organisms,
Peptide etc) and chemical type (terpenes, steroids, alkaloids, flavonoids, poliketides, peptides, etc). In some cases,
Antitubercular the selection covers those structurally relevant natural products with low bioactivity (MICs of
128 mg/
mL), and also those semisynthetic derivatives with remarkable antitubercular activity (MICs of
10 mg/
mL). Additionally, this review includes a special section for those natural products that specifically target
genes or enzymes of M. tuberculosis.
Ó 2012 Elsevier Masson SAS. All rights reserved.

1. Introduction
Currently, one third of the world’s population is infected with
Mycobacterium tuberculosis and 8.9e9.9 million new and relapse
cases of tuberculosis are reported every year [1]. The emergence of
new cases, the increased incidence of multi-drug resistant strains of
M. tuberculosis, the adverse effects of first- and second-line anti-
tuberculosis drugs, and the increased incidence of tuberculosis
associated with viral infections (Human Immunodeficiency Virus,
HIV) have led to renewed research interest in natural products in
the hope of discovering new antitubercular leads [2,3]. During the
last two decades, there has been a lot of progress in new techniques
to evaluate the antimycobacterial potential of a large number of
compounds. With the development of time-saving assays, many
naturally occurring compounds have been reported to exhibit
promising inhibitory activity against M. tuberculosis and, in some
cases, the mechanism of action has also been determined [4e6].
* Corresponding authors. Tel.: þ52 81 83294000 3463; fax: þ52 81 83529025.
E-mail addresses: edgar.garciazp@uanl.edu.mx (A. García), gildardors@
hotmail.com (G. Rivera).
Natural products and some of their derivatives have been re-
ported to exhibit remarkable growth inhibitory activity towards
M. tuberculosis and some of them have been selected as prototype
molecules for the development of new antitubercular agents [6,7].
Some interesting reviews of antimycobacterial natural products
have been published covering literature from 1990 to 2005 [8e10].
This review covers literature published from 2006 to 2011 about
natural products with reported growth inhibitory activity in vitro
towards sensitive and resistant M. tuberculosis strains. Those
compounds with antitubercular properties at minimal inhibitory
concentrations (MICs) of less than 50 mg/mL or 60 mM were selected
and grouped according to their source of origin and chemical type.
The compendium includes those secondary metabolites isolated
from plants, bacteria, fungi, marine organisms and algae, which
were grouped according to their chemical type as terpenes
(sesquiterpenes, diterpenes, sesterterpenes, triterpenes), steroids
(sterols), alkaloids (indole, quinoline, pyridoacridone, and manz-
amine alkaloids, etc), aromatics (flavonoids, chalcones, coumarins,
lignans, xanthones, anthracenes, anthraquinones, naphthalenes,
chromones, etc), polyketides (acetylenic fatty acids, polycyclic
esters, quinones, etc), and peptides. In some cases, the selection
covers those structurally relevant natural products with low

0223-5234/$ e see front matter Ó 2012 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2011.12.029
2 A. García et al. / European Journal of Medicinal Chemistry 49 (2012) 1e23

bioactivity (MICs of
128 mg/mL) and also those synthetic

analogues with remarkable antitubercular activity (MICs of
10 mg/ H OH H
O
mL). This review also covers natural products that have been
previously reported in literature, but which have been reisolated
HO H O
and found to possess antitubercular activity. Additionally, those
antitubercular natural products that specifically target genes or
enzymes of M. tuberculosis were selected and grouped in one final
OH
section. 9
OH
2. Terpenes
H

2.1. Sesquiterpenes O

One new (1) and two known (2 and 3) dihydroagarofuranoid H

sesquiterpenes (from Microtropis japonica), named 15-
acetoxyorbiculin G (1), salasol A (2), and celahin C (3), exhibi-
ted potent activity towards M. tuberculosis H37Rv with MICs of
39.6, 28.2, and 30.6 mM, respectively, in comparison with drug
ethambutol (MIC of 30.6 mM) [11]. Reinvestigation of Microtropis
fokienensis led to the isolation of two new dihydroagarofuranoid
sesquiterpenes (4 and 5), which were tested against a clinical
susceptible strain of M. tuberculosis (90-221387), exhibiting
potent activity with MICs of 19.5 and 15.8 mM, respectively [12].
Additionally, three known dihydroagarofuranoid sesquiterpenes
were reported as mutangin (6), orbiculin G (7), and triptogelin
G-2 (8), which exhibited moderate and potent activity towards
the clinical isolate 90-221387 with MICs of 51.8, 14.6, and
26 mM, respectively, in comparison with ethambutol (MIC of
30.6 mM) [12].
10 11
Seven known 3,10-epoxygermacrolide-6,7-lactone sesquiter-
penes were isolated, from the whole plant Camchaya calcarea, and
identified as goyazensolide (12), centratherin (13), lychnophor-
olide B (14), isogoyazensolide (15), isocentratherin (16), 5-epi-
isogoyazensolide (17), and 5-epi-isocentratherin (18). All sesqui-
terpenes showed potent activity against M. tuberculosis H37Ra
with MICs of 3.1, 3.1, 6.2, 1.5, 3.1, 3.1, and 3.1 mg/mL, respectively.
In addition to these potent antitubercular sesquiterpenes, the
known germacrane 19 was isolated and found to exhibit a modest
activity towards the same mycobacterial strain with a MIC of
50 mg/mL [16].

O
R4
R1 O
R2

O O
R3
O O O
1 R1, R4 = OCOCH3 R2, R3 = OCOC6H5 R1

2 R1 = OH R2, R3, R4 = OCOCH3

O
3 R1, R3, R4 = OCOCH3 R2 = OH R2
4 R1 = OCOCH3 R2 = OH R3, R4 = OCOC6H5
7 R1, R2 = OCOC6H5
5 R1 = OH R2 = OCOCH3 R3, R4 = OCOC6H5
8 R1, R2 = CH3
6 R1, R2, R3 = OCOCH3 R4 = OCOC6H5

The bisphenol-sesquiterpene named ramiferin (9) was isolated 2.2. Diterpenes

from the culture broth of Kionochaeta ramifera BCC 7585 and
showed activity against M. tuberculosis H37Ra (MIC of 12.7 mM),
cytotoxicity against Vero cells (Medium Inhibitory Concentration, IC50,
of 9.7 mM), and exhibited no antitubercular selectivity with an index
of 0.7 (adequate selectivity index, SI, should be higher than 10) [13].
Roots of Beilschmiedia erythrophloia afforded a known caryophyllane-
type sesquiterpene named suberosol B (10), which showed moderate
activity against M. tuberculosis H37Rv with a MIC value of 28.9 mg/mL if
compared with ethambutol (6.25 mg/mL) [14]. The previously re-
ported a-humulene (11) was isolated from Polyalthia cerasoides and
was found to exhibit moderate activity against M. tuberculosis H37Ra
(MIC of 6.25 mg/mL) in comparison with isoniazid (0.05 mg/mL) [15].
Corallolide B (20), a 12-membered macrocyclic diterpene
exhibiting a novel carbon skeleton, was isolated from the Caribbean
gorgonian octocoral Pseudopterogorgia bipinnata. Despite the new
bicyclo[9.2.1]tetradecane system, 20 weakly inhibited the growth
of M. tuberculosis by 95% at 128 mg/mL [17]. In addition to this new
skeleton, a novel oxapolycyclic diterpene possessing an interesting
12-membered pseudopterane carbon skeleton, bipinnapterolide B
(21), was isolated from the Colombian gorgonian octocoral P.
bipinnata and tested in vitro against M. tuberculosis H37Rv.
Compound 21 caused 66% of mycobacterial growth inhibition at
128 mg/mL [18].
 A. García et al. / European Journal of Medicinal Chemistry 49 (2012) 1e23 3

O O O

R R R
O O O

HO O HO O HO O
O O O

O O O HO2C O
R= 15 17 R =
12 R= O
19
O O O
13 R= 16 R= 18 R =

O
14 R=

(33), and 6,7-dehydroroyleanone (34), isolated from Plectranthus

OH O H O grandidentatus, inhibited the growth of susceptible M. tuberculosis
HO H37Rv strains and multi-drug resistant strains with MICs of 25 and
O
12.5 mg/mL, respectively, while the diterpene 7a-acetoxy-6b-
O O O H
H hydroxyroyleanone (35) inhibited growth of both strains with MICs
H
O of 25 and 3.12 mg/mL, respectively [23]. Surprisingly, derivatization
O of 7a-acetoxy-6b-hydroxyroyleanone (35) yielded two highly
H
O O active derivatives (36) and (37), which showed MICs of 0.39 and
20 21 0.78 mg/mL against M. tuberculosis multi-drug resistant strains,
respectively. Compound 36 was found to be the most active not
only against the resistant strain (MIC of 0.39 mg/mL) but also the
Some natural azorellane- and mulinane-type diterpenes, susceptible one with a MIC of 3.12 mg/mL. However, compound 36
previously isolated from the medicinal plants Azorella compacta showed potent cytotoxic activity against Vero cells with an IC50 of
and Mulinum crassifolium, and their synthetic analogues have been 2.58 mg/mL and exhibited no therapeutic selectivity (SI of 6.6) [23].
reported to exhibit moderate antimycobacterial activity against Moderate antitubercular activity was observed for the known
susceptible strains (M. tuberculosis H37Rv ATCC 27294) and drug- abietane-type diterpene carnosic acid 38 (isolated from the aerial
resistant strains (M. tuberculosis CIBIN/UMF 15:99 clinical isolate) parts of Salvia africana-lutea) when tested against M. tuberculosis
with MICs of 6.25, 12.5, and 25 mg/mL. Natural diterpenes azor- H37Rv (MIC of 28 mM) [24]. A new seco-abietane diterpene 39,
ellanone (22), azorellanol (23), 17-acetoxy-13a-hydroxyazorellane isolated from leaves and twigs of Callicarpa pilosissima, was re-
(24), and mulinol (25) exhibited weak activity against the suscep- ported to exhibit a MIC of 38 mM towards M. tuberculosis H37Rv,
tible and resistant strains with MICs in the range of 12.5 and 25 mg/ while callicarpic acid (40) exhibited weak activity with a MIC of
mL (positive control ofloxacin exhibited MICs of 0.125 and 0.250 mg/ 63.6 mM [25].
mL). On the contrary, derivatives 26e28 were more potent than the Four trachylobane-type diterpenes, ent-3b-hydroxy-
natural products against both strains with MICs of 6.25 mg/mL trachylobane (41), ent-trachyloban-2-one (42), ent-3b-acetoxy-19-
[19e21]. hydroxytrachylobane (43), and ent-trachyloban-17-al (44), were

H
OH O O
H O H H
OH
R2 H H H H
R1
O OR

22 R1 = O R2 = H OH 27 R = (CH2)2CH3
O O
25 26 28 R = (CH2)3CH3
23 R1 = OCOCH3 R2 = H

24 R1 = H R2 = OCOCH3

The aerial parts of Anisochilus harmandii afforded one pimarane-
type diterpene named pimaric acid (29) and two abietane-type
diterpenes named 9a,13a-epidioxyabiet-8(14)-en-18-oic acid (30)
and 15-hydroxydehydroabietic acid (31), which exhibited weak
activity against M. tuberculosis (50 mg/mL) [22]. The structurally
related abietanes 6b,7a-dihydroxyroyleanone (32), horminone
isolated from the bryophyte Jungermannia exsertifolia subsp. cor-
difolia. The trachylabanes 41e44 were reported to inhibit the
growth of M. tuberculosis H37Rv with MICs of 61, 50, 59, and 24 mg/
mL, respectively [26].
A known kaurane-type diterpene named kaurenoic acid (45)
was isolated and found to exhibit the growth of M. tuberculosis
4 A. García et al. / European Journal of Medicinal Chemistry 49 (2012) 1e23

OH
O
O O

H
O
H H
HO2C HO2C R2
H
29 30 R1
OH OH 32 R1, R2 = OH
O
R
33 R1 = H, R2 = OH
O
H
HO2C H 35 R1 = OH, R2 = OCOCH3
O O 31 34
O
OCH3
O HO O
O O
CH3CO2
O H3CO
H HO O
OH H
O
H H
36 R = OCH3
38 39 40
37 R = Cl

R3

H
H H
O
R1 H
H
R2
42
HO
41 R1 = OH R2 = H R3 = CH3 O
O
OH
43 R1 = OCOCH3 R2 = OH R3 = CH3
46
R1, R2 = H R3 = CHO H
44 HO2C
45

H37Rv by 88.6% at 25 mg/mL, which is comparable to the control
isoniazid that caused mycobacterial growth inhibition by 94% at the
same concentration [27]. An unusual compound possessing a new
class of C15-rearranged pentanorditerpene, named elisabethin H
(46) and isolated from the Caribbean sea whip Pseudopterogorgia
elisabethae, was shown to inhibit 51% of mycobacterial growth
(H37Rv strain) at 6.25 mg/mL [28].
The reported rhamnofolane-type diterpene, named caniojane
(47), was reisolated and found to moderately inhibit growth of
M. tuberculosis H37Ra with a MIC of 25 mg/mL [29]. Structurally
related compounds were isolated from the latex of Pedilanthus
tithymaloides and characterized as three new jatrophane-type
diterpenes 48e50. Moderate activity against M. tuberculosis
H37Ra was observed for 48e50, which exhibited MICs of 12.5, 50,
and 50 mg/mL, respectively [30]. Screening of previously reported
compounds led to the identification of geranylgeraniol (51) as
a potent antitubercular natural product, which inhibited the
growth of M. tuberculosis H37Rv ATCC 27294 with a MIC of 1.56 mg/
mL [31]. A simple natural product named (E)-phytol (52) was iso-
lated from leaves of Pourthiaea lucida and reported to be less active
than its congener 51 towards M. tuberculosis H37Rv with a MIC of
12.5 mg/mL [32]. Two new cassane-type diterpenes, named
escobarine A (53) and B (54) and isolated from Calliandra cal-
ifornica, were tested against M. tuberculosis H37Rv and a multi-drug
resistant strain (CIBIN/UMF15:99). Escobarine A (53) was the most
active with MICs of 25 and 12.5 mg/mL towards the susceptible and
resistant strains respectively. The less active compound 54 inhibi-
ted the growth of both strains with a MIC of 50 mg/mL [33].
2.3. Sesterterpenes
Bioassay-guided fractionation of cultured terrestrial cyanobac-
terium Scytonema sp (UTEX 1163) afforded a scalarane-type ses-
terterpene, scytoscalarol (55), which represents one of the few
terpenes reported in cyanobacteria. Compound 55 represents the
first cyanobacterial guanidine-bearing sesterterpene, which
exhibited weak inhibitory activity towards M. tuberculosis H37Rv
(MIC of 110 mM) and weak cytotoxicity against Vero cells (IC50 of
135 mM) and no selectivity (SI < 1) [34].
2.4. Triterpenes
The hopane-type triterpene named hopane-6b,11a,22,27-tetraol
(56) was isolated from an insect pathogenic fungus Conoideocrella
 A. García et al. / European Journal of Medicinal Chemistry 49 (2012) 1e23 5

O
OH O O
HO O
O O O
O OH O
HO O O O O
O H O H O
O O H O
O O O
H O O
O
47
48 49

O O O
OH
O O
O
O O O 51 R
H
O H O
O H
HO O
O
O O 53 R = CHO
OH

50 52 54 R = CH2OH

tenuis BCC 18627 and exhibited moderate activity (MIC of 52 mM)
when tested against M. tuberculosis H37Ra [35]. The fractionation of
the organic extract obtained from leaves and twigs of Radermachera
boniana led to the isolation of two new antitubercular triterpenes,
bonianic acids A (57) and B (58), which presented MICs of 34.8 and
9.9 mM against M. tuberculosis H37Rv, respectively. It is interesting
to note that the highly active bonianic acid B (58) showed weak
toxicity against Vero cells with an IC50 of 74.2 mM and low selec-
tivity with a SI < 8 [36]. Two known limoids azadiradione (59) and
epoxyazadiradione (60) were tested against M. tuberculosis H37Ra
and showed potent and moderate activity with MICs of 6.25 and
25 mg/mL, respectively [37].
isogenic strains (H37Rv and H37Rv GFP, MICs of 65 and 30 mg/mL,
respectively), when a sample of 61 contained an impurity of
26% of oleanolic acid (62) according to quantitative proton
nuclear magnetic resonance analyses [38]. Investigation of the
mushroom Astraeus pteridis led to the isolation of two lanostane-
type triterpenes, new 3-epi-astrahygrol (63) and known 3-epi-
astrapteridiol (64), which exhibited moderate activity towards
M. tuberculosis H37Rv (ATCC 27294) with MICs of 34 and
58 mg/mL, respectively [39].
Bioassay-guided fractionation of the organic extract obtained
from the stem and bark of Clavija procera afforded the oleanane-
type triterpene named aegicerin (65), which inhibited the growth

HN NH2

NH H
HO OH
H
OH
H O
H H OH H H
H O
OH
H HO2C

55 56 57

O
O O

O O
O
H H O
O
O O O
HO2C O O
O

58 59 60

The known ursane-type triterpene named ursolic acid (61)
was tested against two isogenic strains of M. tuberculosis (H37Rv
and H37Rv GFP) and was found to exhibit no activity towards the
H37Rv strain (MIC of 256 mg/mL) and moderate activity towards
the H37Rv GFP strain (MIC of 98 mg/mL). The antitubercular
activity of ursolic acid (61) was increased against the two
of M. tuberculosis H37Rv with a MIC of 3.1 mg/mL and also inhibited
the mycobacterial growth of two isoniazid-resistant clinical isolates
and 13 multi-drug resistant isolates in the range of 1.6e3.1 mg/mL
[40]. Compound 65 exhibited low cytotoxicity against Vero cells
with an IC50 of 40 mg/mL, which makes it very selective (SI higher
than 12) [40]. The structurally related triterpene betulinic acid (66),
6 A. García et al. / European Journal of Medicinal Chemistry 49 (2012) 1e23

O
O

H CO2H H CO2H

H H
H
HO HO
H H HO

61 62 63
OH
O
O

H H CO2H
O
H H
H HO
HO
HO H H

64 65 66

isolated from Diospyros decandra, exhibited activity against

M. tuberculosis H37Ra with a MIC of 25 mg/mL [41]. On the other
hand, the new seco-taraxane-type triterpene 67, isolated from
Elateriospermun tapos, was reported to exhibit potent activity 70
against M. tuberculosis H37Ra with a MIC of 3.13 mg/mL, which was
OH
comparable to control kanamycin (MIC of 3.13 mg/mL) [42]. Inves- OH
tigation of the whole plant Blepharodon nitidum allowed the
isolation of two known hydroperoxycycloartanes (68 and 69),
which exhibited moderate activity against M. tuberculosis H37Rv OH
HO
with a MIC of 25 mg/mL; however, triterpene 69 showed potent 71
activity towards a multi-drug resistant strain with a MIC of
12.5 mg/mL, while compound 68 caused moderate inhibitory
activity (MIC of 25 mg/mL) [43]. 3. Steroids

Two known steroids, ergosterol peroxide (72) and b-sitostenone

OOH (73), were isolated from the leaves and twigs of R. boniana as
antitubercular (M. tuberculosis H37Rv strain) compounds with MICs
of 3.5 and 39.5 mM, respectively. The potent bioactivity of
CO2H compound 72 must be highlighted because of its lacking toxicity
H3CO2C against Vero cells at 200 mM and its remarkable selectivity (SI > 57),
H3CO2C which makes it a very promising antitubercular lead for further
HO
drug development [36]. The antitubercular activity of 72 supports
67 68 findings in a report published in 2007, in which investigation of
Dracaena angustifolia afforded the same compound with a MIC less
OOH than 2.0 mg/mL towards the same strain [46].
A new epidioxysterol (74) was isolated from the fungus Stereum
hirsutum together with a known one (75). Both sterols exhibited
significant activity against M. tuberculosis H37Rv with MICs of
HO 16 mg/mL [47]. The bioassay-guided fractionation of the organic
extract, obtained from the Caribbean Sea sponge Zvenzea zeai,
69
allowed the isolation and characterization of two new antituber-
cular steroids, parguesterol A (76) and B (77). The novel 6-5-6-5
fused rings sterols [5(6 / 7)abeo-sterols] 76 and 77, exhibited not
only remarkable activity against M. tuberculosis H37Rv with MICs of
Previous reports have shown that squalene (70) exhibited 7.8 and 11.2 mg/mL, respectively, but also modest toxicity against
poor activity towards M. tuberculosis H37Rv (MIC of 100 mg/mL), Vero cells (with IC50 values of 52 mg/mL) and modest selectivity
but no activity against M. tuberculosis H37Ra; however, a struc- (SI < 7) [48].
turally related triterpene named tetrahydroxysqualene (71)
exhibited potent activity against M. tuberculosis H37Rv (MIC of 4. Alkaloids
10 mg/mL), moderate toxicity against Human T-cells (IC50 of
25.5 mg/mL), and no selectivity (SI < 2.6) [44]. Interesting results The next largest group of antitubercular natural products
were observed for squalene (70) when it was tested against the includes alkaloids with complex structures and potent inhibitory
susceptible M. tuberculosis 90-221387 strain exhibiting a MIC of activity against susceptible M. tuberculosis isolates and, in some
28 mg/mL [45]. cases, towards resistant strains. Five new indole alkaloids
 A. García et al. / European Journal of Medicinal Chemistry 49 (2012) 1e23 7

O O
O H H O H
HO O HO
72 73 74 R= H

75 R = CH3

H H
H H
HO H H
HO
CHO HO CHO
76 77

ambiguine K (78), L (79), M (80), and N (81), isolated from the
culture broth of cyanobacterium Fischerella ambigua, showed
potent and moderate inhibitory activity against M. tuberculosis
H37Rv with MICs of 6.6, 11.7, 7.5, and 46.7 mM, respectively [49]. In
this study, the authors also reported six known indole alkaloids
named ambiguine A isonitrile (82), ambiguine C isonitrile (83),
ambiguine E isonitrile (84), ambiguine I isonitrile (85), hapalindole
G (86), and hapalindole H (87), which exhibited antitubercular
activity with MICs of 46.7, 7.0, 21.0, 13.1, 6.8, and 58.8 mM, respec-
tively [49]. Reinvestigation of F. ambigua afforded two new indole
alkaloids, fischambiguine B (88) and ambiguine G nitrile, (89) with
significant inhibitory activity against M. tuberculosis H37Rv at MICs
of 2.0 and 53.7 mM, respectively. Fischambiguine B (88) exhibited
low cytotoxicity against Vero cells with an IC50 of 128 mM, which
makes it very selective as an antimycobacterial (SI of 64). The
antitubercular results suggested that the spiro-epoxy six-
membered ring E in the structure of 88 is essential to its potent
activity [50].
activity against M. tuberculosis H37Rv at MICs of 15.3 and 2.0 mg/mL,
respectively [51]. A new bis-piperidine alkaloid neopetrosiamine A
(92) was isolated as an antitubercular compound from the sea
sponge Neopetrosia proxima. Neopetrosiamine A (92) exhibited
potent activity towards M. tuberculosis H37Rv with a MIC of 7.5 mg/
mL, poor toxicity against Vero cells with an IC50 of 42.4 mg/mL, and
modest selectivity (SI of 5.7) [52]. Bioassay-guided fractionation of
the marine sponge Haliclona sp 05A08 afforded the new tetracyclic
diamine alkaloid halicyclamine A (93), which exhibited significant
growth inhibition of M. tuberculosis H37Ra under aerobic and
hypoxic conditions with MICs in the range of 1.0e5.0 mg/mL [53].
Reinvestigation of extracts from the ascidian Lissoclinum notti and
Diplosoma sp. led to the isolation of reported pyridoacridone alka-
loids named ascididemin (94), diplamine (95), isodiplamine (96),
lissoclinidine (97), kuanoniamine D (98), and shermilamine B (99),
which exhibited moderate activity towards M. tuberculosis H37Rv
with MICs of 0.35, 17, 17, 17, 34, and 32 mM, respectively. Despite the
potent antitubercular activity of ascididemin (94), further consider-

R R R3

HO HO R2
OH NC
H NC H NC H
R1
NH NH NH
78 R = Cl 80 R = Cl 82 R1 = R2 = H R3 = Cl
79 R = H 81 R = H
83 R1 = R2 = OH R3 = H
R
86 R1, R2 = H R3 = Cl
H
HO
O NC Cl Cl
NC H
H
OH
NH
NH
87 H CN O H CN
84 R = Cl

85 R = H NH NH
88 89

Bioassay-guided fractionation of the marine sponge Hymenia- ation in drug development is not feasible because of its high toxicity
cidon sp afforded an interesting new diterpenoid b-lactam alkaloid against Vero cells with an IC50 of 0.14 mM (SI values < 1). In addition,
named monamphilectine A (90), along with the known 8,15- the authors synthesized two natural pyridoacridone alkaloids,
diisocyano-11(20)-amphilectene (91), which exhibited potent 11-hydroxyascididemin (100) and kuanoniamine A (101), which
8 A. García et al. / European Journal of Medicinal Chemistry 49 (2012) 1e23

O
N NC
HN H3C CH3 N
H3C CH3 O N N OH
N OH H
CH3 H H
CH3 H
H OH
H OH N
N
H H
H H
CN H N
H N
CN CH3
CH3
90 91
O
104
105
H
H H N N R
N
N H H
H N
H N H
OH
H N

H N

92 93

106 R= H

107 R = OH
inhibited M. tuberculosis H37Rv with MICs of 42 and 10.7 mM,
respectively [54]. Two known bromine-bearing pyrroles hymenidin
(102) and monobromoisophakellin (103), isolated from the Carib-
Investigation of the Jamaican sponge Monanchora unguifera led
bean sponge Prosuberites laughlini, exhibited antitubercular activity
to the isolation of three new polycyclic guanidine alkaloids named
towards the H37Rv sensitive strain. Hymenidin (102) showed a MIC
batzelladine L (108), M (109), and N (110), along with three known
of 6.1 mg/mL, a higher potency than its congener 103, which exhibited
alkaloids batzelladine C (111), dehydrobatzelladine C (112), and
a MIC of 64 mg/mL [55].
crambescidine 800 (113). The guanidine alkaloids 108 and 110

R O O O O
N
HN HN HN

N H
H
N R1 N S N S N

94 R=H O N
O
100 R = OH N N N
R2
O 95 R1 = SCH3 R2 = H 97 98

96 R1 =H R2 = SCH3 Br H
HN
N Cl
H NH2
H N N N
S N H H
O Br
O
O N S N 102 H H NH
H N
N H2N
N
N N
99 N

101 103

Four reported manzamine alkaloids ()-8-hydroxymanzamine
A (104), ()-manzamine F (105), manzamine A (106), and (þ)-8-
hydroxymanzamine A (107) were tested against M. tuberculosis
H37Rv, exhibiting MICs of 0.91, 12.5, 1.56, and 6.25 mg/mL, respec-
tively. Biotransformation of manzamine alkaloids 104e107 yielded
13 derivatives with MICs of 6.25 mg/mL, but their structures are not
displayed in this revision because they were found to be less active
than natural products 104 and 106 [56].
exhibited the most potent inhibitory activity against M. tuberculosis
H37Rv (ATCC 27294) with MICs of 1.68 and 3.18 mg/mL, respectively,
while alkaloids 109 and 111e113 exhibited moderate activity with
MICs of 28.5, 34.7, 37.7, and 46.5 mg/mL, respectively [57].
Quinoline alkaloids 4-methoxy-2-phenylquinoline (114),
graveolinine (115), and kokusagine (116), isolated from Lunasia
amara, displayed significant activity towards M. tuberculosis H37Rv
with MICs of 16 mg/mL [58]. The known quinoline alkaloids
 A. García et al. / European Journal of Medicinal Chemistry 49 (2012) 1e23 9

H H
N
O
O
N N H
H H H
N
N O H 109
H
N N
N N O N H 6
H
108 N N
H 8
O
H H
H H H2N N
O N
N O
H NH
N N
N N O N
H 111 H 6

110 N N
H 6 NH2
H O NH2

3
O H 2
H H N
H2N N N O 15
O N OH
O
NH N N
N N O H O
6
112
113

dictamnine (117) and g-fagarine (118), isolated from roots of Zan- Six cyclostelletamine alkaloids named cyclostelletamines AeF
thoxylum wutaiense, were reported to exhibit moderate antituber- (119e124), isolated from sponge Pachychalina sp, inhibited the
cular activity (H37Rv strain) with MICs of 30 mg/mL [59]. growth of M. tuberculosis H37Rv with MICs of 32, 4.0, 4.0, 8.0, 11.0,
and 8.0 mg/mL, respectively [60]. An interesting dimeric alkaloid
OCH3 OCH3 named hirsutellone F (125), isolated from the seed fungus of Tri-
choderma sp BCC 7579, exhibited potent activity against
M. tuberculosis H37Ra with a MIC of 3.12 mg/mL [61]. A carbazole
N O alkaloid 7-hydroxymukonal (126) was isolated from the roots of
N
Clausena harmandiana as a modest inhibitor of mycobacterial
O (M. tuberculosis H37Ra) growth with a MIC of 25 mg/mL [62].
114 115 A novel pyridine N-oxide alkaloid (127), isolated from Allium stip-
itatum, caused the inhibition of M. tuberculosis H37Rv (ATCC 27294)
OCH3 OCH3 with a MIC of 1.25 mg/mL. The disulphide 127 was also tested in
a mouse model of tuberculosis infection at an oral dose of 20 mg/kg,
but no significant activity was observed in the reduction of bacteria
N O O in lungs and spleens compared to the untreated controls [63].
O N
O A potent antitubercular (M. tuberculosis H37Ra, MIC of 6.25 mg/
R
mL) dimeric aporphine alkaloid, bidebiline E (128), was isolated
116 117 R=H from the roots of P. cerasoides [15]. Two oxoaporphine alkaloids
named liriodenine (129) and oxostephanine (130) (from Pseudu-
118 R = OCH3
varia setosa), exhibited moderate antitubercular activity with MICs
of 12.5 and 50 mg/mL, respectively [64]. Investigation of flowers of

H
Y H
N
N OH O
H H H
H NH O
X N O

119 X=3 Y=3 O O

O H O H
H H
120 X=3 Y=4
H
X=4 Y=4 125
121 H

122 X=3 Y=5 S

OHC OCH3 N S
123 X=4 Y=5 O
HO N
H 127
124 X=5 Y=5
126
10 A. García et al. / European Journal of Medicinal Chemistry 49 (2012) 1e23

Goniothalamus laoticus afforded a known aporphine alkaloid towards M. tuberculosis H37Ra with MICs of 50, 50, 50, 50, 12.5, and
()-nordicentrine (131), which exhibited activity against 12.5 mg/mL, respectively [68]. The previous described study of
M. tuberculosis H37Ra with a MIC of 12.5 mg/mL [65]. Dalbergia parviflora led to the isolation of the known flavanone
pinocembrine (154) and the new isoflavone dalparvone (155),
O which were reported to exhibit significant and moderate activity
OCH3 against M. tuberculosis H37Ra with MICs of 12.5 and 50 mg/mL,
O NH
respectively [69].

5.2. Chalcones, coumarins

O One known coumarin, scopoletin (156), and two known chal-

OCH3 HN
cones, isobavachalcone (157) and compound 158, were isolated as
O antitubercular constituents of the whole plant Fatoua pilosa. Chalcone
128 157 was the most active against M. tuberculosis H37Rv with a MIC of
O O 18 mg/mL, while compounds 156 and 158 exhibited moderate activity
with MICs of 42 and 30 mg/mL, respectively [70]. Bioassay-guided
O N NH
O fractionation of Helichrysum melanacme afforded two new chal-
H cones 159 and 160, which exhibit potent antitubercular activity with
O MICs of 0.05 mg/mL [71].

R H3CO
5.3. Lignans, other phenols
129 R=H OCH3
130 R = OCH3 131 Three new epoxyfuranoid lignans, 4a,5a-epoxybeilschmin A
(161) and B (162), and beilschmin D (163), together with known
beilschmin A (164) and B (165), were isolated from leaves of
Beilschmiedia tsangii as antitubercular (M. tuberculosis 90-221387
Four pyrrolidine alkaloids, sarmentine (132), pyrrolidine 133,
strain) constituents with MICs of 30, 40, 50, 2.5, and 7.5 mg/mL,
sarmentosine (134) and brachyamide B (135), and two alkyl amides,
respectively [45]. Compound 164 was more active than drug
pellitorine (136) and brachystamide B (137), were isolated from
ethambutol (6.2 mg/mL) [45].
roots of Piper sarmentosum. Alkaloids 132e137 exhibited moderate
Bioassay-guided fractionation of roots from Litsea hypophaea
inhibitory activity against M. tuberculosis H37Ra with MICs of 50,
led to the isolation of a known phenylpropanoid amide,
25, 50, 50, 50, and 50 mg/mL, respectively [66].
feruloyltyramine 166, which potently inhibited mycobacterial

O O
O N
N
n

132 O
O 134 n = 1
135 n=3
N
H
136
O
O
O N
O N 7 H
O
O 133 137

5. Flavonoids, chalcones, coumarins, lignans, other phenols
5.1. Flavonoids
Three new prenylated flavonoids khonklonginol A (138), B (139),
and H (140), together with five known flavonoids lupinifolinol
(141), dehydrolupinifolinol (142), flemichin (143), eriosemaone A
(144), and lupinifolin (145), isolated from roots of Eriosema chi-
nense, were reported to show significant growth inhibition of
M. tuberculosis H37Ra with MICs of 25, 50, 25, 25, 12.5, 12.5, 12.5,
and 12.5 mg/mL, respectively [67]. Two new flavonoids 146 and 147,
isolated from roots of Derris indica, were reported to exhibit
significant activity against M. tuberculosis H37Ra with MICs of 25
and 6.25 mg/mL, respectively. In addition, six known flavonoids,
demethoxykanugin (148), 3,7-dimethoxyflavone (149), lacheolatin
B (150), maackiain (151), karanjachromene (152), and pinnatin
(153), were also isolated, which cause significant growth inhibition
growth (M. tuberculosis H37Rv) with a MIC of 1.6 mg/mL, more
active than positive control ethambutol (MIC of 6.25 mg/mL) [72].
A new cinnamyl derivative dalparvinene (167), isolated from
stems of D. parviflora, was reported to exhibit moderate activity
against M. tuberculosis H37Ra with a MIC of 50 mg/mL [69]. The
simple aromatic caffeic acid methyl ester 168, isolated from
C. calcarea, was found to exhibit moderate activity against
M. tuberculosis H37Ra with a MIC of 25 mg/mL [16]. Rhizomes of
Kaempferia galanga afforded the known ethyl p-methox-
ycinnamate (169), which inhibited the growth of M. tuberculosis
H37Ra and H37Rv with MICs of 0.485 and 0.242 mM, respec-
tively, as compared to control pyrazinamide (MIC of 0.81 mM)
[73]. On the other hand, the curcuminoid demethoxycurcumin
(170), isolated from rhizomes of Curcuma longa, caused no inhi-
bition of M. tuberculosis H37Rv at a MIC of 200 mg/mL; however,
its derivative 171 exhibited potent antitubercular activity with
a MIC of 7.182 mg/mL [74].
 A. García et al. / European Journal of Medicinal Chemistry 49 (2012) 1e23 11

R3 OH

O O O O

R2
R1 OH
OH O OH O

138 R1 = βOH R2 = H R3 = OCH3 142

139 R1 = αOH R2 = H R3 = OCH3 OH

O O
140 R1 = H R2 = OH R3 = OCH3
OH
141 R1 = βOH R2 = H R3 = OH
OH O
143 R1 = H R2, R3 = OH
144
R1, R2 = H R3 = OH O R1
145
O R2

O H3CO O H3CO O
O
O
O OCH3
O OH
O O
O O 147
148 R1 + R2 = O-CH2-O

OCH3 149 R1 = R2 = H
O O
O
146 O
O
O
HO O O
150
H CH3O O
O O
H 153
O O
OCH3
O
151 O
152
HO O
OCH3
HO O

OH O
OCH3
OH O
OH
154 155

OH
OH O

H3CO HO HO

HO O O
OH O OH O
156

157 158
OH

HO OH O OH

OH O OH O
159 160
12 A. García et al. / European Journal of Medicinal Chemistry 49 (2012) 1e23

R2O O OR4 H3CO OR2

O O
R1O OR3 H3CO OR1

H3CO OCH3 H3CO OCH3

164 R1 + R2 = CH2
161 R1 = R2 = CH3 R3 + R4 = CH2

162 165 R1 = R2 = CH3

R1 = R2 = R3 = R4 = CH3

163 R1 + R2 = R3 + R4 = CH2

HO OCH3
H OH
N OCH3
H3CO
O HO OCH3
OH
167
166 OCH3
O
HO O
O OH
O
HO 168
H3CO
169
HO OH
O OH
170 OCH3

O O
O O
O OCH3 O
171

6. Polyketides and simple aromatics In addition to the described antitubercular hopane-type tri-
terpene 56, two new bioxanthracenes 175 and 176 were reported to
6.1. Xanthones, anthracenes, anthraquinones, naphthalenes, exhibit weak antitubercular activity against sensitive strains
quinones (M. tuberculosis H37Ra) with MICs of 75 mM [35]. The new dep-
sidone mollicellin K (177), isolated from fungi Chaetomium brasi-
The significant antitubercular activity (MIC of 15.24 mM) of the liense, was reported to exhibit significant activity against
prenylated xanthone a-mangostin (172), previously isolated from M. tuberculosis H37Rv with a MIC of 12.5 mg/mL [77].
Garcinia mangosta, was improved after its fungal transformation to Investigation of roots of Rumex nepalensis and Rumex hastatus
derivative a-mangostin-3-sulphate (173), which showed a MIC of afforded a new antitubercular naphthalene acylglucoside,
6.75 mM [75]. Bioassay-guided fractionation of roots of Ehretia rumexneposide A (178), together with four known antitubercular
longiflora allowed the isolation of the new antitubercular quinone, naphthalene and anthraquinones, torachrysone (179), nepodin-
ehretiquinone (174), which showed moderate activity against 8-O-b-D-glucopyranoside (180), torachrysone-8-O-b-D-glucopyr-
M. tuberculosis H37Rv with a MIC of 25 mg/mL [76]. anoside (181), and chrysophanol-8-O-b-D-glucopyranoside (182),
which showed MICs of 20.7, 6.1, 26.6, 8.9, and 4.1 mM, respec-
tively [78].
Two new naphthalenones 183 and 184 and one new dimeric
O OH naphthoquinone 185, together with known naphthalenone 186 and
H3CO naphthoquinones 187 and 188, were isolated from the culture broth
of Phaeosphaeria sp BCC8292 and tested against sensitive
HO OH M. tuberculosis H37Ra strains. Naphthoquinones 185 and 188 were
found to be the most potent with MICs of 6.25 and 0.39 mg/mL,
172 O respectively, while compounds 183, 184, 186, and 187 showed
O moderate activity with MICs of 12.5, 25, 12.5, and 12.5 mg/mL,
O OH respectively [79]. Compound 188 exhibited the most promising
H3CO HO antimycobacterial activity (MIC of 0.39 mg/mL), but it showed
O potent activity against Vero cells (IC50 of 0.33 mg/mL) and no
HO OSO3H selectivity (SI < 1) [79]. Cultured cyanobacteria Eucapsis sp. (UTEX
1519) produced a new anthraquinone named eucapsitrione (189),
173 174 which inhibited growth of M. tuberculosis with a MIC of 3.1 mM [80].
Investigation of roots of Engelhardia roxburghiana afforded a new
 A. García et al. / European Journal of Medicinal Chemistry 49 (2012) 1e23 13

CH3O OH CH3O OH

O O O

H3CO H3CO O
O
O2CCH3 O2CCH3
HO O
O2CCH3 O2CCH3
CHO
H3CO H3CO OH
177
O O

CH3O OH CH3O OH
175 176

O
OR2 OH OH O
HO O
HO O
O
H3CO HO O O OH
HO O OH O
OH
OH 179

R1
OH O O
OH O
178 R1 = H R2 = 182
O
180 R1, R2 = H OCH3 H3CO OH
OH OH
181 R1 = OCH3 R2 = H 183 184

naphthoquinone, engelharquinone (190), and two known quinones,
2-methoxyjuglone (191) and 3-methoxyjuglone (192), which were
reported to inhibit M. tuberculosis H37Rv with MICs of 20, 30, and
3.125 mg/mL, respectively [81]. A congener, 7-methyljuglone (193),
isolated from roots of Euclea natalensis, exhibited potent activity
against M. tuberculosis H37Rv, two clinical isolates (WC 64/02 and
WH 51/02) with MICs of 0.5 mg/mL, and moderate toxicity against
lymphocytes (SI < 8) [82].
Three known a-tocopheroids, a-tocospiro A (194) and B (195),
and a-tocopherylquinone (196), isolated from leaves of P. lucida, were
reported to exhibit moderate activity against M. tuberculosis H37Rv
with MICs of 30, 50, and 25 mg/mL, respectively [32]. Leaves and twigs
of C. pilosissima contained not only seco-abietane diterpenes but also
the a-tocopherol trimer B (197), which exhibited potent antituber-
cular activity with a MIC of 31.2 mM towards M. tuberculosis H37Rv,
while control ethambutol exhibited a MIC of 30.6 mM [25].

O O OH O R OH O
HO OH H3CO OCH3

HO H3CO OCH3
OH O CH3 OH O OH O
186 187 R= H
185

OH O OH O 188 R = OCOCH3
O
OH O
OCH3
HO
O O OH O HO
189 190 OH O
OH O O
191
OCH3 H3C

O OH O
192 193
14 A. García et al. / European Journal of Medicinal Chemistry 49 (2012) 1e23

O HO O HO
O O
O O

194 195

O O
O O
O
O
O
O HO C16H33
C16H33
196 197 C16H33

A new azaphilone chaetoviridine E (198), isolated from fungi
Chaetomium cochloides VTh01 and CTh05, showed moderate
activity against M. tuberculosis H37Ra with a MIC of 50 mg/mL [83].
From roots of Cordia globifera a new terpenoid benzoquinone
globiferin (199), together with two known quinones, cordiach-
rome C (200) and B (201), were isolated, which inhibited
M. tuberculosis H37Ra with MICs of 6.2, 1.5, and 12.5 mg/mL,
respectively [84].
M. tuberculosis H37Ra with MICs of 25, 25, 50, and 50 mg/mL,
respectively [87].
6.2. Cyclic and linear esters
Interesting polycyclic antibiotics, ()-abyssomicin C (208) and
()-atrop-abyssomicin C (209), caused growth inhibition of
M. tuberculosis H37Rv with MICs of 3.6 and 7.2 mM, respectively,

Cl
O O O
O

O
O
H H
O O O O
O 199 200 201
198
OH O
H
O N
CH3O HO N O O H3CO O
H
H
OH O HO
OCH3
H3CO O
O 204
203
202 OCH3 OH O

OH O OH O
O O
OH OH
H3CO O O O
205
206 207

One new complex benzopyran-type flavagline, desacetylpyr-
amidaglain D (202), isolated from the leaves of Aglaia forbesii,
showed moderate activity against M. tuberculosis H37Ra with
a MIC of 25 mg/mL [85]. Study of roots of Bauhinia purpurea
afforded a new dihydrodibenzoxepin, bauhinoxepin J (203), which
was reported to exhibit inhibitory activity of M. tuberculosis H37Ra
with a MIC of 24 mg/mL [86]. Two new chromones, perforamone B
(204) and D (205), together with the known peucin-7-methyl
ether (206) and greveichromenol (207), isolated from branches
of Harrisonia perforata, were reported to inhibit the growth of
which makes them more active than ethionamide (MIC of 18 mM)
[88]. Investigation of L. hypophaea afforded one new antitubercular
butanolide, litseakolide L (210), which was found to moderately
inhibit M. tuberculosis H37Rv with a MIC of 25 mg/mL [72]. An
endiandric acid analogue named erythrophloin C (211), isolated from
roots of B. erythrophloia, exhibited moderate activity of M. tuberculosis
H37Rv with a MIC of 50 mg/mL [14]. Two known styryllactones,
(þ)-altholactone (212) and howiinin A (213), isolated from flowers of
G. laoticus, were reported to exhibit potent activity against
M. tuberculosis H37Ra with the same MICs of 6.25 mg/mL [65].
 A. García et al. / European Journal of Medicinal Chemistry 49 (2012) 1e23 15

H3C CH3 H3C CH3 O O

H
O O O O
O O H
H
O O H H
O O
CH3 CH3 H
OH OH 211
208 209
O

1
HO 2 O O
H
H
O O
O O
H3CO O O OH H O H
210 212 213

6.3. Acetylenic and branched-chain fatty acids
Five-membered ring polyketide endoperoxides epiplakinic acid
F methyl ester (214), plakortolides J (215) and F (216), isolated from
the sponge Plakortis halichodriodes, showed modest activity against
M. tuberculosis H37Rv with MICs of 62, 71, and 59 mg/mL, respec-
tively. Interestingly, chemical derivatization of 214 and 215 yielded
lactones 217 and 218, which exhibited higher antitubercular
activity than their congeners with MICs of 30 and 13 mg/mL,
respectively [89].
and modest antitubercular selectivity (SI of 6.2) [91]. Structural
related polyyne 225, isolated from A. sinensis, showed potent anti-
mycobacterial activity against the pathogenic Erdman strain (MIC of
1.4 mg/mL) and moderate activity towards the H37Rv strain (MIC of
25.3 mg/mL) [92]. Significant antitubercular activity was observed
with the new metabolite phomoenamide (226), isolated from fungi
Phomopsis sp. PSU-D15, which exhibited a MIC of 6.25 mg/mL [93].
Three new cyclopentylalkynoic acids, anthelminthicins A (227),
B (228), and C (229), together with known chaulmoogric acid (230)
and ethyl chaulmoograte (231), isolated from seeds of Hydnocarpus

CO2CH3
H3C O O CH3
214
CH3 CH3
O
O
CH3 CH3 O
O 215 O
H
O
O
HO 216 O OH
H CH3
H3C
O
CH3 CH3
O 217 O
O
HO
HO
218 H

Bioactivity-guided fractionation of stems of Exocarpus latifolius
allowed the isolation of new antitubercular polyacetylenic fatty
acids, exocarpic acid (219) and natural analogues 220 and 221, which
exhibited moderate activity against M. tuberculosis H37Ra with MICs
of 20, 25, and 25 mg/mL, respectively. Additionally, 219 was found to
inhibit M. tuberculosis H37Rv under aerobic and low oxygen condi-
tions with MICs of 20 and 87 mg/mL, respectively [90]. Preliminary
analysis of microarrays for 219 showed a dose dependent up-
regulation of lipid metabolism and channel-transporter genes in
M. tuberculosis H37Rv, therefore authors suggested that 219 inter-
feres with its fatty acid metabolism [90]. P. cerasoides allowed the
isolation of a new octadeca-9,11,13-triynoic acid (222), which was
found to exhibit potent activity against M. tuberculosis H37Ra with
a MIC of 6.25 mg/mL [15]. Polyyne oplopandiol (223), isolated from
stem bark of Oplopanax horridus and roots of Angelica sinensis,
showed activity against M. tuberculosis with MICs of 61.5 (H37Ra)
and 50.2 (H37Rv) mg/mL, while its congener falcarindiol (224)
exhibited potent antimycobacterial activity with a MIC of 6.2 mg/mL
anthelminthica, were reported to exhibit potent activity against
M. tuberculosis H37Rv with MICs of 5.54, 16.70, 4.38, 9.82 and
16.80 mM, respectively [94].
Three new linear polyacetylenic C25 and C27 acetogenins,
debilisones B (232), C (233), and E (234), isolated from roots of
Polyalthia debilis, inhibited the growth of M. tuberculosis H37Ra
with MICs of 25, 12.5 and 25 mg/mL, respectively [95]. One known
furanoid polyacetylene 235 was isolated from roots of Polyalthia
evecta and tested against M. tuberculosis H37Ra. Compound 235
showed a MIC of 6.25 mg/mL, which was less potent than the
synthetic 236, which exhibited a MIC of 3.1 mg/mL [96].
Whole plant of Euphorbia platyphyllos afforded a new cerebro-
side 237, which exhibited activity against M. tuberculosis H37Rv and
H242 strains with the same MIC of 40 mg/mL [97]. Four new acyl-
ated tetrasacharides, tyrianthinic acids 238e241, isolated from
roots of Ipomoea tyrianthina, caused moderate inhibition of myco-
bacterial growth (M. tuberculosis H37Rv ATCC 27294) with the same
MICs of 25 mg/mL [98].
16 A. García et al. / European Journal of Medicinal Chemistry 49 (2012) 1e23

R O O OH

OH O
6 6
OH
2 2 221
219 R= H

220 R= OH OH

O
HO 222

OH HO
223
OH
OH 224
O O OH
HO H
O N
225 N
H
OH O
226

15.6 mg/mL [99]. Bioassay-guided fractionation of roots of E. long-

O O iflora resulted in the isolation of quinone 174 and a known aromatic
243, which showed moderate activity against M. tuberculosis H37Rv
OH
with MICs of 30 mg/mL [76]. The roots of P. sarmentosum also
227 afforded an aromatic alkene (253), which was found to moderately
inhibit M. tuberculosis H37Ra with a MIC of 25 mg/mL [66]. Two
O known acylphenols malabaricone A (245) and dodecanoylphlor-
oglucinol (246), isolated from fruits of Knema glauca, exhibited
O OH moderate activity against M. tuberculosis H37Ra with MICs of 25
n
OH and 50 mg/mL, respectively [100].
228 n=1 Investigation of C. globifera also allowed the identification of one
hydroquinone, alliodorin (247), and two chromenes, elaeagin (248)
229 n=5
and cordiachromene (249), which showed significant antituber-
cular activity with MICs of 12.5 mg/mL [84]. Bioassay-guided frac-

O O

O 3
OH
5

230 231
O
O
7
7 O
O OH

OH 233
OH 232
11
OH
O
O
7
O
235
O O
OH 234 11
OCH3
236

6.4. Simple aromatics, hydroquinones, chromenes, benzofurans
Searches for antitubercular lichen substances resulted in the
identification of depsidone diffractaic acid (242), which showed
significant activity towards M. tuberculosis H37Rv with a MIC of
tionation of the root of Z. wutaiense afforded two new benzofuran
analogues, methyl 7-methoxyanodendroate (250) and 7-
methoxywutaifuranal (251), along with one known wutaiensal
(252), which were reported to inhibit M. tuberculosis H37Rv with
MICs of 35, 35, and 30 mg/mL, respectively [59].
 A. García et al. / European Journal of Medicinal Chemistry 49 (2012) 1e23 17

O HO
HO O
HN
14 6
O HO OH
OH OH
HO HO
OH HO O
O O
HO O HO
OH 6 OH O O
OH
O O O
237 HO O
OH HO O
HO O
HO O 240 O
HO
HO O O HO
HO
HO O
O O HO OH

HO O O HO
HO O HO O O
OH O HO
O R
O O
O O
O O O
HO O
238 R= Ethyl OH HO O

239 R= sec-Butyl 241 O

CH3 H3CO OH O
OH
CO2H
CH3 O 7

O OH OH OH
CH3
H3CO OCH3 243 245
CH3
HO
242 HO
CHO
OH O O CHO
OH
248 R= CHO
9 247
249 R= CH3
HO OH O
246 O O
H
OCH3 O H
HO HO
O OCH3 O
OCH3 251 OCH3
250 252

7. Peptides The pathogenic bacteria Nocardia pseudobrasiliensis produced

Interesting natural products of this group include three novel
aminolipopeptides, trichoderin A (253), A1 (254), and B (255),
isolated from the marine sponge derived fungus of Trichoderma
sp. 05FI48 strain, which showed potent inhibitory activity
towards M. tuberculosis H37Rv under aerobic and hypoxic
conditions with MICs of 0.12, 2.0, and 0.13 mg/mL, respectively
[101]. The proline-rich peptide pitiprolamide (256), isolated from
the cyanobacteria Lyngbya majuscula, was reported to possess
weak antitubercular activity in the Disk Diffusion Assay with
a diameter of zone of inhibition of 13 mm at 50 mg and 26 mm at
100 mg [102]. Investigation of fungus Streptomyces sp. SS afforded
the new nucleosidyl-peptides sansanmycin A (257), F (258) and G
(259), which showed significant antitubercular activity towards
M. tuberculosis H37Rv (ATCC 27294) with the same MIC value of
16 mg/mL [103,104].
a new thiopeptide nocardithiocin (260), which potently inhibi-
ted the growth of susceptible M. tuberculosis H37Rv strain and
a resistant strain to rifampicin with MICs of 0.025e6.25 and
0.025e46.25 mg/mL, respectively [105]. The culture broth of
Mortierella alpina FKI-4905 produced a new hexapeptide calpi-
nactam (261), which exhibited moderate activity against
M. tuberculosis H37Rv sensitive strain with a MIC of 12.5 mg/mL
as determined by the Liquid Microdilution method [106]. A
novel cyclodepsipeptide named cordycommunin (262), isolated
from fungus Ophiocordyceps communin BCC 16475, was found to
inhibit the mycobacterial growth of a susceptible strain (H37Ra)
with a MIC of 15 mM [107]. The cyclohexadepsipeptides pul-
lularin A (263) and C (264), isolated from fungus Pullularia sp.
BCC 8613, exhibited modest inhibitory activity towards
M. tuberculosis H37Ra with MICs of 25 and 50 mg/mL, respec-
tively [108]. Fermentation broth of fungus Streptomyces lydicus
18 A. García et al. / European Journal of Medicinal Chemistry 49 (2012) 1e23

R1
O
O O
7 H
N N
N N
H H
O O
O O
H H H
N N N OH
N N N
H H
O O

R2
OH O
253 R1 = R2 = CH3

O
254 R1 = R2 = CH3

OH O
255 R1 = R2 = H

H3CS
O H
N CO2H
O N O O O
NH O H
N O
N N N N NH
O H H H
O O
O N OH
O O OH
N O
O O NH2
N O 257
N
N H
H N CO2H
O O O
H
N O
256 N N N N NH
H H H
O O
H3CS N OH
H OH
N CO2H O
O O O
H HN
N O
N N N N NH
H H H
O O
N OH 259
OH
O
HN
258

led to the isolation of cyclodepsipeptide lydiamycin A (265),
which inhibited the growth of M. tuberculosis H37Rv and the
resistant strain No. 246 with MICs of 12.5 and 25 mg/mL,
respectively. The authors suggested that inhibition of the resis-
tant strain by 265 operates by a mechanism of action different
from that of control isoniazid, which showed no inhibition at
100 mg/mL [109].
8. Natural products towards specific targets
8.1. Inhibitors of fatty acid biosynthesis
Search for new mycothiol ligase inhibitors resulted in the
discovery of the highly active natural products, ochratoxin A (266),
borrelidin (267), cis-pentacin (268) and mupirocin (269), which
exhibited IC50 of 2.5, 2.0, 4.0, and 5.0 mM, respectively [110]. The
previously reported antitubercular thiolactomycin 270 (62.5 mM) was
tested against plant type II fatty acid synthases (FAS-II), which
provides essential building blocks for bacterial cell walls. Compound
270 was found to selectively inhibit the b-ketoacyl-acyl carrier
protein synthases (Kas A and B), which are involved in chain elon-
gation of meromycolic acids in the FAS-II system of M. tuberculosis.
This thiotetronic acid-containing natural product 270 exhibited
potent inhibitory activity against KasA and B with MICs of 4 and 6 mM,
respectively. On the other hand, 270 showed no significant inhibition
of the human FAS-I system (MIC higher than 100 mM) [111,112].
Related new congeners pseudopyronines A (271) and B (272),
isolated from fermentation of Pseudomonas sp. F92591, were re-
ported to exhibit not only potent activity against M. tuberculosis
H37Rv but also against the bacterial enoyl-acyl carrier protein
reductase (Fab-I). Pyrones 271 and 272 inhibited mycobacterial
growth with MICs of 3.125 and 0.78e1.56 mg/mL, respectively,
while pyrone 272 was the only one that inhibited enzyme Fab-I
with an IC50 of 3.8 mM [113].
Previously described microarray data for the antitubercular
exocarpic acid (219) suggested inhibition of fatty acid metabolism
as its plausible mode of action [90]. Further microarray analysis
established that 219 inhibits the mycolic acid biosynthesis and that
probably targets some enzymes in the FAS-II system [114].
8.2. Inhibitiors of RNA polymerase
Two previously reported a-pyrones myxoporin A (273) (from
Myxococcus fuluus) and corallopyronin A (274) (from Corallococcus
coralloides), and the 14-membered macrolactone ripostatin A (275)
(from Sorangium cellulosum), were observed to potently inhibit the
 A. García et al. / European Journal of Medicinal Chemistry 49 (2012) 1e23 19

OCH3
O
NH O
HN N
N
O O O
S S H H H
N N N N NH
H2N N N
H H
O O O
N
S N
OH HO O
O N S OH
HO HN 261
O OH
NH
H2N O OH
N H
N
O NH S N
N HN HN O
H
O N O O N
H3CO O N
S O O O O
H O
O
260 NH O NH NH
H
N O N R
O
O O
HO
O
263 R= CH3
H NH
N 264 R= H
N OO 262
OO NH O
O
O N CO2H
N N
H
265

NH2
OH
O OH O CO2H
OH O
HO2C N O
H O 268
NC
CO2H H3C
Cl
266 S
267 O
OH
O HO
O O
270
HO O 8 CO2H OH
OH OH
269
O O
O O
272
271

bacterial RNA polymerase (RNAP, an enzyme involved in the tran-
scription functions for microbial growth) with IC50 of 1.0, 4.0, and
0.8 mM, respectively. An interesting fact is that these compounds
potently inhibited the bacterial RNAP, but not the mammalian
RNAP-II, as was observed for rifamycin (the first-line drug for
tuberculosis treatment) [115].
8.3. Inhibitors of p-aminobenzoic acid biosynthesis
The naphthalene torachrysone (179), previously described as
a constituent of Rumex species, was found to potently inhibit the p-
aminobenzoic acid (PABA) biosynthesis (an attractive pathway
found in bacteria but not in mammals) with a MIC of 12.6 mM,
which is comparable to the positive control abyssomicin C (8.3 mM)
[78]. The non-structurally related antitubercular anthelminthicin C
(229), from H. anthelminthica, inhibited the biosynthetic pathway
between chorismate and PABA with a MIC value of 11.3 mM, which
resembles the inhibitory activity of abyssomicin C [94].
8.4. Inhibitors of miscellaneous mechanism
The macrolide antibiotic thuggacin A (276), isolated from myx-
obacterium S. cellulosum, exhibited potent inhibitory activity against
M. tuberculosis H37Rv with a MIC of 8.0 mg/mL. In this study, the
authors suggested that tuggacin A (276) inhibited the cellular
electron-transport chain because of the complete inhibition of
20 A. García et al. / European Journal of Medicinal Chemistry 49 (2012) 1e23

O OH

H
N OCH3
O O HO O
O
273 O
CO2H
O OH O
275
H
OH N OCH3
O O
274 O

oxygen consumption at 2.5 ng/mL and inhibition of reduced nico-
tinamide adenine dinucleotide (NADH) oxidation at the cytoplasmic
membranes in Micrococcus luteus [116]. The cyanobacteria Tycho-
nema sp. afforded two new cyclohexapeptides, brunsvicamide B
(277) and C (278), which inhibited the M. tuberculosis protein tyrosine
phosphatase B (MptpB), involved in the interferon-g signalling
pathways with IC50 values of 7.3 and 8.0 mM, respectively. The enzyme
MptpB is a potential drug target for tuberculosis therapy since
mycobacterial cells excrete the enzyme in order to disrupt the
hostecell defence mechanism against such parasitism [117].
biosynthesis of required building blocks for bacterial cell walls
(mycolic acids, FAB-I and FAB-II, etc). On the other hand, myxoporin
A (273), corallopyronin A (274), and ripostatin A (275) inhibited the
mycobacterial RNAP, but not the mammalian RNAP-II. Additionally,
tuggacin A (276) showed inhibition of NADH oxidation while
cyclohexapeptides brunsvicamide B (277) and C (278) exhibited
inhibition of the enzyme MptpB. Finally, torachrysone (179) and
anthelminthicin C (229) inhibited PABA biosynthesis. Interestingly,
compounds 273e275, 179, and 229 exhibited specific inhibition
towards the mycobacterial RNAP activity and the PABA biosynthetic

HO
OH
HO

N O OH OH

S O

H
N CHO
276
NH

N N
NH NH
O O O
O NH O O NH O
O HN O O HN O
O O
HN O HN O
N N N N
H H H H
OH OH
277 278

9. Conclusion pathway, so those substances would be considered as useful scaf-

The present review compiled 278 natural products and some
derivatives isolated from plants, algae, fungi, cyanobacteria, and
sponges. Those molecules with antitubercular selectivity indexes
(SIs) higher than 10 and MICs less than 10 mg/mL would be
considered as promising leads for further investigations in the
development of new antitubercular drugs. For example, aegicerin
(65), ergosterol peroxide (72), parguesterol A (76), and fischambi-
guiene B (88) are remarkable scaffolds for drug development,
because of their potent antimycobacterial activity, their low or
negligible toxicity against Vero cells and their antitubercular
selectivity indexes higher than 10. During the last five years, little
progress has been made in the discovery of new natural products
towards specific mycobacterial targets. This review highlighted that
exocarpic acid (219), ochratoxin A (266), borrelidin (267), cis-pen-
tacin (268), and mupirocin (269) exhibited activity towards the
folds for structureeactivity relationship studies and further
development of new antituberculosis drugs.
Acknowledgements
We wish to express our gratitude to the “Facultad de Ciencias
Quimicas, Universidad Autonoma de Nuevo Leon”, IUPAC project
No. 2099-033-1-700: “A survey of research into new drugs for
neglected diseases in Latin America” and proofreader Sam Williams
for their support in this study.
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