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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5596_Библиотеки_им_академика_М_И_Перельмана
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manzamine- related alkaloids have been isolated from Indo- Pacic sponges and have
shown potent anti- HIV, antitumor, antibacterial, and cytotoxic activities (Yousaf et al.
2004; Peng et al. 2003). Similarly, the compound azin was isolated from the fruiting
bodies of Suillus granulatus and displayed moderate anti- HIV- 1 activity (Su et al.
2002; Dong et al. 2007; Nakatsuka et al. 1986). The isolation of these compounds
β- Carbolines
from natural sources allows for the identication of new and unique chemical entities
with potential therapeutic applications.
9.3.2 cheMicAl syNThesis
The synthesis of β- carboline derivatives is of interest due to their various biological
activities, including anti- HIV potential. Several synthetic routes have been explored
to prepare 1- substituted β- carbolines, which are of particular interest for medicinal
chemistry research. These routes include the Pictet– Spengler reaction, Bischler–
Napieralski reaction, cyclization of 2- acyltryptamine, and dehydrogenation of appropriate 1,2,3,4- tetrahydro- 9H- β- carboline derivatives (Peduto et al. 2012; Suzuki et al.
2005; Hagen et al. 1989; Hagen and Cook 1988). However, some of these synthetic
methods pose challenges in terms of yields, regioselectivity, and efciency. The use
of microwave- assisted reactions has shown promise in improving the yields of certain
β- carboline derivatives.
In summary, the exploration of β- carboline derivatives for anti- HIV studies
involves two main approaches: isolation from natural sources, particularly marine
organisms, and synthesis through various chemical reactions. Both approaches contribute to the discovery and development of potential anti- HIV agents with diverse
chemical structures and biological activities.
9.4 BIOLOGICAL DISCUSSION OF β- CARBOLINES AS
ANTI- HIV AGENTS
The following section present an overview of the research conducted thus far on
β- carboline- based anti- HIV activities. The structures and corresponding EC50 values
of these compounds are provided in the gure (Name or coding of structures are
given as presented in original research paper). This study aims to provide a concise
overview of the progress made in identifying and evaluating β- carboline derivatives
as potential agents against HIV.
Junko Ishida et al. pioneered the reports of β- carbolines as anti- HIV agents. They
discussed the isolation of 1- methoxycanthinone (1) and 5- methoxycanthinone (2) and
other compounds, out of which 1- methoxycanthinone and 5- methoxycanthinone
are the β- carbolines (Figure 9.2) (Xu et al. 2000). The study evaluated the biological
activities of these compounds, focusing on their anti- HIV and cytotoxic effects. The
results showed that 1- methoxycanthinone, a β- carboline derivative, exhibited EC50
value of 0.26 µg/ mL and a therapeutic index (TI) greater than 39 establishing itself
as potent anti- HIV agent. This suggests its potential as an anti- AIDS drug candidate.
5- methoxycanthinone, a β- carboline derivative, exhibited potent anti- HIV activity
against HIV- infected H9 cells, with an impressive TI of over 391. The IC50 value
(concentration that inhibited uninfected H9 cell growth by 50%) was greater than
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β-Carbolines as Anti- HIV Agents
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FIGURE 9.2 Structure of 1- methoxycanthinone, and 5- methoxycanthinone.
100 µg/ mL, while the EC50 value (concentration that inhibited viral replication by
50%) was 0.256 µg/ mL. This discovery highlights the potential of β- carbolines as a
new class of compounds for anti- AIDS drug development. The study suggests that
further research, including structure– activity relationship studies of β- carbolines, is
warranted to explore their potential as anti- HIV agents. The ndings provide clues
about the therapeutic potential of β- carboline derivatives and their potential application in the development of therapeutic compounds for the treatment of HIV/ AIDS.
Further, their group discussed the evaluation of the anti- HIV potency of
β- carboline derivatives (derivatives 1 to 28, Figures 9.3 and 9.4), particularly focusing
on harman (structure a, Figure 9.3) and its analogues (Ishida et al. 2001). Harman, a
β- carboline compound, was identied from Symplocos setchuensis and observed to
inhibit HIV replication in H9 lymphocyte cells. Among the 28 derivatives of harman
evaluated, compound 19 (N- butylharmine) exhibited anti- HIV activity (EC50= 0.037
µM) with a therapeutic index (TI) of 210. This compound demonstrated the most
signicant potency in the series. Other compounds, such as harmine (Figure 9.3, 3),
N- ethylharmine (Figure 9.3, 12), 6- bromoharmine hydrobromide (Figure 9.4,
18), along with 33, showed considerable activity with moderate TI values. Other
derivatives were less potent compared to harman. The study revealed several trends in
the anti- HIV activity of the β- carboline derivatives. Functionalization with methoxy
group at the 7- position of harmine (3) resulted in improved activity, while the
isopropoxy, hexyloxy, decyloxy, hexadecyloxy, and 7- camphanoyl derivatives were
inactive. The addition of a methyl group at the 1- position of harman was found to be
important for activity. Hydrogenation of harman to produce derivative 15 (3,4- dihydro
β- carboline) resulted in lower anti- HIV activity. Bromination of 9 at C- 6 resulted in
the most potent compound (18), with improved water solubility. The fully conjugated
derivative (27) maintained some activity. Compound 28 highlights the signicance
of β- carbolines, as the benzimidazole- containing compound exhibited no anti- HIV
activity. Additionally, alkylating the nitrogen of indole (11, 12, and 13) enhances the
anti- HIV activity, with derivative 13 (N- butyl) exhibiting greater potency than 12
(N- ethyl), suggesting the importance of the alkyl chain length.
Karumanchi V. Rao et al conducted two studies focusing on the investigation of
manzamine- type alkaloids for their bioactivity against HIV- 1 (Figure 9.5) (Rao et al.
2006; Rao et al. 2004). In the rst study, from Indonesian spone, several new manzamine-
type alkaloids were isolated. They evaluated anti- HIV- 1 activities of these manzamines
and their oxa- derivatives. They observed that manzamine A and 8- hydroxymanzamine
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β- Carbolines
FIGURE 9.3 Structure of harman (5) and its analogues from 7 to 22 evaluated for antiHIV study.
A displayed greater potency than manzamines E, F, and Y, emphasizing the signicance
of functionalization of hydroxyl group and introduction of the eight- membered ring
on β- carboline moiety for HIV- 1 activity. In the second study, a series of manzamine
alkaloids were isolated from a sponge species of the genus Acanthostrongylophora. The
researchers found that manzamine A, manzamine A N- oxide, and 8- hydroxymanzamine
A exhibited higher anti- HIV- 1 activity compared to manzamines E and F, indicating the
crucial role of the eight- membered ring in their effectiveness. The ndings contribute to
the understanding of structure– activity relationships of manzamine alkaloids and their
potential as antimicrobial and anti- HIV agents.
P.- W. Hsieh et al. reported two carbolines, drymaritin and an isomer of canthin- 4one, isolated from Drymaria diandra (Figure 9.6) (Hsieh et al. 2004). They investigated
the anti- HIV activity in H9 lymphocytes and found that drymaritin exhibited signicant anti- HIV effects, with an EC50 value 0.699 µg/ mL and a therapeutic index (TI)
of 20.6. The canthin- 4- one isomer also showed anti- HIV activity with EC50 and TI
values same as drymaritin, indicating the potential of this series of compounds.
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β-Carbolines as Anti- HIV Agents
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FIGURE 9.4 Structure of harman and its analogues from 23 to 34 evaluated for anti-
HIV study.
In a study by Jian- Guo Tang, azin and its derivatives were subjected to the anti-
HIV activity test. Flazin, isolated from the fruiting bodies of Suillus granulatus,
exhibited weak anti- HIV activity with an EC50 of 2.36 µM (AZT (3’- azido- 3’-
deoxythymidine) was used as a standard with an EC50 value of 0.009 µM (Tang et al.
2008). To explore the structure– activity relationship of azin, 46 derivatives were
developed and evaluated for their anti- HIV activities (Figures 9.7, 9.8, 9.9, 9.10).
Among them, the most effective derivative was found to be azinamide (9a), which
had an EC50 value of 0.38 µM and TI of 312. Substitutions such as amide modication
at C(3) and S- atom in the 1’- position enhanced the anti- HIV activity, while the
introduction of a carboxylate or CH2OH group at C(3) yielded inactive compounds.
The study suggests that azinamide (9a) can be viewed as a hopeful anti- HIV agent.
The SAR analysis provides insights into the role of functionalization in enhancing the
anti- HIV activity of azin and its derivatives, guiding the design and development of
more potent molecules for anti- HIV therapy.
Ashok et al. designed and explored novel β- carboline derivatives as inhibitors of
HIV- 1 reverse transcriptase (RT) (Ashok, Sharma, et al. 2015). They aimed to address
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β- Carbolines
FIGURE 9.5 Structure of Manzamine alkaloids explored for their anti- HIV activity by Rao
et al. 2004.
the issue of resistance that arises with the use of existing HIV- 1 RT inhibitors. Using
Autodock v4.2 they carried out molecular docking studies to assess the binding afnity
of the designed analogues against wild and mutant strains of HIV- 1 RT. The results
of the docking studies indicated that several β- carboline analogues demonstrated signicant binding free energy against wild and mutant strains of HIV- 1 RT. Compounds
9H3NH4CN, 9H6CNP, and 9H4CN exhibited notable binding free energy values
against both strains, comparable to standard drugs. Additionally, these drugs projected
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FIGURE 9.6 Structure of drymaritin and an isomer of canthin- 4- one explored for their anti-
HIV activity.
FIGURE 9.7 Structure and EC50 of Flazin and its analogues (5a- 5i).
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β- Carbolines
FIGURE 9.8 Structure and EC50 of Flazin and its analogues (5j- 6l).
inhibitory constant values (Ki) indicate encouraging action against both stains of HIV-
1 RT (Figure 9.11, 9.12, 9.13, 9.14, 9.15). The designed derivatives also demonstrated
a variety of molecular interactions with target protein, including electrostatic and
hydrogen bonding interaction. The hydrogen bonding interactions with hydrophilic
amino acids of the HIV- 1 RT enzyme were discovered to be caused by hydrophilic
body substitution and hydrogen bond donor group of the phenyl ring. Additionally,
the target protein’s non- nucleoside inhibitor binding pocket (NNIBP) aromatic amino
acids were contacted by hydrophobic wings of β- carbolines derivatives through
π- π and π- cation interaction. Like previous non- nucleoside reverse transcriptase
inhibitors (NNRTIs), the designed β- carboline derivatives takes up the buttery like
shape, which allowed for interaction between amino acid residues of HIV- 1 RT. The
proposed analogues’ potential as next- generation NNRTIs with promising anti- HIV- 1
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FIGURE 9.9 Structure and EC50 of Flazin and its analogues (8a- 11b).
effectiveness and enhanced pharmacokinetic proles was shown by assessments of
the Lipinski drug similarity and ADMET (absorption, distribution, metabolism,
excretion, and toxicity) features. To corroborate their docking ndings their active
methyl groups then carried out the experimental studies as discussed in the following.
Further, P. Ashok et al carried out a study focusing on the synthesis of new
β- carboline derivatives (29- 44) (Figure 9.16, 9.17) and their evaluation as inhibitors
of HIV- 1 and 2 strains (Ashok, Chander, et al. 2015). From those synthesized
derivatives, 30, 34, 39, and 40 exhibited selective inhibition of the HIV- 2 strain with
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β- Carbolines
FIGURE 9.10 Structure and EC50 of Flazin and it’s analogues (11c- 14).
comparable activity to nucleoside reverse transcriptase inhibitors Nevirapine (EC50 HIV
1– 0.027 μM and HIV- 2 >4), Lamivudine (EC50 HIV 1– 0.89 μM and HIV 2– 3.56 μM),
Zidovudine (EC50 HIV 1– 0.0019 μM and HIV 2– 0.0016 μM), and Dideoxyinosine
(EC50 HIV 1– 2.56 μM and HIV 2– 2.27 μM). These compounds showed EC50 values
ranging from 2.6 to 5.4 μM against HIV- 2, with selectivity indices greater than or
equal to 72. Interestingly, these compounds did not demonstrate in vitro HIV- 2
reverse transcriptase inhibition, suggesting that their specic anti- HIV- 2 activity may
involve a different mechanism. The structure– activity relationship analysis revealed
that electron- donating groups on the phenyl ring increased the anti- HIV potency,
while electron- withdrawing groups decreased the potency. Substitution with uorine
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FIGURE 9.11 β- carboline analogues as inhibitors of HIV- 1 reverse transcriptase (RT)
(Series 1).
FIGURE 9.12 β- carboline analogues as inhibitors of HIV- 1 reverse transcriptase (RT)
(Series 1).
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