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Isoquinoline Alkaloids and Their Antiviral, Antibacterial, and Antifungal

Activities and Structure-activity Relationship

Article  in  Current Organic Chemistry · October 2017

DOI: 10.2174/1385272821666170207114214

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Current Organic Chemistry, 2017, 21, 1-15 1

REVIEW ARTICLE

Isoquinoline Alkaloids and Their Antiviral, Antibacterial, and Antifungal Activities

and Structure-Activity Relationship

Zhi-Xing Qinga,b, Peng Yangb, Qi Tanga, Pi Chenga, Xiu-Bin Liua, Ya-jie Zhenga, Yi-Song Liua* and
Jian-Guo Zenga,b,c*

a
Hunan Co-Innovation Center for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha 410128,
China; bSchool of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China; cHunan Engineering Research
Center of Botanical Extraction, Changsha 410331, China

ARTICLE HISTORY
Received: March 17, 2016
Revised: July 02, 2016
Accepted: November 09, 2016
DOI:
10.2174/1385272821666170207114214
Abstract: The emergence of multidrug-resistant virus, bacteria and fungi has created an urgent need for the
development of novel antibiotic drugs from nature products with different mechanism of action. Therefore, in
this review, seventeen types of isoquinoline alkaloids, including benzyltetrahydroisoquinoline, benzylisoqui-
noline, bisbenzylisoquinoline, aporphine, tetrahydroprotoberberine, N-methyltetra-hydroprotoberberine, pro-
toberberine, protopine, benzophenanthridine, dihydrobenzophenanthridine, pavine, cularine, phthalideiso-
quinoline, spirobenzylisoquinoline, promorphine, morphine and ipecac, were screened and regarded as an at-
tractive target for the discovery of new antiviral, antibacterial and antifungal lead compounds or agents. Nota-
bly, sixteen types of alkaloids were biosynthesized from the central precursor benzyltetrahydroisoquinoline in
herbal medicine. Finally, the antiviral and antimicrobial activities of 210 isoquinoline alkaloids were uncov-
ered and the structure-activity relationships were also summarized. The quaternary nitrogen and the methyle-
nedioxy at C-2 and C-3 played an important role in increasing the antiviral, antibacterial and antifungal activ-
ity of N-methyltetrahydroprotober-berine, protoberberine and benzophenanthridine alkaloids.

Keywords: Isoquinoline alkaloids; antiviral; antibacterial; antifungal; antimicrobial; structure-activity relationship; HIV.

1. INTRODUCTION Isoquinoline alkaloids, such as anti-bacterial agent berberine,

Since widespread introduction antibiotics in the 1940s, antibiot-
ics agents make great contributions to the modernization of medi-
cine, and it is difficult to imagine the reducing morbidity and mor-
tality and increasing life expectancy of recent years without them.
However, the intensive use of antibiotics and the emergence of the
resistance limit the useful lifespan of antibiotics and result in the
requirement for a constant discovery of new compounds. Therefore,
producing new antibiotics in the 21st century has been an urgent
task [1-5]. Plant medicine and nature products have been used for
human health and served as a major source of drugs for a long time,
and about 50% of today’s pharmaceutical agents are derived from
nature origin. The growing interest in natural products as a source
of new antibiotics agents (antiviral, antibacterial and antifungal) or
lead compounds can be contributed to the urgent therapeutic re-
quirement and the wide range of chemical structure of natural sec-
ondary metabolites [6]. Teixobactin, which is a new antibiotic
without detectable resistance, has been successful discovered and
isolated recently from uncultured bacteria in their natural environ-
ment [1, 2]. Therefore, natural products are a good source for
screening new and high-efficiency antiviral, antibacterial and anti-
fungal drugs.
*Address correspondence to these authors at the Department of Hunan Co-Innovation
Center for Utilization of Botanical Functional Ingredients, Hunan Agricultural Univer-
sity, Changsha 410128, China; Tel/Fax: +86-731-84686560; E-mails:ginkgo@world-
way.net; liuyisong@vip.qq.com
palmatine, magnoflorine and sanguinarine, the antitussive and anti-
cancer drug noscapine, and the analgesic compounds morphine and
codeine, are a larger and diverse group of compounds within the
natural products kingdom and regarded as an important source for
the discovery new antibiotic agents or lead compounds [7, 8].
Therefore, in this review, seventeen types of isoquinoline alkaloids,
including benzyltetrahydro-isoquinoline, benzylisoquinoline, bis-
ben- zylisoquinoline, aporphine, tetrahydroprotoberberine, N-
methyltetrahydroprotoberberine, protoberberine, proto- pine, ben-
zophenanthridine, dihydrobenzophenanthridine, pavine, cularine,
phthalideisoquinoline, spirobenzyl- isoquinoline, promorphine,
morphine and ipecac, were screened for their antiviral, antibacterial
and antifungal activity. Notably, the benzyltetrahydroisoquinoline-
type alkaloid is the central precursor to biosynthesze the remaining
sixteen types of isoquinoline alkaloids in plant medicine (Fig. 1),
such as papaver somniferum [9-15]. Finally, the antiviral, antibacte-
rial and antifungal activity of 210 isoquinoline alkaloids was sum-
marized and the structure and activity relationship was also dis-
cussed.
2. BENZYLTETRAHYDROISOQUINOLINE AND BEN-
ZYLISOQUINOLINE ALKALOIDS
(S)-norcoclaurine (1), (R)-coclaurine (2), (R)-N-methylco-
claurine (3), armepavine (4) and lotusine (5) (Fig. 2) were isolated
from the leaves of Nelumbo nucifera (Nymphaceae) and regarded
as anti-HIV components. Alkaloids 1 and 2 possessed potent anti-

1385-2728/17 $58.00+.00 © 2017 Bentham Science Publishers

2 Current Organic Chemistry, 2017, Vol. 21, No. 00
Fig. (1). Biosynthetic pathways to various isoquinoline alkaloids derived from the central precursor benzyltetrahydro- isoquinoline (the positively charged and
uncharged fundamental skeletons are typical forms existing widely in the natural environment).
HIV activity with EC50 values of ＜0.8 and 0.8 µg/mL, respec-
tively, and their therapeutic index (TI) values were ＞25 and ＞125,
respectively. Alkaloids 3 and 4 showed comparable anti-HIV activ-
ity (EC50 ＜0.8 µg/mL), however, the cytotoxicity of those two
compounds (IC50 1.45 and 1.77 µg/mL for 3 and 4, respectively,
compared with＞100 µg/mL for 2) increased corresponding to the
existing of N-methyl. Therefore, alkaloids 3 and 4 exhibited low TI
values of ＞1.8 and＞2.2, respectively. Compound 5, which com-
prises a N, N-methyl moiety, demonstrated weak activity against
HIV with EC50 value of 20.7 µg/mL and less cytotoxicity with IC50
value of ＞100 µg/mL (Table 1) [16]. 5’-methoxylcoclaurine (6),
3’,5’-methoxylcoclaurine (7), tetrahydropapaveroline (11), N-
methyl-papaveroline (15), papaverine (16), N-methylpapaverine
(17), O-methyl-sevanine (18) and N-methyl-O-methylsevanine (19)
(Fig. 2) were tested against HIV, however, none of them display
anti-HIV activity. Those data indicated that the number of substitu-
ent of A-, C-ring (≥ 4, inactive) may be a significant factor for anti-
HIV activity [16-18]. The tested reticuline (8) and norjuziphine (10)
(Fig. 2) were observed to possess an inhibition effect against DNA
virus Herpes simplex (HSV) and RNA virus parainfluenza (PI-3).
Juziphine (9), laudanidine (13), alkaloids 2 and 3 were tested
against HSV-1, however, none of them showed significant activity
at a concentration of 50 µg/mL [19].
Alkaloids 8 and 10 appeared to be more active against Gram-
negative bacteria (MICs 32 µg/mL, Escherichia coli, Pseudomonas
aeruginosa, Proteus mirabilis, Klebsiella pneumonia and Acineto-
bacter baumannii) than Gram-positive ones (MICs 64 µg/mL,
Staphylococcus aureus and Bacillus subtilis). And they also dis-
played significant antifungal activity (MICs 8 µg/mL, Candida
albicans) [20]. Alkaloid 8 showed medium and weak inhibitory
activity on Tricophyton rubrum and Microsporum gypseum, respec-
tively, at a concentration of 500 µg/mL [21]. Alkaloids 11 and 15
(Fig. 2) displayed weak activity against E. coli and S. aureus (MICs
＞250 µg/mL). Magnocurarine (12), laudanosine (14), 16, 17, 18
and 19 (Fig. 2) were tested against S. aureus, E. coli and Candida
albicans, however, none of them show antibacterial or antifungal
activity [18, 22].
Qing et al.
3. BISBENZYLISOQUINOLINE ALKALOIDS
Liensinine (20), neferine (21) and isoliensinine (22) (Fig. 2),
which were isolated from the leaves and embtyo of Nelumbo
nucifera, were evaluated for anti-HIV activity. Bisbenzylisoquino-
line alkaloids 20-22 displayed notable anti-HIV activities with EC50
values of ＜0.8 µg/mL and TI values of ＞9.9, ＞8.6, and ＞6.5,
respectively. And they were less cytotoxic (IC50 7.97, 6.87 and 5.17
µg/mL for 20, 21 and 22, respectively) than 3 or 4, although they
had same partial structure. However, the cytotoxicity of those three
alkaloids was still higher than 1 or 2, which may be due to the N-
methylation [16] (Table 1). Fangchinoline (23) (Fig. 2) was isolated
from Radix stephaniae tetrandrae, a traditional Chinese medicine,
which has been used for a thousand years, and was estimated for
antiviral activity against HIV-1 laboratory strains NL4-3, LAI and
BaL in MT-4 and PM1 cells. The data showed that fangchinoline
(23) exhibited potent inhibition HIV-1 replication activity with
EC50 values ranging from 0.49 to 1.03 µg/mL by interfering with
gp160 proteolytic processing. However, the alkaloids showed
cytotoxicity for MT-4 and PM1 cells with CC50 4.20 and
3.89µg/mL, respectively [23] (Table 1). Cepharanthine (25) (Fig. 2)
was isolated from Stephania cepharantha Hayata and had been
tested for anti-HIV activity against two chronically HIV-1-infected
cell lines, UI (monocytic) and ACH-2 (tlymphocytic). The result
indicated that cepharanthine (25) possessed higher effective anti-
HIV-1 activity with EC50 values of 0.016 µg/mL than 3’-Azido-3’-
deoxythymidine (Zidovudine, AZT), which was a clinical drug for
anti-HIV-1 with EC50 of 0.045 µg/mL. However, the TI value of
cepharanthine (25) was only 137.5 corresponding to the high cyto-
toxicity with IC50 of 2.2 µg/mL(Table 1). Alkaloids 25 should be
regarded as a lead compound for further development of anti-HIV
drug by structure modification [24-27]. Bioassay-guided isolation
of the most active extracts of root tuber of Stephania cepharantha is
discussed. Two N-methylcoclaurine dimers, namely Aromoline (26)
and Obamegine (27) (Fig. 2), were finally screened and regarded as
activity components against HIV-1 on MT-4 cells. Alkaloid 26 had
medium anti-HIV-1 activity with IC100 values of 31.3 µg/mL, how-
ever, compound 27 appeared inactive to this virus, which demon-
Antiviral, Antibacterial and Antifungal Activities of Isoquinoline Alkaloids Current Organic Chemistry, 2017, Vol. 21, No. 00 3

Table 1. Anti-HIV activity of isoquinoline alkaloids.

Compound EC50 (µ g/mL) IC50 / CC 50 (µ g/mL) TI/SI

1 ＜0.8 HIV-1 (H9) 20 ＞25

2 0.8 HIV-1 ( H9) ＞100 ＞125

3 ＜0.8 HIV-1 ( H9) 1.45 ＞1.8

4 ＜0.8 HIV-1 ( H9) 1.77 ＞2.2

5 20.7 HIV-1 ( H9) ＞100 ＞4.8

20 ＜0.8 HIV-1 ( H9) 7.97 ＞9.9

21 ＜0.8 HIV-1 ( H9) 6.87 ＞8.6

22 ＜0.8 HIV-1 ( H9) 5.17 ＞6.5

23 0.49 HIV-1 NL4-3 ( MT-4) 4.20 ( MT-4) 8.6

0.91 HIV-1 NL4-3 ( PM1) 3.89 ( PM1) 4.3

0.79 HIV-1 LAI ( MT-4) 5.3

1.03 HIV-1 BaL ( PM1) 3.8

24 ＞18.3 HIV-1; 1.83 HIV-2 15.68 9.0

25 0.016 HIV-1 ( UI) 2.2 137.5

50 0.84 HIV-1 (H9) 7.8 9.3

51 0.8 HIV-1 (H9) 29.0 36.3

52 ＜0.8 HIV-1 ( H9) 35.2 ＞44

88 22.54 HIV-1 ( H9) 18.13 1.24

103 0.04HIV-1 NL4-3(CEM-GFP) 0.70 16.0

104 0.90HIV-1 NL4-3(CEM-GFP) 54.4 60.42

105 51 HIV-1 reverse transcriptase (RT) \ \

106 71 HIV-1 RT \ \

137 4.3 HIV protease \ \

138 8.5HIV-1 RT; 9.5HIV-2 RT \ \

140 7.4HIV-1 RT; 7.1HIV-2 RT \ \

142 1.77 HIV-1 ( H9) 25.8 14.6

193 7.8 HIV-1 ( MT-4) \ \

204 21.8 HIV-1 RT; 6.4 HIV-2 RT \ \

205 18.3 HIV-1 RT; 6.0 HIV-2 RT \ \

strated that the linkage sites between two benzyltetrahydroisoquino-
line alkaloids had an effect on anti-HIV activity [28]. Cycleanine
(24), isochondodendrine (28) and cycleanine N-oxide (29) (Fig. 2)
belonged to bisbenzyltetrahydroisoquinoline alkaloids and were
isolated from the root bark of Epinetrumvillosum.
Alkaloids 24 and 28-29 were evaluated against HIV-1 (Ⅲ-B-
strain) and HIV-2 (ROD-strain). Cycleanine (24) displayed activity
against HIV-1 and HIV-2 with EC50 values of ＞18.3 and 1.83
µg/mL, respectively, and the selectivity index (SI) of this com-
pound against HIV-2 was 9.0, with a CC50 value of 15.68 µg/mL
(Table 1). However, alkaloids 28 and 29 did not show any signifi-
cant activity against HIV-1 or HIV-2, which indicated that the N-
oxide has an effect on anti-HIV activity [29].
Methanol and water extracts of 30 traditional Chinese herbal
medicines were screened for anti-HSV-1 activity, and the methanol
part from Stephania cepharantha (Chinese name “Bai-Yao-Zi”),
especially the alkaloid fractions, displayed significant activity. 14
bisbenzylisoquinoline alkaloids, including 3, 4-dehydrocycleanine
(30), norcycleanine (31), 2-norcepharanoline (32), obaberine (33),
homoaromoline (34), isotetradrine (35), berbamine (36), thalrugos-
4 Current Organic Chemistry, 2017, Vol. 21, No. 00 Qing et al.

R2 4 4'
3
6 R2 R7 6' 3'
N R Linkage
R3 1 N
8 R6 1 N R3 R8 7'
R1 7 Site 8' 1' R6
R4 5' 1 8
1' 11 R9 11'
R4 (LS)
9 9'
R5
3' R10 12' 14'
14 12 R5
1: R1=R4=H, R2=R3=R5=OH, R6= H
2: R1=R4=H, R3=R5=OH, R2=OCH3, R6= H 20: R1=R6=CH3, R2=R3=R7=OCH3, R5=R10=OH, LS1=C11-O-C7'
3: R1=CH3, R2=OCH3, R3=R5=OH, R4=H, R6= H 21: R1=R6=CH3, R2=R3=R5=R7=OCH3, R10=OH, LS1=C11-O-C7'
4: R1=CH3, R2=R3=OCH3, R4=R6=H, R5=OH 22: R1=R6=CH3, R2=R7=R10=OCH3, R3=R5=OH, LS1=C11-O-C7'
5: R1=(CH3)2, R2=R5=OH, R3=OCH3, R4=H, R6= H 23: R1=R6=CH3, R2=R5=R7=OCH3, R3=OH, LS1=C8-O-C7', LS2=C11-O-C12'
6: R1=R6=H, R2=R4=OCH3, R3=R5=OH 24: R1=R6=CH3, R2=R3=R7=R8=OCH3, LS1=C8-O-C12', LS2=C12-O-C8'
7: R1=R6=H, R3=OH, R2=R4=R5=C3'=OCH3 25: R1=R6=CH3, R2=R5=OCH3, R7,R8=OCH2O, LS1=C7-O-C8', LS2=C11-O-C12'
8: R1=CH3, R2=R3=OCH3, R3=R4=OH, R6=H 26: R1=R6=CH3, R2=R7=OCH3, R5=R8=OH, LS1=C7-O-C8', LS2=C11-O-C12'
9: R1=CH3, R5=C8=OH, R3=OCH3, R2=R4=R6=H 27: R1=R6=CH3, R2=R7=OCH3, R3=R5=OH, LS1=C8-O-C7', LS2=C11-O-C12'
10: R1=R2=R4=R6=H, R5=C8=OH, R3=OCH3 28: R1=R6=CH3, R2=R7=OCH3, R3=R8=OH, LS1=C8-O-C12', LS2=C12-O-C8'
11: R1=R6=H, R2=R3=R4=R5=OH 29: R1=CH3, R6=CH3(O-), R2=R3=R7=R8=OCH3, LS1=C8-O-C12', LS2=C12-O-C8'
12: R1=(CH3)2, R3=R5=OH, R2=OCH3, R4=R6=H 30: R1=R6=CH3, R2=R3=R7=R8=OCH3, LS1=C8-O-C12', LS2=C12-O-C8', !3(4)
13: R1=CH3, R2=R3=R5=OCH3, R5=OH, R6=H 31: R1=R6=CH3, R2=R7=R8=OCH3, R3=OH, LS1=C8-O-C12', LS2=C12-O-C8'
14: R1=(CH3)2, R2=R3=R4=R5=OCH3, R6=H 32: R1=H, R2=OCH3, R5=OH, R6=CH3, R7,R8=OCH2O, LS1=C7-O-C8', LS2=C11-O-C12'
33: R1=R6=CH3, R2=R5=R7=R8=OCH3, LS1=C7-O-C8', LS2=C11-O-C12'
34: R1=R6=CH3, R2=R5=R7=OCH3, R8=OH, LS1=C7-O-C8', LS2=C11-O-C12'
35: R1=R6=CH3, R2=R3=R5=R7=OCH3, LS1=C8-O-C7', LS2=C11-O-C12', 1-R, 1'-S
36: R1=R6=CH3, R2=R3=R7=OCH3, R5=OH, LS1=C8-O-C7', LS2=C11-O-C12'
37: R1=R6=CH3, R2=R5=R7=OCH3, R3=OH, LS1=C8-O-C7', LS2=C11-O-C12'
38: R1=H, R6=CH3, R2=R3=R7=OCH3, R5=OH, LS1=C8-O-C7', LS2=C11-O-C12'
39: R1=CH3, R6=H, R2=R5=R7=R8=OCH3, LS1=C8-O-C7', LS2=C11-O-C12', !1'(2')
40: R1=R6=CH3, R2=R5=R8=OCH3, R7=OH, LS1=C7-O-C8', LS2=C11-O-C12'
R2 41: R1=R6=CH3, R2=R3=R5=R7=OCH3, LS1=C8-O-C7', LS2=C11-O-C12', 1-S, 1'-S
42: R1=R6=CH3, R2=R10=OCH3, LS1=C6-O-C7', LS2=C7-O-C8', LS3=C12-O-C11'
R3 N+ R 43: R1=R6=CH3, R2=R5=OCH3, R10=OH, LS1=C7-O-C6', LS2=C8-O-C7', LS3=C11-C11', 1-R, 1'-S
1
8 1
44: R1=CH3, R6=H, R2=R5=OCH3, R10=OH, LS1=C7-O-C6', LS2=C8-O-C7', LS3=C11-C11',1-R, 1'-S
R4 5'
1' 45: R1=R6=CH3, R2=R5=OCH3, R10=OH, LS1=C7-O-C6', LS2=C8-O-C7', LS3=C11-C11', 1-S, 1'-S
R5 46: R1=CH3, R6=H, R2=R10=OCH3, R5=OH, LS1=C7-O-C6', LS2=C8-O-C7', LS3=C11-C11'
3' 47: R1=CH3, R6=H, R2=R5=OCH3, R10=OH, LS1=C7-O-C6', LS2=C8-O-C7', LS3=C11-C11',1-S, 1'-S
15: R1=H, R2=R3=R4=R5=OH 48: R1=R6=CH3, R2=R5=R7=OCH3, R3=OH, LS1=C8-O-C7', LS2=C11-O-C12', 1-R, 1'-S
16: R1=H, R2=R3=R4=R5=OCH3
49: R1=H, R6=CH3, R5=OH, R7=OCH3, LS1=C6-O-C7', LS2=C7-O-C8', LS3=C11-O-C12'
17: R1=CH3, R2=R3=R4=R5=OCH3
18: R1=H, R2=R3=OCH3, R4,R5=OH2O
19: R1=CH3, R2=R3=OCH3, R4,R5=OH2O

Fig. (2). Chemical structures of benzyltetrahydroisoquinoline, benzylisoquinoline and bisbenzylisoquinoline alkaloid.

ine (37), 2-norberbamine (38), 1’,2’-dihydrostephasubine (39),
stephibaberine (40), 25, 26 and 27 (Fig. 2) were finally isolated
from the alkaloid parts guided by Vero monkey kidney cell line
infected with HSV-1 7401H. And all alkaloids exhibited potent
activity against HSV-1 with EC50 values ranging 14.8-43.2 µg/mL
except for 25 and 40, which indicated that substituent at C-6’/C-7’
with -CH2O- (25) or OH and OCH3 (40), reduced the activity. Alka-
loids 26-27 and 30-39 were further estimated for their activity
against HSV-1 KT- and HSV-2, and 26, 27, 31 and 34-37 showed
prominent activity with EC50 values ranging from 16.3 to 24.9
µg/mL [19]. The alkaloid fraction of the root of Mahonia bealei
(Fort), which was a Chinese medicine named “Shi-Da-Gong-Lao”
mainly used for defervescence, purging fire and curing cold, pos-
sessing anti-influenza activity, and alkaloid 35 was isolated and
regarded as activity component [30].
Tetrandrine (41), isotrilobine (42), 24, 35 and 36 (Fig. 2) were
screened for anti-bacterial effect against five G(＋) bacteria (S.
aureus, Staphylococcus epidermidis, Sarcina lutea, B. Subtilis and
Bacillus anthracis) and two G(－) bacteria (E. coil and K. pneumo-
nia). The result indicated that those alkaloids were not active on
gram-negative bacteria but exhibited activity against gram-positive
ones, particularly for compounds 24, 41 and 42, which showed
remarkable activity against S. lutea with MIC 15.6, 7.8 and 7.8
µg/mL, respectively [31]. Tiliacorinine (43), 2’-nor- tiliacorinine
(44) and tiliacorine (45) (Fig. 2) were isolated from an edible plant
named Tiliacora triandra, which was used as an ingredient in Thai
cuisines, and were tested for anti-mycobacterial activity against 59
clinical isolates of multidrug-resistant Mycobacterium tuberculosis
(MDR-MTB). The data demonstrated that alkaloids 43-45 possess-
ing potent activity towards MDR-MTB strain with MIC values
ranging from 0.7 to 6.2 µg/mL than some of the current clinical
first-line drugs [32]. Tiliarine (46), 2’-nortiliacorine (47) and 44
(Fig. 2) were isolated from the fruits of Tiliacora racemosa, which
was an Indian herbal medicine, applied as an antidote to snake bite
or scorpion sting. Alkaloids 44 and 46-47 displayed strong activity
toward E. coil, S. aureus and B. subtilis but were inactive against
strains of Vibrio cholera and P. aeruginosa [33]. Demethyltetran-
drine (48) and 41 (Fig. 2) were evaluated for their antibacterial
activity against clinical isolates of methicillin-resistant S. aureus
(MRSA), and the MIC values ranging from 64 to 128 µg/mL for
Antiviral, Antibacterial and Antifungal Activities of Isoquinoline Alkaloids Current Organic Chemistry, 2017, Vol. 21, No. 00 5

3 4 5
4
R2 2 5 R2 3 6
A B R1
R3 1 6a N N
R1 R3 2 8
7
1 C
R4 11 13 9 R6
8 D
R5 10 12
R5
9 11 10
R6 R4
50: R1=CH3, R2,R3=OCH2O, R5=OH, R4=R6=H 87: R1=R4=H, R2=R3=R5=R6=OH
51: R1=CH3, R2=R3=OCH3, R5=OH, R4=R6=H 88: R1=R6=H, R2=R3=R4=R5=OH
52: R1=CH3, R2=R5=OH, R3=OCH3, R4=R6=H 89: R1=R6=H, R2,R3=OCH2O, R4=
53: R1=CH3, R2=R4=R5=OCH3, R3=OH, R6=H R5=OCH3, C1-OCH3, C12-CH2OH
54: R1=CH3, R2=R3=R5=OCH3, R4=OH, R6=H 90: R1=CH3, R2,R3=OCH2O, R4=R5=
OCH3, C1-OCH3, C12-CH2OH,R6=H
55: R1=CH3, R2=R4=OCH3, R3=R5=OH, R6=H
91: R1=R4=H, R2,R3=R5,R6=OCH2O
56: R1=CH3, R2=R5=OCH3, R3=R6=OH, R4=H
92: R1=CH3, R2,R3=R5,R6=OCH2O, R4=H
57: R1=CH3, R2=R3=R5=R6=OCH3, R4=H 93: R1=R4=H, R2,R3=OCH2O, R5=R6=OCH3
58: R1=CH3, R2=R3=R5=OCH3, R6=OH,R4=H 94: R1=CH3, R2,R3=OCH2O, R5=R6=OCH3, R4=H
59: R1=CH3, R2=R3=OCH3, R4=R5=R6=H 95: R1=R4=H, R2=R3=R5=OCH3, R6=OH
60: R1=H, R2,R3=OCH2O, R5=OCH3, R6=OH, R4=H 96: R1=R4=H, R3=R5=R6=OCH3, R2=OH
61: R1=CH3, R2,R3=OCH2O, R5=OCH3, R6=OH, R4=H 97: R1=R4=H, R2=R5=R6=OCH3, R3=OH
62: R1=CH3, R2,R3=OCH2O, R4=OH, R5=OCH3, R6=H 98: R1=R4=H, R2=R3=R5=R6=OCH3
99: R1=R4=H, R2=R3=R5=R6=OCH3, C12-CH3
63: R1=CH3, R2,R3=OCH2O, R6=OH, R5=OCH3, R4=H
100: R1=CH3, R2,R3=OCH2O, R4=H, R5=
64: R1=H, R2,R3=OCH2O, R4=R5=R6=H R6=OCH3, C13-CH2CH3
65: R1=H, R2,R3=OCH2O, R4=R5=H, R6=OCH3 101: R1=CH3, R2,R3=OCH2O, R4=H,
66: R1=CH3, R2,R3=OCH2O, R4=R5=R6=H, !6"(7) R5=R6=OCH3, C13-CH3
67: R1=CH3, R2,R3=OCH2O, C7=OH, R4=R5=R6=H 102: R1=CH3, R2=R3=R5=R6=OCH3, R4=H, C13-CH3
68: R1=CH3, R2,R3=OCH2O, C8=OH,R6=OCH3, R4=R5=H
69: R1=CH3, R2,R3=OCH2O, C8=OH,R6=C3=OCH3, R4=R5=H
70: R1=COOCH3, R2,R3=OCH2O, R5=R6=OCH3, R4=H
71: R1=COOCH3, R3=R5=R6=OCH3, R2=OH, R4=H
72: R1=COOCH3, R2=R3=R5=R6=OCH3, R4=H
73: R1=H, R2=R3=OCH3, C7-C=O, R4=R5=R6=H, !3(4), !6(6")
74: R1=H, R2,R3=OCH2O, R4=OCH3, C7-C=O, R5=R6=H, !3(4), !6(6")
75: R1=H, R2=R3=OCH3, R6=OH, C7-C=O, R4=R5=H, !3(4), !6(6") 4 5
R1 3 6
76: R1=COOCH3, R2=R6=OCH3, R3=R5=OH, R4=H
R2 2 N
77: R1=R4=H, R2=OCH3, R3=OH, C3-OCH3, R5,R6=OCH2O 8
1 O
78: R1=CH3, R2,R3=OCH2O, R5=OH, R6=OCH3, R4=H 13 9 R
4
79: R1=CH3, R2,R3=OCH2O, R4=R5=R6=H
12
80: R1=CH3, R2,R3=OCH2O, C8-OH, R4=R5=R6=H 10 R3
11
81: R1=CH3, R2,R3=OCH2O, C8-OCH3, R4=R5=R6=H 131: R1,R2=R3,R4=OCH2O
82: R1=CH3, R2=OH, R3=OCH3, C8-OCH3, R4=R5=R6=H 132: R1,R2=OCH2O, R3=R4=OCH3
83: R1=CH3, R2,R3=OCH2O, R5=R6=OCH3, R4=H 133: R1,R2=OCH2O, R3=R4=H, C11=C12-OCH3
84: R1=H, R2=R5=OCH3, R3=R6=OH, R4=H 134: R2=OCH3, R1=R4=H, C1-OCH3, C11,R3=OCH2O
135: R1=R2=OCH3, R3,R4=OCH2O
85: R1=(CH3)2, R2=R5=OCH3, R3=R4=OH, R6=H, 6a-R
136: R1,R2=OCH2O, R3=R4=OCH3, C13-OAc
86: R1=(CH3)2, R2=R5=OCH3, R3=R4=OH, R6=H, 6a-S

Fig. (3). Chemical structures of aporphine, tetrahydroprotoberberine N-methyltetrahydroproto-berberine and protopine alkaloid.

both alkaloids. Interesting, compound 48 combined with cefazoline
showed significant synergies against MRSA with their MICs being
reduced 75-94%, respectively [34]. Investigation of the active
methanol fractional of the root of Epinetrum villosum led to the
isolation of the cocsoline (49), 24, 28 and 29 (Fig. 2). Cocsoline
(49) inhibited the growth of Shigella sonnei, Shigella dysenteriae,
Shigella flexneri, Shigella boydii with MIC values of 31.25, 125,
62.50 and 62.50 µg/mL, respectively. Alkaloid 49 also showed
remarkable activity against Campylobacter jejuni and Campylobac-
ter coil with MIC values of 15.62 and 31.25 µg/mL, respectively.
This compound also displayed antifungal activity toward C. albi-
cans with MIC values of 31.25 µg/mL. However, the remaining
three bisbenzylisoquinoline alkaloids did not show any significant
activity against all tested bacteria and fungus [29]. Alkaloids 24 and
49 were isolated from Albertisia villosa (Menispermaceae), which
was a traditional African plant medicine, used for various infectious
diseases, and was estimated for antibacterial and antifungal activity.
Compound 24 showed the most significant antibacterial activity
against K. pneumonia and potent antifungal activity against Tricho-
phyton longiformis, Aspergillus flavis and Emoniliform spp [35].
4. APORPHINE ALKALOIDS
Three aporphine alkaloids 10-hydyoxyl-roemerine (50), 10-
hydyoxylnuciferine (51) and nornuciferine (52) (Fig. 3) were iso-
lated from the leaves of Nelumbo nucifera Gaertn, which was
6 Current Organic Chemistry, 2017, Vol. 21, No. 00
mainly used to treat fever, sweating and strangury as traditional
oriental medicines, and were tested for anti-HIV activity against H9
cells infected with HIV (ⅢB isolate). The data indicated that alka-
loids 50-52 showed prominent activity toward HIV-1 with EC50
values of 0.84, 0.8 and ＜0.8 µg/mL, respectively. However, the
low Tl values for those three alkaloids were 9.3, 36.3 and＞44 cor-
responding to the medium cytotoxicity with IC50 of 7.8, 29.0 and
35.2 µg/mL, respectively [16] (Table 1). Corydine (53), isocorydie
(54), isocorytuberine (55) and isoboldine (56) (Fig. 3) were isolated
from Stephania cepharantha and were estimated for antiviral activ-
ity against HSV-1, HSV-1 KT- and HSV-2, unfortunately, none of
them exhibited significant activity at the concentration of 50 µg/mL
[19]. Glaucine (57), N-methyl- laurotetanine (58), nuciferine (59),
actinodaphnine (60), cassythicine (61) and 56 (Fig. 3) were tested
for antiviral activity against human poliovirus. Alkaloids 56-59
displayed potent activity with ED50 values of 15, 9, 15 and 16.7
µM, respectively. However, compounds 60 and 61 did not show
any significant activity, which indicated the methylenedioxy at C-1,
C-2 reducing or losing of the antipoliovirus activity [36]. Compar-
ing the antipoliovirus [37] and anti-HSV-1 [19, 37] activity of this
aporphine series, an interesting phenomenon was apparent; the
active alkaloids against poliovirus being inactive against HSV-1
and vice versa. Both HSV and PI-3 were employed for antiviral
activity assessment of alkaloids bulbocapnine (62) and 56 (Fig. 3).
The data showed that compounds 62 possessed medium activity
against PI-3 with MIC values ranging from 32-4µg/mL, and alka-
loid 56 was inactive for both viruses [20].
N-methylactinodaphnine (63), anonaine (64), xylopine (65), an-
hydroaporphines (66), ushinsunine (67) and 60 (Fig. 3) were tested
for their antibacterial and antifungal activities. Alkaloids 60 and 63-
66 had inhibitory activities against three Gram-positive bacteria
(Bacillus cereus, Micrococcus sp. and S. aureus) with MIC values
of ≥50 µg/mL, however, only compounds 60 displayed weak activ-
ity against two Gram-negative bacteria (E. coil and K. pneumonia)
with MIC values of 300 µg/mL [22]. 8-hydroxy-9-methoxy-1,2-
methylenedioxy-aporphine (68) and 8-hydroxy-3,9-dimethoxy-1,2-
methylenedioxy aporphine (69) (Fig. 3) were isolated from the
Fissistigma poilanei, and were evaluated for antibacterial ability
against four Gram-positive bacteria (Lactobacillus fermentum, En-
terococcus faecium, S. aureus and B. subtilis). Alkaloid 69 was
active towards all tested bacterial strains with IC50 values of 109.3,
116.6, 43.7 and 83.9 µg/mL, respectively. However, alkaloid 68
only displayed inhibitory effect against S. aureus and B. subtilis
with IC50 values of 45.5 and 57.7 µg/mL, respectively [38]. N-
(methoxylcarbony)-N-nordicentrin (70), N-(methoxyl- carbony)-N-
norpredicentrin (71) and N-norlaucine (72) (Fig. 3) were obtained
from the 70% EtOH extracts of the barks of Litsea cubeba. Com-
pounds 70-72 showed antibacterial activity against S. aureus with
MIC values of 0.68, 0.79 and 2.14 mM, respectively [39]. Lysi-
camine (73) (Fig. 3) was isolated from the leaves of Phoebe grandis
(Nees) Merr. (Lauraceae), and exhibited good activity toward three
G(＋) bacteria (Staphylococcus epidermidis, S. aureus and B. sub-
tilis) with inhibition zones of 12.00±0.00, 13.33±0.57 and
15.50±0.57 mm, respectively. Especially the remarkable ability
against S. aureus, which was compared with the positive control
streptomycin sulfate with inhibition zones of 13.36±0.57 mm.
However, Alkaloid 73 was ineffective to two G(－) bacteria (Pas-
teurella multocida and Enterobacter cloacae), which were not sur-
prising due to these bacteria are more resistant than G(＋) ones
[40]. Oxoputerine (74) and subsessiline (75) (Fig. 3) had been
tested for their antibacterial and antifungal activity by 8 Gram-
positive bacteria, 8 Gram-negative bacteria and 1 yeast. The result
Qing et al.
revealed that alkaloid 74 showed prominent activity against S.
aureus, S. epidermidis, Staphylococcus pyogenes, B. subtilis and B.
albicans with MIC values of 6, 6, 3, 3 and 6 µg/mL, respectively.
Compound 75 possessed potent activity against S. epidermidis and
B. subtilis with MIC values of 6 and 3 µg/mL, respectively. How-
ever, the rest microorganisms were not susceptible to both
oxoaporphine alkaloids [41]. Four aporphine alkaloids named N-
(methoxycarbonyl)-N-norboldine (76), 3-methoxy-nor- domesticine
(77), 10-hydroxy-9-methoxy-1,2-methylene- dioxy-6-methyl-
4,5,6,6a-tetrahydro-7H,6-azabenzanthrene SSV (78) and roemerine
(79) (Fig. 3) were isolated from the aerial part of Litsea cubeba, the
wood of Ocotea macrophylla, the marine actinomycete called
Streptomyces sp. KS1908 and the fresh rattan stem of Fibraurea
recisa, respectively. Alkaloid 76 was active to S. aureus with the
inhibitory zones values of 9 mm and 77 displayed antibacterial
activities against two Gram-positive bacteria (S. aureus and E. fae-
cium) evaluated with values of 30 AU [42, 43]. Aporphine alkaloid
SSV exhibits remarkable activity against both Gram-positive and
Gram-negative bacteria (E. faecium, Salmonella typhl, Vibrio chol-
era and E. coil) with MIC values ranging 1-100 µg/mL. Particularly
towards S. typhl with the inhibitory zone values of 14 mm at the
lowest MIC of 1 µg/mL, and the data demonstrated that SSV pos-
sessed comparable antimicrobial activity with some antibiotics
(ciprofloxacin and flucanozole) [44]. Alkaloid 79 was active to
MRSA strains and S. aureus with MIC50s values ranging 16-32 and
32 µg/mL, respectively [45].
Fibrecisine (80), stephanine (81) and 79 (Fig. 3) were isolated
from the rattan stem of Fibraurea recisa pierre, which was a folk
herbal commonly used for the treatment of various skin diseases,
and were tested for antifungal activity against nine kinds of Canidia
strain and Cryptococcus neoformans. Alkaloids 79-81 showed ac-
tivity toward the tested fungi with MIC values of ranging 80-320
and 80-160 µg/mL, respectively [46]. The antifungal activity
against Canidia strains of alkaloids 79 was also reported, with
MIC50s and MIC80s values of ranging 16-128 and 32-256 µg/mL,
respectively [45]. N-methylasimilobine (82), 59 and 79 (Fig. 3)
were isolated from the leaves of Nelumbo nucifera (an aquatic
plant), and only alkaloids 79 showed significant activity against C.
albicans with IC50/MIC values of 4.5/10 µg/mL [47]. The structure-
activity relationship studies indicated that the methylenedioxy at C-
1, C-2 was an important factor for antifungal activity of aporphine
alkaloids. The methanolic extract and total alkaloids of the aerial
parts of Glaucium oxylobum displayed strong activity toward Mi-
crosporum canis, Microsporum gypseun, Trichophyton mentagro-
phytes and Epidermophyton floccosum. Two alkaloids, dicentrine
(83) and 57 (Fig. 3), were isolated and identified as the compounds
responsible for the antifungal activity of this plant. Alkaloid 83
exhibited remarkable activity against those four fungi at the concen-
trate of 300 µg/mL, however, alkaloids 57 only showed moderate
activity toward M. canis, M. gypseun, T. mentagrophytes at the
concentrate of 300 µg/mL [48]. Laurelliptine (84), 56 and 64 (Fig.
3) were isolated from the bark of Annona salzmanii D.C. (Annona-
ceae) and were tested for the antifungal activity against Tricophyton
rubrum and M. gypseun. Alkaloid 56 and 64 showed strong inhibi-
tion for T. rubrum at the concentrate of 500 and 250 µg/mL, respec-
tively. However, only compound 64 showed strong inhibition for
M. gypseun at the concentrate of 500 µg/mL [21]. β-magnoflorine
(85) and α-magnoflorine (86) (Fig. 3) were isolated from the aerial
of Clematic parviloba and were estimated for antifungal activity.
The minimal inhibition amounts of alkaloids 85 and 86 against
Penicillium avellaneum were 10 and 5 µg/ disc, respectively. Com-
pound 85 displayed weak activity toward Pyricularia oryzae with
Antiviral, Antibacterial and Antifungal Activities of Isoquinoline Alkaloids
R2 Quaternary
3 3
nitrogen
R1
N activity
R3 2 Ehancing
antiviral activity
Methylenedioxy
at C-2 and C-3 R6
R4
9
13-Alkylsubstituent
10 R5
Key structure for increasing
antibacterial activity Adjacent methoxyl
a at C-9 and C-10
Fig. (4). The structure-antibacterial and antiviral inhibitory activities of N-methyltetrahydroproto-berberine (a) and protoberberine (b) alkaloid.
the minimal inhibition amount values of 100 µg/disc, however,
alkaloid 86 was inactive to these fungi at the same concentrate [49].
Aporphine alkaloids 56, 60, 62-66, 70-72 and 74 were also tested
for their antifungal activity. Compounds 56 and 62 displayed
prominent activity against C. albicans with MICs values of 8 and 4
µg/mL, respectively [20]. In another experiment, alkaloid 56 exhib-
ited medium antifungal activity against Alternaria alternate, Sac-
charomyces cerevisiae and Colletotrichum nicotianae with the in-
hibition zones of 8, 11 and 7, respectively, at the concentrate of 50
µg/disk [42]. Alkaloids 60 and 63-66 showed medium antifungal
activity against Candida parapsilosis and Cryptococcus neofor-
mans with MIC values ranging from 62.5 to 250 µg/mL [22]. Com-
pounds 70-72 possessed antifungal activity toward A. alternate and
C. nicotianae with MIC values ranging 0.64-1.41 and 0.80-1.70
µg/mL, respectively [38]. Alkaloids 74 displayed strong activity
against C. albicans with MICs values of 6 µg/mL [42].
5. TETRAHYDROPROTOBERBERINE AND N-METHYL-
TETRAHYDRO PROTOBERBERINE ALKALOIDS
2,3,9,10-tetrademethyltetrahydropalmatine (87) and 2,3,10,11-
tetrademethyl-pseudotetrahydro palmatine (88) (Fig. 3) were tested
for their anti-HIV activity against H9 cells infected with HIV-1.
The data indicated that alkaloid 88 showed anti-HIV activity with
EC50 values of 22.54 µg/mL (Table 1). However, compound 87 did
not display any significant activity, which demonstrated that the
linkage site of hydroxyl (C9-OH, active; C11-OH, inactive) has an
effect on anti-HIV activity. The antibacterial activity of 87 and 88
was also evaluated; however, none of them were active towards S.
aureus and E. coil [17]. The phytochemistry investigation of the
aerial parts of Papaver pseudocanescens resulted in the isolation of
two tetrahydroprotoberberine alkaloids named mecambridine (89)
and mecambridine methohydroxide (90) (Fig. 3). Alkaloid 90 pos-
sessed significant activity against the replication of poliovirus type
1 with the IC50 values of 21.4±3.68 µM. Interesting, the SI value of
90 was 8.79, which was comparable to the Disoxaril (positive con-
trol) with the SI values of 12.5. Therefore, compound 90 was a
promising drug-like nature product for against poliovirus type 1.
Alkaloid 89 was inactive to this virus, which demonstrated that the
quaternary nitrogen was a pivotal factor for antiviral activity against
poliovirus type 1 [50] (Fig. 4a). Stylopine (91), N-methylstylopine
(92), canadine (93) and N-methylcanadine (94) (Fig. 3) were tested
for antibacterial activity against Staphylococcus gallinarum, Sal-
monella choleraesuis, S. aureus and E. coil. Alkaloids 92 and 94
exhibited significant activity toward S. gallinarum and S. aureus
with MIC values of 31.25 - 125 µg/mL, however, compounds 91
and 93 were inactive to both bacteria, which indicated that N-
methyl group (quaternary nitrogen atom) be an important factor to
Current Organic Chemistry, 2017, Vol. 21, No. 00 7
Substitution R2
Key structure for
of OH with Quaternary
A B ehancing antiviral
MeO at C-3 nitrogen
N
R3 2 Aromatization
of ring C
Methylenedioxy C Substitution of
at C-2 and C-3
R4 9 R6 OH with MeO
or EtO at C-9
13-Alkylsubstituent D
10 R5
Key factor for increasing
Adjacent methoxyl
antibacterial activity
b at C-9 and C-10
increase the antibacterial activity (Fig. 4a). In comparison, com-
pound 94 against S. gallinarum and S. aureus with MIC values of
31.25µg/mL, however, alkaloids 92 against both bacteria with MIC
values of 62.5 and 125 µg/mL, respectively, which demonstrated
that the adjacent methoxyl at C-9 and C-10 may increase the anti-
bacterial activity [51]. Corydalmine (95), corypalmine (96), isoco-
rypalmine (97), tetrahydropalmatine (98), corydaline (99) and 93
(Fig. 3) were evaluated for their antifungal activity against nine
kinds of fungi. The results show that only Crytococcus neoformans
was sensitive to all tested alkaloids with MIC values of 80, 80, 40,
80, 80 and 80 µg/mL, respectively [46]. 13-ethyl-N-methyl tetrahy-
droberberine (100), 13-methyl-N-methyltetrahydro- berberine
(101), 13- methyl-N-methyl- tetrahydroberberine (102) (Fig. 3) and
others 27 analog alkaloids were tested for their antibacterial (S.
aureus and E. coil) and antifungal (C. albicans). The result demon-
strated that the 30 tested tetrahydroprotoberberine alkaloids were
more active against Gram-positive than Gram-negative and fungi.
The structure-activity relationship studies strongly indicated that the
quaternary nitrogen atom, an alkyl substituent at C-13 and a meth-
ylenedioxy at C-2 and C-3 were the key factors for enhancing anti-
bacterial activity [52] (Fig. 4a).
6. PROTOBERBERINE ALKALOID
Five protoberberine alkaloids, berberine (103), berberrubine
(104), columbamine (105), jatrorrhizine (106) and palmatine (107)
(Fig. 5), were evaluated for their anti-HIV activity. Compound 103
and 106 displayed remarkable anti-HIV activity against HIV-1 NL
4.3 virus in CEM-GFP cells with EC50 values of 0.13 and 2.8 µM,
respectively. To our surprise, both alkaloids have the comparable TI
values (16.07 and 60.42, respectively) with the AZT (22.91, posi-
tive control), which indicated that alkaloids 103 and 106 have great
potential to become drug candidate against HIV-1[53]. Colum-
bamine (105) and jatrorrhizine (106) (Fig. 5) also showed anti-HIV
reverse transcriptase (RT) with IC50 values of 58 and 71 µg/mL,
respectively [54] (Table 1), however, alkaloids 107 did not exhibit
any significant activity against HIV [55]. Structure-activity rela-
tionship studies of compounds 103-107 showed that the methyle-
nedioxy linkage at C-2 and C-3 was a pivotal moiety of increasing
anti-HIV activity (Fig. 4b). Furthermore, anti-HIV activity and
cytotoxicity increased simultaneously when a hexyl group was
introduced to the position of 13 for alkaloids 103 and 107 [56].
Dehydrocavidine (108), dehydroapocavidine (109), dehydroisoapo-
cavidine (110), berbinium (111), 103 and 106 (Fig. 5) were isolated
from the methanol part of the herb Corydalis saxicola (Papav-
eraceae) and were tested for antivirus activity against the 2.2.15 cell
line infected with hepatitis B virus (HBV). The data indicated that
the average inhibitory rates of 108-110 on HBeAg were 51%, 54%
8 Current Organic Chemistry, 2017, Vol. 21, No. 00
and 58%, and on HBsAg were 41%, 42%, and 40%, respectively
(HBeAg and HBsAg were marker proteins whose level was indica-
tive of HBV replication). However, alkaloids 103 and 106 did not
display any significant activity inhibitory of HBeAg and HBsAg,
which demonstrated that the inhibitory effect was strongly influ-
enced by the substituent at C-13 (introduction a methyl group at C-
13 increase the anti-HBV activity) [57, 58] (Fig. 4b). In vitro anti-
viral activity of alborine (112) (Fig. 5) from Papaver pseudocanes-
cens against human poliovirus 1 with IC50 values of 49.7±2.26 was
reported [50]. However, alkaloid 89 was inactive to poliovirus 1,
which demonstrated that the quaternary nitrogen atom was an im-
portant factor for anti-poliovirus activity (Fig. 4b). Alkaloid 103
was also assessed for the anti-human cytomegalovirus (HCMV)
activity, the result showed that the anti-HCMV activity (IC50
0.68µM) of berberine (103) was higher than that of ganciclovir
(GCV, positive control, IC50 0.91µM) [59].
Coptisine (113), epiberberine (114), 103, 106 and 107 (Fig. 5)
were isolated from rhizome of Coptis chinensis Franch and were
assessed for antibacterial activity against S. aureus. The result
showed that these alkaloids had significant antibacterial activity
with IC50 values of 67, 214, 57, 272 and 119 µg/mL, respectively
[60]. The effect of 9-O-ethyl-13-ethylberberine (115), 13-ethylber-
berine (116), 13-methylberberine (117), 13-methylpalmatine (118),
berberrubine (119) and 9-O-ethyl berberine (120) (Fig. 5) on S.
aureus growth was investigated, the data revealed that the five pro-
toberberine alkaloids displayed significant antibacterial activity
with IC50 values ranging from 31.3 to 1000 µg/mL. And the se-
quence of antibacterial activity against S. aureus of the twelve pro-
toberberine alkaloids was: 115＞116＞117＞120＞118＞103＞
113＞106＞107＞114＞119＞102. The structure-activity relation-
ship studies of those protoberberine alkaloids indicated that 1) re-
duction of the protoberberine alkaloids yield the tetrahydroproto-
berberine greatly reduced the antibacterial activity (102 with the
lowest MIC values among the twelve alkaloids), 2) a methylenedi-
oxy group at C-2 and C-3 strong increased the activity (MIC values:
117＜118, 103＜107). The alkyl substitution at C-13 enhanced the
antibacterial activity and the function of ethyl was more than
methyl (MIC values: 116＜117＜103, 118＜107), 3) the substituent
group at C-9 has great effect on the antibacterial activity (-
OCH2CH3 (120)＞-OCH3 (103)＞-OH (119)), 4) bearing the same
functional group at C-2 and C-3, the adjacent methoxyl at C-9 and
C-10 showed more activity on bacterial than methylenedioxy at the
C-9 and C-10 (MIC values: 103＜113, 107＜114), 5) two methyle-
nedioxy groups linkage at C-2,C-3 and C-9,C-10, respectively,
displayed more antibacterial activity than four methoxyl groups
linkage at C-2, C-3, C-9 and C-10, respectively (MIC values:
113＜107, 117＜118), 6) replacement of -OCH3 at C-3 by OH led
to a reduction of the antibacterial activity (MIC values: 106＜107)
[52, 60] (Fig. 4b). Bioassay-guided isolation studies on the root
extract of Polyalthia longifolia var. pendula led to the isolation of
two protoberberine alkaloids pendulamine A (121) and pendu-
lamine B (122). Compounds 121 and 122 (Fig. 5) exhibited re-
markable antibacterial activity against seven Gram-positive (B.
subtilis, Corynebacterium hoffmanii, S. aureus, Streptococcus fae-
calis, S. pyogenes, Streptococcus viridians and Micrococcus
lysodeikticus) and seven Gram-negative (E. coil, K. pneummoniae,
P. aeruginosa, Proteus mirabilis, Salmonella paratyphi A, Salmo-
nella paratyphi B and Salmonella typhi) bacterial strains with MIC
values ranging from 0.02 to 20 µg/mL. Interesting, alkaloids 121
and 122 were found to be 500, 1250, 200 and 200 times more active
against B. subtilis, S. aureus, K. pneummoniae and P. aeruginosa,
respectively, than the clinically used berberine, which indicated that
Qing et al.
121, 122 and analogous compounds may have potential drug-like
property [61]. 8-methyl-dihydropseudo-berberine (123), 8-ethyldi-
hydro-pseudoberberine (124), 8-methyl- dihydropalmatine (125)
and 8-ethyldihydropalmatine (126) (Fig. 5) were 8-substituted ber-
berine derivatives and assessed for their anti-mycobacterial activity
toward Mycobacterium tuberculosis strain H37Rv. Pseudo- berber-
ine and palmatine displayed weak or no inhibitory activity, how-
ever, alkaloids 123-126 showed significant activity against M. tu-
berculosis with MIC values of 32, 16, 128 and 8 µg/mL, respec-
tively, which demonstrated that the a large group at the 8-position
may be beneficial for the anti-mycobacterial activity [62]. Rhizoma
coptidis, which was a traditional Chinese medicine, has been used
for a thousand years to treat diarrhea, fever and other infective dis-
eases. Alkaloids 103, 106, 107, 113 and 114 were the main compo-
nents of this medicine plant and regarded as the active substances
against MRSA [63, 64]. Berberine (103) was a protoberberine alka-
loid and widely used in Chinese medicine and native American
medicines for its antibacterial activities including against 20
Staphylococci strains with MIC values ranging from 25 to 500
µg/mL [65], S. aureus and Staphylococcus gallinarum with MIC
values 15.63 µg/mL [50], Hydrastis Canadensis with MIC values
ranging 25-100 µg/mL [66], S. aureus surface protein anchoring
transpeptidase named sortase with IC50 values of 8.7 µg/mL [67],
human intestinal bacterial [68] and Enterococcus faecium [69].
Berberine has also evaluated its antibacterial activity against two
Gram-positive and two Gram-negative bacteria stains, the MIC
values revealed the sensitively decreasing as follows: S. aureus＞P.
aeruginosa＞E. coil＞B. subtilis [70]. Interestingly, a series of 9-
phenoxyalkyl berberine derivatives were synthesized. Compared to
the parent compound of berberine, the derivatives displayed a re-
markable enhancement of antibacterial activity toward clinically
relevant bacteria, such as MRSA, E. coil and K. pneummoniae [71].
Stepharanine (127), palmatrubine (128), groenlandicine (129),
103, 106, 107, 111 and 113 (Fig. 5) were isolated from the rattan
stem of Fibraurea recisa Pierre and examined for antifungal activ-
ity against three C. albicans, two Candida glabraatas, two Candida
krusei, one Cryptococcus neoformans and two Candida parapsilo-
sis stains. The results revealed that all tested alkaloids possessing
significant antifungal activity with MIC values ranging from 2.5 to
320 µg/mL. Alkaloids 106 and 114 displayed the comparable activ-
ity to fluconazole (MIC values of 2.0 µg/mL, positive control)
against C. neoformans with MIC values of 2.5 µg/mL, however,
alkaloids 103 and 113 were less two-fold active toward C. neofor-
mans than compounds 106 and 114, which indicated that the meth-
ylenedioxy linkage at C-9 and C-10 was a remarkable factor to
enhance the antifungal activity [46]. 1-methoxylberberine (130)
(Fig. 5) was isolated from Corydalis longipes and tested its antifun-
gal activity against A. brassicae, Alternaria alternata, Curvularia
sp., Curvularia maculans, Colletotrichum sp., Colletotrichum
gloeosporioides, Helminthosporium sp., H. pennisetti, Helminthos-
porium speciferum and Ustilago cynodontis. This alkaloid showed
high efficacy on all tested fungi at the concentration of 50-150 ppm
[72]. Alkaloids 103 and 106-107, the main components of stem
bark of Mahonia aquifolium, were screened for their inhibitory
activity against a series of dermatophytes and two Candida species
of human origin. The data revealed that jatrorrhizine (106) was the
most active antifungal alkaloid against all tested fungal species with
MIC values ranging from 62.5 to 125 µg/mL and low host toxicity,
which suggested that this alkaloid should be served as a lead com-
pound for further studies to develop new antifungal agents [73-75].
By introducing various benzyl or alkyl groups in 13-C of berberine
(103), berberrubine (104) and palmatine (107), a series of 13-
Antiviral, Antibacterial and Antifungal Activities of Isoquinoline Alkaloids Current Organic Chemistry, 2017, Vol. 21, No. 00 9

5 12 1
4
R1 3 6 11 2 R3
A B 10
R2 2 N+ 9 3 R2
13a 8
1 C 4
8 N
13 9 R4 R1
R4 7 6
D R5
12
10 R3 137: R1=CH3, R2,R3=R4,R5=OCH2O
11
138: R1=CH3, R2=R4=OCH3, R3=OH, R5=H, C9-OCH3
103: R1,R2=OCH2O, R3=R4=OCH3 139: R1=R5=H, R2=R4=OCH3, R3=OH, C9-OCH3
104: R1,R2=OCH2O, R3=OCH3, R4=OH 140: R1=CH3, R2,R3=OCH2O, R4=OCH3, R5=H, C9-OCH3
105: R2=OH, R1=R3=R4=OCH3 141: R1=CH3, R2,R3=OCH2O, R4=R5=OCH3
106: R1=OH, R2=R3=R4=OCH3 149: R1=H, R2,R3=R4,R5=OCH2O
107: R1=R2=R3=R4=OCH3 154: R1=H, R2,R3=OCH2O, R4=OH, R5=OCH3
108: R1,R2=R3,R4=OCH2O, C13-CH3 155: R1=H, R2,R3=OCH2O, R4=R5=OCH3
109: R1=OCH3, R2=OH, R3,R4=OCH2O, C13-CH3 160: R1=H, R2=OCH3, R2,C1=R4,R5=OCH2O
110: R1=OH, R2=OCH3, R3,R4=OCH2O, C13-CH3 12 1
11 2 R3
111: R1=OCH3, R2=OH, R3,R4=OCH2O
10
112: R1,R2=OCH2O, R3=OCH3, C1=C3-OCH3, C12-CH2OH 9 R2
3
113: R1,R2=R3,R4=OCH2O 4
8 N
114: R1=R2=OCH3, R3,R4=OCH2O R4 R1
7
115: R1,R2=OCH2O, R3=OH, R4=OCH2CH3, C13-CH2CH3 R5 R6
116: R1,R2=OCH2O, R3=R4=OCH3, C13-CH2CH3 142: R1=CH3, R2,R3=OCH2O, R4=R5=OCH3, R6=CH2COCH3
117: R1,R2=OCH2O, R3=R4=OCH3, C13-CH3 143: R1=CH3, R2,R3=R4,R5=OCH2O, R6=H
118: R1=R2=R3=R4=OCH3, C13-CH3 144: R1=CH3, R2,R3=OCH2O, R4=R5=OCH3,R6=H
119: R1,R2=OCH2O, R3=OCH3, R4=OH 145: R1=CH3, R2,R3=R4,R5=OCH2O, R6=O
120: R1,R2=OCH2O, R3=OH, R4=OCH2CH3 146: R1=CH3, R2,R3=OCH2O, R4=R5=OCH3,R6=O
121: R1=R3=OH, R2=H, R4=OCH3, C8-C=O, C11-OCH3, 147: R1=CH3, R2,R3=R4,R5=OCH2O, R6=OCH2CH3
7,8-dihydro, 13,13a-dihydro 148: R1=CH3, R2,R3=OCH2O, R4=R5=OCH3, R6=OCH2CH3
122: R1=R3=OH, R2=H, R4=OCH3, C8-C=O, C11-OCH3, 7,8-dihydro 150: R1=CH3, R2,R3=R4,R5=OCH2O, R6=OH
123: R1,R2=OCH2O, R3=OCH3, R4=H, C11-OCH3, C8-CH3, 7,8-dihydro 151: R1=CH3, R2,R3=OCH2O, R4=R5=OCH3, R6=OH
124: R1,R2=OCH2O, R3=OCH3, R4=H, C11-OCH3, C8-CH2CH3, 7,8-dihydro 152: R1=CH3, R2,R3=R4,R5=OCH2O, R6=OCH3
125: R1=R2=R3=R4=OCH3, C8-CH3, 7,8-dihydro 153: R1=CH3, R2,R3=OCH2O, R4=R5=OCH3, R6=OCH3
126: R1=R2=R3=R4=OCH3, C8-CH2CH3, 7,8-dihydro 156: R1=CH3, R2,R3=OCH2O, R4=R5=OCH3, R6=CH2CO(CH2)10CH3
127: R1=R4=OCH3, R2=R3=OH 157: R1=CH3, R2,R3=OCH2O, R5=OCH3, C9-OCH3, R6=CH2COCH3
128: R1=R2=R3=OCH3, R4=OH 158: R1=CH3, R2,R3=OCH2O, R4=R5=OCH3, R6=CH=CH-Ph-OH(OCH3)
129: R1=OH, R2=OCH3, R3,R4=OCH2O 159: R1=CH3, R2,R3=R4,C9=OCH2O, R6=CH2COCH3
130: R1,R2=OCH2O, R3=R4=OCH3, C13-OCH3 161: R1=CH3, R2,R3=R4,R5=OCH2O, R6=CH2COOH

Fig. (5). Chemical structures of protoberberine, benzophenanthridine and dihydrobenzophenanthridine alkaloid.

substituented proto- berberine derivatives were synthesized and
evaluated for their antifungal activity against various pathogenic
fungi. The 13-substituented protoberberine displayed potent anti-
fungal activity than protoberberine alkaloids and the length of the
alkyl sidechain at 13-poaition has great effect on the antifungal
activity (13-hexyl＞13-ethyl＞13-methyl derivatives) [76-78].
7. PROTOPINE ALKALOIDS
Protopine (131) and β-allocryptopine (132) (Fig. 3), the most
common protopines alkaloid in nature product field, were screened
for their antiviral activity against HBV. Protopine displayed me-
dium activity in reducing the level of HBeAg and HBsAg with the
average IC50 values of 2.62 and＞4.25µM, respectively. However,
alkaloids 132 did not show any significant activity against HBeAg
and HBsAg, which indicated that the replacement of the adjacent
methoxyl at the position of C-9 and C-10 by methylenedioxy could
enhance the anti-HBV activity [58, 79, 80]. Alkaloids 131 and 132
were also tested for anti-HSV and PI-3 virus. Both alkaloids pos-
sessed strong activity against PI-3 virus with MIC values ranging 1-
32 and 8-32µg/mL, respectively, however, both alkaloids were
inactive to HSV [20, 81]. Argemexicaine A (133), argemexicaine B
(134), 131 and 132 (Fig. 3) were tested for anti-HIV-1 activity,
unfortunately, none of them showed significant activity [82].
Crytopine (135), 131 and 132 (Fig. 3) were obtained from Turk-
ish Fumaria and Corydalis species and tested for antibacterial ac-
tivity against one Gram-positive (S. aureus) and two Gram-negative
bacteria (E. coil and P. aeruginosa). All alkaloids exhibit medium
activity toward the tested bacteria with the inhibitory zone diameter
ranging from10 to13 mm at the concentrate of 20 µg/disc [82].
Alkaloids 131 and 132 were also the main components of Macleaya
cordata, which was a traditional Chinese herbal medicine and suc-
cessfully used in veterinary medicine and agriculture, and examined
for their antibacterial activity against E. coil, P. aeruginosa, S.
aureus and Streptococcus. agalactiae. Both alkaloids displayed
medium activity toward E. coil, P. aeruginosa and S. agalactiae
with MIC values of 125 µg/mL, however, compounds 131 and 132
only showed weak against against S. aureus with MIC values of
250 µg/mL [83, 84]. Further studies demonstrated that both alka-
loids possessed strong antibacterial activity against K. pneumonie
and A. baumannii with MIC values of 8 µg/mL [4]. Protopine also
exhibit medium activity against H. pylori with MIC values ranging
from 25 to 100 µg/mL [65]. Oreophiline (136) and 131 (Fig. 3) was
estimated for their antifungal activity against phytopathogenic fungi
named Cladosporium herbarum. The minimum amount needed for
both alkaloids to inhibit fungal growth on thin layer chromatogra-
phy (TLC) plate being＞10 µg [85, 86]. Alkaloids 131 and 132
10 Current Organic Chemistry, 2017, Vol. 21, No. 00
displayed prominent antifungal activity against C. albicans with
MIC values of 4 µg/mL, respectively [20]. Compounds 131 and 135
were tested for their activity against seven kinds of fungi, however,
only compounds 135 showed remarkable activity against Epider-
mophyton floccosum at the concentration of 300 µg/mL [47]. Fur-
ther studies reported the alkaloid 132 possessed weak antifungal
activity against S. gallinarum with MIC values of 250 µg/mL [50].
Interesting, alkaloids 131, 132, 135 and related 15 synthesized de-
rivatives were evaluated for their activity against ten phytopatho-
genic fungi, the structure-activity relationship studies indicated that
the methylenedioxy linkage at C2, C3 or C9, C10 was an important
moiety for enhancement the antifungal activity [87].
8. BENZOPHENANTHRIDINE AND DIHYDROBENZO-
PHENANTHRINE ALKALOIDS
2000 drugs and nature products were screened for their antiviral
activity against HIV. Finally, sanguinarine (137) (Fig. 5), which
was regarded as a non-peptidomimetic HIV protease inhibitor,
showed strong activity with IC50 values of 4.3 µg/mL [88] (Table 1).
156 pure natural products, including fagaronine cholride (138), N-
demethyl- fagaronine (139), nitidine chloride (140) and chel-
erythrine chloride (141) (Fig. 5), were tested against HIV-1 and
HIV-2 reverse transcriptase (RT). Alkaloids 138 displayed potent
activity against both viruses with IC50 values of 8.5 and 9.5 µg/mL,
respectively (Table 1). However, N-demethylfagaronine (139) did
not show any significant activity, which suggested that the iminium
ion (-C=N+-CH3) was the key structural characteristic for anti-HIV
activity. Alkaloids 140 exhibited remarkable activity against HIV-1
and HIV-2 RT with IC50 values of 7.4 and 7.1 µg/mL, respectively
(Table 1). However, alkaloid 141 did not show any significant ac-
tivity, which indicated that the adjacent methoxyl at C-8 and C-9
was easy integration with HIV RT protein than this group at C-7
and C-8. Furthermore, the methylenedioxy at C-2 and C-3 played
an important role on enhancement of the antiviral activity by com-
paring the anti-HIV-1 and HIV-2 effect of 138 and 140 [89, 90]. 6-
acetonyldihydrochelerythrine (142) (Fig. 5) was isolated from the
MeOH fraction of Formosan Argemone Mexicana L., and estimated
for its antiviral activity against H9 cells infected with HIV-1. The
result suggested that alkaloid 142 displayed significant anti-HIV
activity with EC50 and TI values of 1.77 µg/mL and 14.6, respec-
tively [91] (Table 1). Dihydrosanguinarine (143), dihydro- chel-
erythrine (144), oxysanguinarine (145), oxychelerythrine (146),
ethoxylsanguinarine (147), ethoxylchelerythrine (148), 137 and
144 (Fig. 5) were tested for their antiviral activity against HBV.
Alkaloids 137 and 144 significantly inhibited HBeAg and HBsAg
secretion and HBV DNA replication on Hep G 2.2.15 cells with
IC50 values of 0.28, ＜0.028, ＜0.014 and 0.068, 0.034, 0.017
mmol/L, respectively. However, both alkaloids possessed high
cytotoxicity. The rest dihydrobenzophenanthridine displayed low
cytotoxicity than sanguinarine and chelerythrine, but the activity
against HBeAg, HBsAg and HBV DNA replication also decreases,
which indicated that the quaternary imine cation in benzophenan-
thridine played an important role in their anti-HBV activity and
cytotoxicity [91, 92]. Norsanguinarine (149) (Fig. 5) estimated its
activity against HCV and PI-3, the result revealed this alkaloid
possessed moderately anti-PI-3 activity with MIC values ranging
from 16 to 32 µg/mL [20].
6-hydroxydihydrosanguinarine (150), 6-hydroxy- dihydrochel-
erythrine (151), and 143-144 (Fig. 5) were isolated from the aerial
part of Chelidonium majus Linn. (Papaveraceae) and evaluated for
their antibacterial activity against clinical strains of MRSA and
Qing et al.
clinical isolates of extend spectrum β-lactamase (ESBL)– produc-
ing strains. Alkaloids 150 and 151 were potently active against
MRSA strains with MICs values ranging 0.49-7.81 and 0.98-15.63
µg/mL, respectively. However, compounds 143-144 were almost
200 and 300-fold less activity than 150 and 151, respectively. Alka-
loids 150 and 151 also showed significant activity against 18 iso-
lates of ESBLs–producing strains from E. coil with MIC values
ranging 15.63-250 and 62.5-500 µg/mL, respectively. However,
compounds 143-144 were almost 50 and 20-fold less activity than
150 and 151, respectively. Above phenomenon suggested that the
hydroxyl at the position of 6 was a key part for dihydrobenzophe-
nanthridine alkaloids to enhance the antibacterial activity [93, 94].
6-methoxyl-sanguinarine (152), 6-methoxylchelerythrine (153),
137, 141 and 143-148 (Fig. 5) were tested for their antibacterial
activity against S. aureus, E. coil, Aeromonas hydrophila and Pas-
teurella multocida. All tested alkaloids displayed antibacterial ac-
tivity against S. aureus and E. coil with MIC values ranging 12.5-
50µg/mL. By comparing the activity of 137 and 141 with those of
their dihydro-derivates (152-153 and 143-148), it can clearly be
seen that the antibacterial activity reduced or disappeared when the
double bond of C=N+ in the molecular of 137 and 141 was reduced
to tertiary amine. Which strongly indicated that the C=N+ group in
benzophenanthridine alkaloids was the determinant for their anti-
bacterial activity [83, 95]. Decarine (154), norchelerythrine (155),
tridecanon-chelerythrine (156), 6-acetonyldihydronitidine (157) and
zanthocapensine (158) (Fig. 5) were isolated from the MeOH frac-
tion of the roots of Zanthoxylum capense and evaluated for their in
vitro antibacterial against two Gram-positive (S. aureus and E. fae-
calis) and three Gram-negative bacteria (P. aeruginosa, E. coil and
M. tuberculosis). Alkaloids 154-155 and 157-158 showed signifi-
cant inhibitory activity against S. aureus ATCC 6538 with MIC
values ranging 12.5-50 µg/mL. Compounds 154 and 156 displayed
strong activity toward M. tuberculosis H37Rv ATCC 27294 with
MIC values of 1.6 and 12.5 µg/mL, respectively, and a low cytotox-
icity against human THP-1macrophage (IC50 value of 66.0 ±
4.5µg/mL) and a high SI (41.2) were observed for alkaloids 154
[96-98]. Two benzophenanthridine alkaloids, 6-acetonyldihydro-
avicine (159) and 157 (Fig. 5), were isolated from the stem bark of
Zanthoxylum tetraspermum and assessed for antibacterial activity
against S. aureus and E. coil. Both alkaloids displayed remarkable
inhibition activity toward S. aureus with MIC values of 1.56 and
3.12 µg/mL, respectively [99]. Alkaloids 137 and 141 possessed
broad and strong antibacterial activity, such as B. subtilis, E.coil
[100, 101], H. pylori [65], Bacillus cereus, Tetracoccus [102] and
some kinds of phytopathogenic bacteria [103]. As we all know, the
emergence of multidrug-resistant bacteria has prompted attempts to
discover novel antibiotics with different mechanism of action. FtsZ,
an essential protein for bacteria cell division, was regarded as an
attractive target for development of new antibacterial agents. There-
fore, a series of 1, 12-phenyl substituted sanguinarine derivatives
were synthesized as FtsZ-targeting antibacterial substances and
tested for their activity against S. aureus and E. faecalis. The data
indicated that the sanguinarine derivatives strongly enhance anti-
bacterial activity relative to the parent alkaloid [104, 105].
Alkaloids 137, 141, 143-144 and 150-151 were isolated from
the herbal of Chelidonium majus Linn and assessed for their anti-
fungal activity against six clinical isolated Candida species. Com-
pounds 150 and 151 showed potent activity against Candida albi-
cans strains with MIC values of 4-32 µg/mL; however, the rest
tested alkaloids displayed comparatively weak activity, which indi-
cated that 6-hydroxy group played an important role in the antifun-
gal activity for dihydro-benzophenanthridine alkaloids [106]. Papa-
Antiviral, Antibacterial and Antifungal Activities of Isoquinoline Alkaloids Current Organic Chemistry, 2017, Vol. 21, No. 00 11

6 5 4 5
7 4 5' 4'
R5 8 3 R4 R1 3 6 R1 6' 3' OCH3
R1 N 2'
R2 2 N N 10 OCH3
R6 9 R2 2 R3 H3CO 7'
1 13 1'
R 11 9
10 11 1 8 8'
12 1
2 8
162: R1=CH3, R2=H, R3,R4=OCH2O, R5=R6=OCH3
9 12
163: R1=CH3, R2=H, R3=R4=R5=R6=OCH3 O N 7
H3CH2C 3
164: R1=CH3, R2=H, R3,R4=OCH2O, R5=R6=OCH3, C12-OH 10 11 4 6
O
165: R1=CH3, R2=H, R3,R4=R5,R6=OCH2O, C12-OH
180: R1=OCH3, R2=OH, C13-OCH2CH3 204: R1=OCH3, R=SO4-.7H2O, !1('2')
166: R1=CH3, R2=O, R3,R4=OCH2O, R5=R6=OCH3
181: R1=OCOCH3, R2=OCH3, C13-OCOCH3 205: R1=OH, R=C2HO4-, !1('2')
167: R1=CH3, R2=H, R3=R5=R6=OCH3, R4,C4=OCH2O
182: R1,R2=OCH2O, C8-OH, C13-O 206: R1=OH, !1('2')
168: R1=CH3, R2=O, R3=R5=R6=OCH3, R4,C4=OCH2O
183: R1,R2=OCH2O, C8-OCOCH3, C13-O
3 4 207: R1=OCH3, R=Cl-
5
184: R1,R2=OCH2O, C8-OH, C13-OH
2
185: R1,R2=OCH2O, C8-O 208: R1=OCH3, !1('2')
N 209: R1=OH, R=Cl-
R2 1 R1 186: R1,R2=OCH2O
O 7 187: R1=OH, R2=OCH3, C13-OCOCH3 210: R1=OCH3
188: R1=OH, R2=OCH3, C8-O, C13-OH
11 8 189: R1,R2=OCH2O, C8-OH
10 9 190: R1=OH, R2=OCH3, C8-O HO
R3 R4 191: R1=OCOCH3, R2=OCH3, C8-O
169: R1=CH3, R2=R3=R4=OCH3 192: R1=OCOCH3, R2=OCH3, C8-OH
170: R1=H, R2=R3=R4=OCH3, !4(5), !6(7), C7-O O
2
171: R1=H, R2=R3=C11=OCH3, R4=H, !4(5), !6(7), C7-O R2 3 1
N
H CH3
11 H
172: R1=H, R2=R3=OCH3, R4=H, C11-OH, !4(5), !6(7), C7-O R HO
3 4 10 16
5 4 12 15
R5
R1 6 3
5 13 9 N
14 203
N R1
8
R2 7
8 1 R4 6 7
11 R5
10 9
O 193: R1=H, R2=OCH3, R3=OH, R4=R5=OAc, C8-OAc, !8(14)
R3 12
13 194: R1=CH3, R2=OCH3, R3=OH, R4=R5=OAc, C8-OAc, !8(14)
R4 O
195: R1=CH3, R2=OCH3, R3=OH, R4=O, R5=OCH3, C8-OCH3, !6(7)
173: R1,R2=R3,R4=OCH2O,
174: R1,R2=OCH2O, R3=R4=OCH3, 196: R1=CH3, R2=OCH3, R3=OH, R4=O, R5=OCH3, !6(7)
175: R1,R2=R3,R4=OCH2O, 197: R1=CH3, R2=OCH3,C2-OCH3, R2=H, R4=O, R5=OCH3, C8-OCH3, !6(7)
176: R1,R2=OCH2O, R3=R4=OCH3, 1R, 9R 198: R1=CH3, R2=OCH3, R3=OH, R4=OCH3, R5=O, D5(6), !8(14)
177: R1,R2=OCH2O, R3=R4=OCH3, 1R, 9S 199: R1=CH3, R2=OCH3, C2-OCH3, R3=H, R4=OCH3, R5=O, !5(6)
178: R1,R2=R3,R4=OCH2O, 1S, 9S and 1R, 9R 200: R1=CH3, R2=OCH3, C2-OCH3, R3=H, R4=OCH3, R5=O, !5(6), !8(14)
179: R1,R2=R3,R4=OCH2O, 1R, 9S and 1S, 9R 201: R1=CH3, R2,C2=OCH2O, R3=H, R4=OCH3, R5=O, !5(6)
202: R1=CH3, R2=R4=OCH3, C2-OCH3, R3=H, R5=O, !5(6), !8(14)

Fig. (6). Chemical structures of pavine, cularine, phthalideisoquinoline, spirobenzylisoquinoline, promorphine, morphine and ipecac alkaloid.

voriendine (160), spallidamine (161) and 144 (Fig. 5) were tested
for their fungitoxic activity against plant pathogenic fungus Cla-
dosporium herbarum. Alkaloids 160 exhibited strong antifungal
activity and the minimum amount of compound needed to inhibit
the growth of the fungi on TLC plates was 3 µg [85-86]. In order to
understand the antifungal activity of benzophenanthridine and di-
hydrobenzophenanthridine alkaloids and their structure-activity
relationship, a series of derivatives were synthesized and assessed
for their activity. The result suggested that the C=N+ group was the
determinant for the antifungal activity of benzophenanthridine alka-
loids, and generally, electron- withdrawing substituents signifi-
cantly enhance the antifungal activity while electron-donating sun-
stituents cause a decrease of the activity [107-109].
9. PAVINE ALKALOIDS
Bioassay-guided fraction of the ethanol extract of Cryptocarya
chinensis has led to the isolation of 5 pavine alkaloids, including
eschscholtizidine (162), argemonine (163), 12-hydroxy-
eschecholtizidine (164), 6-hydroxycry- chine (165) and esch-
scholtizidine N-oxide (166) (Fig. 6). Alkaloids 162-166 have tested
their antiviral activity against H9 cells infected with HIV, however,
none of the tested compounds showed significant activity [110,
111]. A pavine alkaloid named -(-)Thalimonine (167) (Fig. 6) was
investigated for its anti-HCV activity, the data showed that the alka-
loid could irreversibly inhibit the replication of HCV in MDBK
cells at a nontoxic concentration range between 0.1 and 100 µM.
Interestingly, zinc complex, which was an clinical drug used for the
inhibition of the key steps of HSV-1 replication, combination with
alkaloid 167 exerted significant anti-HSV activity and decreased
cytotoxicity [112-114]. -(-)Thalimonine N-oxide (168) and 167
(Fig. 6) were isolated from the Mongolian plant Thalictrum simplex
(Ranunculaceae) and estimated for their anti-influenza virus activity
against strain Weybridge (H7N7) and strain Rostock (H7N1). Alka-
loids 167 displayed remarkable antiviral activity against both virus
replication with EC50 values of 0.1 (SI=640) and 0.6 (SI=106.6)
µM, respectively. However, compound 168 was less active to both
virus strains (SI values of 15 and 60, respectively) [115-120]. The
antibacterial and antifungal activities of pavine alkaloids were
rarely reported in the past several decades.
10. CULARINE ALKALOIDS
Four cularine alkaloids, cularine (169), oxocularine (170),
oxosarcocapnine (171) and oxosarcocapnidine (172) (Fig. 6) were
assessed for their antiviral activity against HSV and PI-3. All tested
12 Current Organic Chemistry, 2017, Vol. 21, No. 00
compounds displayed medium anti-HSV and PI-3 activity with
MIC values ranging from 8 to 32 µg/mL; however, none of alka-
loids was active to HSV. At the same time, the four cularine alka-
loids were tested for their antibacterial and antifungal activity
against seven bacterial strains (B. subtilis, S. aureus, E. coil, P.
aeruginosa, P. mirabilis, K. Pneumonia and A. baumannii) and one
fungal stain (C. albicans). Only alkaloids 172 showed significant
antibacterial and antifungal activity toward K. pneumonia, A. bau-
mannii and C. albicans with MIC values of 8, 8, 4 µg/mL, respec-
tively [5, 20, 83].
11. PHTHALIDEISOQUINOLINE ALKALOIDS
Adlumidine (173) (Fig. 6) and other seventeen alkaloids were
isolated from Corydalis saxicola and were tested for their anti-HBV
activity, alkaloid 173 displayed medium activity on HBsAg and
HBeAg with IC50 values of 1.35 and ＞2.73 µM [58, 121]. α-
Hydrastine (174) and (±)-bicuculline (175) (Fig. 6) exhibited me-
dium or weak anti-PI-3 activity with MIC values ranging from 16 to
32 µg/mL. However, alkaloid 174 showed significant antibacterial
(K. pneumonia and A. baumannii) and antifungal (C. albicans)
activity with MIC values of 8, 8 and 4 µg/mL, respectively [5, 20].
(1R, 9R)-β-hydrastine (176) and (1S,9R)-β-hydrastine (177) (Fig. 6)
were isolated from the traditional American herbal medicine Gold-
enseal (Hydrastis canadensis) and evaluated for their antibacterial
activity against H. pyroil. Interestingly, both alkaloids showed me-
dium activity with the same MIC50 values of 100 µg/mL, which
indicated that the different configuration of both alkaloids has less
effect on the antibacterial activity [66, 122]. Alkaloid 176 was also
isolated from Coptis chinensis Franch (Ranunculaceae) and as-
sessed for their inhibitory activity against eight bacterial strains (E.
coil, K. pneumonia, B. subtilis, S. aureus, S. epidermidis, M. luteus,
Proteus vulgaris and Salmonella typhimurium). Unfortunately, all
tested bacterial strains were not susceptible to the alkaloid (MIC
values more than 400 µg/mL) [67]. (±)- α-Hydrastine (178) and (±)-
β-hydrastine (179) (Fig. 6) were isolated from Corydalis longipes,
and both alkaloids showed considerable activity against some sap-
rophytic and phytopathogenic fungi. Interesting, mixture of both
alkaloids was more effective than each one individually [123, 124].
12. SPIROBENZYLISOQUINOLINE ALKALOIDS
Eight spirobenzylisoquinoline alkaloids, including 13-ethoxyl-
8-dehydroxylfumaritine (180), fumarophycine (181), (±)-sibiricine
(182), (±)-sibiricine acetate (183), dihydrosibiricine (184), fumar-
iline (185), 8-dehydroxylcapreoline (186) and fumarophycine (187)
(Fig. 6), were obtained from sixteen Fumaria and six Corydalis
species growing in Turkey and estimated for their antiviral activity
against HBV. Alkaloids 183 and 187 displayed remarkable anti-
HBV activity with IC50 values of 196.3 and 67.68 nM, respectively.
Furthermore, both alkaloids were 90- and 250-fold more potent,
respectively, than tenofovir (positive control) in reducing the level
of HBsAg. And the TI values of alkaloids 183 (TI, 187) and 187
(TI, 492) were 94- and 246-fold, respectively, higher than the posi-
tive drugs. The above result suggested that both compounds, espe-
cially alkaloid 187, possessed great potential become candidate
drug of anti-HBV [5, 79]. (-)-corpaine (188), (-)-dihydrofumariline
(189), (+)-parfumine (190), parfumine acetate (191), dihydropar-
fumine acetate (192), 181-185 and 187 (Fig. 6) were also isolated
from Fumaria and Corydalis species growing in Turkey and tested
for their antiviral, antibacterial and antifungal activity. All tested
alkaloids showed significant activity against PI-3 with CPE inhibi-
tory concentration ranging from 2 to 32 µg/mL, especially for com-
Qing et al.
pound 187 (2 µg/mL). Alkaloids 182-184, 187 and 192 showed
strong antibacterial (K. pneumonia and A. baumannii) and antifun-
gal activity (C. albicans) with MIC values of 8, 8, 4 µg/mL, respec-
tively [20].
13. PROMORPHINAN AND MORPHINAN ALKA LOIDS
FK-3000 (193), cephakikicine (194), cephamonine (195), 14-
episinomenine (196), tannagine (197) and sinoacutine (198) (Fig. 6)
were isolated from the MeOH extract of stephania cepharantha.
Those promorphine-type alkaloids were tested for their antiviral
activity against HSV. Alkaloid 193 displayed remarkable activity
against HSV-1, HSV-1 TK¯ and HSV-2 (IC50 values of 7.8, 9.9 and
8.7 µg/mL, respectively) with in vitro TI values of 90, 71 and 81,
respectively, and visible cytotoxicity was not detected at a concen-
tration higher than 30µg/mL, which indicated that alkaloid 193 was
a promising compound as an anti-HSV agent against HSV-1, acy-
clovir resistant-type HSV-1 and HSV-2 [19]. The anti-HIV-1 activ-
ity of compound 193 was also examined, the result uncovered that
FK-3000 was a potent inhibitory substance and it is completely
inhibited the cytopathic activity of HIV-1 on MT-4 cell at 7.8
µg/mL [25] (Table 1). Alkaloid 194 showed medium activity
against HSV-1 with IC50 values of 44.4µg/mL, while alkaloids 195-
198 were inactive [19]. Three promorphine-type alkaloids including
8,14-dihydroflavinantine (199), flavinantine (200) and 8,14-
dihydroamurine (201) (Fig. 6) were isolated from the aerial parts of
papaver pseudocanescens M. Pop. of Mongolian origin. Their anti-
viral effect against several viral diseases which belong to different
taxonomic groups and represent significant human pathogens were
assessed. Alkaloids 199 and 200 displayed significant activity
against human rhinovirus 14 with IC50 values of 199±15.56 and
65±7.07, respectively; however, alkaloid 201 was inactive [50]. O-
methylflavinantine (202) (Fig. 6) was isolated from the methanolic
extract of Glaucium oxylobum and tested its antifungal activity
against six fungal strains. Unfortunately, this alkaloid did not show
any significant activity [48]. It is has been well known that mor-
phine (203) (Fig. 6) has been used for long time as local anesthetics
agent. Other investigation showed that morphine possessed anti-
HSV-1 activity by modifying the host response to HSV-1 infection
instead of reducing viral replication rates [125, 126]. The antibacte-
rial and antifungal activity of alkaloid 203 against 11 microorgan-
isms was also studied; however, morphine did not show any signifi-
cant activity [127].
14. IPECAC ALKALOIDS
Six ipecac-type alkaloids including O-methyl- psychotrine sul-
fate heptahydrate (204), psychotrine- dihydrogen oxalate (205),
psychotrine free base (206), emetine hydrochloride (207), dihydro-
emetine (208) and cephaeline hydrochloride (209) (Fig. 6) were
tested for their antiviral activity against HIV-1 and HIV-2 reverse
transcriptase. Alkaloids 204 and 205 showed remarkable activity
toward HIV-2 RT with IC50 values of 6.4 and 6.0µg/mL, respec-
tively. Notably, these values were approximately four-fold less than
those observed with HIV-1 RT (21.8 and 18.3µg/mL for alkaloid
204 and 205, respectively) (Table 1). However, alkaloids 206-209
did not show any significant activity toward HIV-1 and HIV-2 RT
[90, 128]. Emetine (210) (Fig. 6) is the main alkaloid of ipecac and
one of the active substances of psychotria ipecacuanha. This natu-
ral plant alkaloid was tested for its antiviral activity against HIV-1,
Dengue virus (DENV) and vaccinia virus. Pharmacological studies
showed emetine possessed significant inhibition activity on HIV-1,
Antiviral, Antibacterial and Antifungal Activities of Isoquinoline Alkaloids
DENV and vaccinia virus replication at a noncytotoxic dose [129-
131].
CONCLUSION
Introduction of new antibiotics or lead compound (antiviral, an-
tibacterial and antifungal) in 21st century has been an urgent and
difficult task. Therefore, 210 compounds which belong to seventeen
types of isoquinoline alkaloids were screened for their antiviral and
antimicrobial activity. Some isoquinoline alkaloids, such as berber-
ine (103) and sanguinarine (137), have great potential to become
antibiotic agents. Furthermore, the structure-activity relationship of
isoquinoline alkaloids was also summarized. The quaternary nitro-
gen and the OCH2O group at C-2 and C-3 have a great impact on
enhancing the antiviral, antibacterial and antifungal activity of N-
methyltetrahydroprotoberberine, protoberberine and benzophenan-
thridine alkaloids.
CONSENT FOR PUBLICATION
Not applicable.
CONFLICT INTEREST
The authors confirm that this article content has no conflict of
interest.
ACKNOWLEDGEMENTS
This work is supported by “Innovation Project of Postgraduate
in Hunan Province (CX2014B302)” and “National Natural Science
Foundation of China (Grant No. 31200615)”.
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